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Sample records for aneuploidy

  1. Aneuploidy in stem cells

    Institute of Scientific and Technical Information of China (English)

    Jorge; Garcia-Martinez; Bjorn; Bakker; Klaske; M; Schukken; Judith; E; Simon; Floris; Foijer

    2016-01-01

    Stem cells hold enormous promise for regenerative medicine as well as for engineering of model systems to study diseases and develop new drugs. The discovery of protocols that allow for generating induced pluripotent stem cells(IPSCs) from somatic cells has brought this promise steps closer to reality. However,as somatic cells might have accumulated various chromosomal abnormalities,including aneuploidies throughout their lives,the resulting IPSCs might no longer carry the perfect blueprint for the tissue to be generated,or worse,become at risk of adopting a malignant fate. In this review,we discuss the contribution of aneuploidy to healthy tissues and how aneuploidy can lead to disease. Furthermore,we review the differences between how somatic cells and stem cells respond to aneuploidy.

  2. Aneuploidy in human spermatozoa.

    Science.gov (United States)

    Templado, C; Vidal, F; Estop, A

    2011-01-01

    We reviewed the frequency and distribution of disomy in spermatozoa obtained by multicolor-FISH analysis on decondensed sperm nuclei in (a) healthy men, (b) fathers of aneuploid offspring of paternal origin and (c) individuals with Klinefelter syndrome and XYY males. In series of healthy men, disomy per autosome is approximately 0.1% but may range from 0.03 (chromosome 8) to 0.47 (chromosome 22). The great majority of authors find that chromosome 21 (0.18%) and the sex chromosomes (0.27%) have significantly elevated frequencies of disomy although these findings are not universal. The total disomy in FISH studies is 2.26% and the estimated aneuploidy (2× disomy) is 4.5%, more than double that seen in sperm karyotypes (1.8%). Increased disomy levels of low orders of magnitude have been reported in spermatozoa of some normal men (stable variants) and in men who have fathered children with Down, Turner and Klinefelter syndromes. These findings suggest that men with a moderately elevated aneuploidy rate may be at a higher risk of fathering paternally derived aneuploid pregnancies. Among lifestyle factors, smoking, alcohol and caffeine have been studied extensively but the compounding effects of the 3 are difficult to separate because they are common lifestyle behaviors. Increases in sex chromosome abnormalities, some autosomal disomies, and in the number of diploid spermatozoa are general features in 47,XXY and 47,XYY males. Aneuploidy of the sex chromosomes is more frequent than aneuploidy of any of the autosomes not only in normal control individuals, but also in patients with sex chromosome abnormalities and fathers of paternally derived Klinefelter, Turner and Down syndromes.

  3. Aneuploidy and Skeletal Health

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    Kamalakar, Archana; Harris, John R.; McKelvey, Kent D.; Suva, Larry J.

    2014-01-01

    The normal human chromosome complement consists of 46 chromosomes comprising 22 morphologically different pairs of autosomes and one pair of sex chromosomes. Variations in either chromosome number and/or structure frequently result in significant mental impairment, and/or a variety of other clinical problems, among them, altered bone mass and strength. Chromosomal syndromes associated with specific chromosomal abnormalities are classified as either numerical or structural and may involve more than one chromosome. Aneuploidy refers to the presence of an extra copy of a specific chromosome, or trisomy, as seen in Down’s syndrome (trisomy 21), or the absence of a single chromosome, or monosomy, as seen in Turner syndrome (a single X chromosome in females: 45, X). Aneuploidies have diverse phenotypic consequences, ranging from severe mental retardation and developmental abnormalities to increased susceptibility to various neoplasms and premature death. In fact, trisomy 21 is the prototypical aneuploidy in humans, is the most common genetic abnormality associated with longevity and is one of the most widespread genetic causes of intellectual disability. In this review, the impact of trisomy 21 on the bone mass, architecture, skeletal health and quality of life of people with Down syndrome will be discussed. PMID:24980541

  4. Oocyte development, meiosis and aneuploidy.

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    MacLennan, Marie; Crichton, James H; Playfoot, Christopher J; Adams, Ian R

    2015-09-01

    Meiosis is one of the defining events in gametogenesis. Male and female germ cells both undergo one round of meiotic cell division during their development in order to reduce the ploidy of the gametes, and thereby maintain the ploidy of the species after fertilisation. However, there are some aspects of meiosis in the female germline, such as the prolonged arrest in dictyate, that appear to predispose oocytes to missegregate their chromosomes and transmit aneuploidies to the next generation. These maternally-derived aneuploidies are particularly problematic in humans where they are major contributors to miscarriage, age-related infertility, and the high incidence of Down's syndrome in human conceptions. This review will discuss how events that occur in foetal oocyte development and during the oocytes' prolonged dictyate arrest can influence meiotic chromosome segregation and the incidence of aneuploidy in adult oocytes.

  5. Prenatal screening methods for aneuploidies

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    Madhusudan Dey

    2013-01-01

    Full Text Available Aneuploidies are a major cause of perinatal morbidity and mortality. Therefore, it is the most common indication for invasive prenatal diagnosis. Initially, screening for aneuploidies started with maternal age risk estimation. Later on, serum testing for biochemical markers and ultrasound markers were added. Women detected to be at high-risk for aneuploidies were offered invasive testing. New research is now focusing on non-invasive prenatal testing using cell-free fetal DNA in maternal circulation. The advantage of this technique is the ability to reduce the risk of miscarriage associated with invasive diagnostic procedures. However, this new technique has its own set of technical limitations and ethical issues at present and careful consideration is required before broad implementation

  6. Correlation between aneuploidy and blastocyst quality

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    Vy Phan

    2014-12-01

    Conclusion: Blastocyst morphology showed a significant link to aneuploidy (P<0.05. However, grading morphology alone can not replace preimplantation aneuploidy screening. Morphology screening or other markers for embryo competence, combined with preimplantation genetic screening for 24 chromosomes may produce the best results.

  7. Mosaic double aneuploidy: Down syndrome and XYY

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    Mayur Parihar

    2013-01-01

    Full Text Available Chromosomal abnormalities are seen in nearly 1% of live born infants. We report a 5-year-old boy with the clinical features of Down syndrome, which is the most common human aneuploidy. Cytogenetic analysis showed a mosaicism for a double aneuploidy, Down syndrome and XYY. The karyotype was 47, XY,+21[19]/48, XYY,+21[6]. ish XYY (DXZ1 × 1, DYZ1 × 2. Mosaic double aneuploidies are very rare and features of only one of the aneuploidies may predominate in childhood. Cytogenetic analysis is recommended even if the typical features of a recognized aneuploidy are present so that any associated abnormality may be detected. This will enable early intervention to provide the adequate supportive care and management.

  8. Aneuploidy: implications for protein homeostasis and disease

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    Ana B. Oromendia

    2014-01-01

    Full Text Available It has long been appreciated that aneuploidy – in which cells possess a karyotype that is not a multiple of the haploid complement – has a substantial impact on human health, but its effects at the subcellular level have only recently become a focus of investigation. Here, we summarize new findings characterizing the impact of aneuploidy on protein quality control. Because aneuploidy has been associated with many diseases, foremost among them being cancer, and has also been linked to aging, we also offer our perspective on whether and how the effects of aneuploidy on protein quality control could contribute to these conditions. We argue that acquiring a deeper understanding of the relationship between aneuploidy, disease and aging could lead to the development of new anti-cancer and anti-aging treatments.

  9. Aneuploidy in mammalian somatic cells in vivo.

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    Cimino, M C; Tice, R R; Liang, J C

    1986-01-01

    Aneuploidy is an important potential source of human disease and of reproductive failure. Nevertheless, the ability of chemical agents to induce aneuploidy has been investigated only sporadically in intact (whole-animal) mammalian systems. A search of the available literature from the EMCT Aneuploidy File (for years 1970-1983) provided 112 papers that dealt with aneuploidy in mammalian somatic cells in vivo. 59 of these papers did not meet minimal criteria for analysis and were rejected from subsequent review. Of the remaining 53 papers that dealt with aneuploidy induction by chemical agents in mammalian somatic cells in vivo, only 3 (6%) contained data that were considered to be supported conclusively by adequate study designs, execution, and reporting. These 3 papers dealt with 2 chemicals, one of which, mercury, was negative for aneuploidy induction in humans, and the other, pyrimethamine, was positive in an experimental rodent study. The majority of papers (94%) were considered inconclusive for a variety of reasons. The most common reasons for calling a study inconclusive were (a) combining data on hyperploidy with those on hypoploidy and/or polyploidy, (b) an inadequate or unspecified number of animals and/or cells per animal scored per treatment group, and (c) poor data presentation such that animal-to-animal variability could not be assessed. Suggestions for protocol development are made, and the future directions of research into aneuploidy induction are discussed.

  10. Cognitive and medical features of chromosomal aneuploidy.

    Science.gov (United States)

    Hutaff-Lee, Christa; Cordeiro, Lisa; Tartaglia, Nicole

    2013-01-01

    This chapter describes the physical characteristics, medical complications, and cognitive and psychological profiles that are associated with chromosomal aneuploidy conditions, a group of conditions in which individuals are born with one or more additional chromosome. Overall, chromosomal aneuploidy conditions occur in approximately 1 in 250 children. Information regarding autosomal disorders including trisomy 21 (Down syndrome), trisomy 13 (Patau syndrome), and trisomy 18 (Edward syndrome) are presented. Sex chromosome aneuploidy conditions such as Klinefelter syndrome (47,XXY), XYY, trisomy X, and Turner syndrome (45,X), in addition to less frequently occurring tetrasomy and pentasomy conditions are also covered. Treatment recommendations and suggestions for future research directions are discussed.

  11. Aneuploidy among prenatally detected neural tube defects

    Energy Technology Data Exchange (ETDEWEB)

    Hume, R.F. Jr.; Lampinen, J.; Martin, L.S.; Johnson, M.P.; Evans, M.I. [Wayne State Univ., Detroit, MI (United States)] [and others

    1996-01-11

    We have reported previously a 10% aneuploidy detection rate among 39 cases of fetal neural tube defects (NTD). Subsequently we amassed an additional experience of over 17,000 prenatal diagnosis cases over a 5-year period. During this period 106 cases of NTDs were identified; 44 with anencephaly, 62 with open spina bifida. The average maternal age of this population with NTDs was 29 years (15-40); 6 patients declined amniocentesis. Six of 100 cytogenetic studies were aneuploid; on anencephalic fetus had inherited a maternal marker chromosome, and 5 NTD cases had trisomy 18. The average maternal age of the aneuploid cases was 21 (19-40); 3 were 35 years or older. Four of 5 trisomy 18 cases had multiple congenital anomalies (MCA). The overall aneuploidy detection rate in our cohort was 5-6, while aneuploidy occurred in 2% of the isolated NTD cases, and 24% of the MCA cases. Combining the earlier experience, 4/39 aneuploidy (2 trisomy 18, 4p+, del 13q) yields an aneuploidy detection frequency of 10/145 (7%), of which most (7/10) had trisomy 18. These data support fetal karyotyping for accurate diagnosis, prognosis, and recurrence-risk counseling. 5 refs., 2 tabs.

  12. STABLE VARIANTS OF SPERM ANEUPLOIDY AMONG HEALTHY MEN SHOW ASSOCIATIONS BETWEEN GERMINAL AND SOMATIC ANEUPLOIDY

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    Abstract.Our objective was to identify men who consistently produced high frequencies of sperm with numerical chromosomal abnormalities (stable variants) and to determine whether healthy men with normal semen quality vary with respect to the incidence of sperm aneuploidy ...

  13. Stable Variants of Sperm Aneuploidy among Healthy Men Show Associations between Germinal and Somatic Aneuploidy

    OpenAIRE

    Rubes, Jiri; Vozdova, Miluse; Robbins, Wendie A.; Rezacova, Olga; Perreault, Sally D; Andrew J. Wyrobek

    2002-01-01

    Repeated semen specimens from healthy men were analyzed by sperm fluorescence in situ hybridization (FISH), to identify men who consistently produced elevated frequencies of aneuploid sperm and to determine whether men who were identified as stable variants of sperm aneuploidy also exhibited higher frequencies of aneuploidy in their peripheral blood lymphocytes. Seven semen specimens were provided by each of 15 men over a 2-year period and were evaluated by the X-Y-8 multicolor sperm FISH met...

  14. Modeling the Aneuploidy Control of Cancer

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    Wang Zhong

    2010-07-01

    Full Text Available Abstract Background Aneuploidy has long been recognized to be associated with cancer. A growing body of evidence suggests that tumorigenesis, the formation of new tumors, can be attributed to some extent to errors occurring at the mitotic checkpoint, a major cell cycle control mechanism that acts to prevent chromosome missegregation. However, so far no statistical model has been available quantify the role aneuploidy plays in determining cancer. Methods We develop a statistical model for testing the association between aneuploidy loci and cancer risk in a genome-wide association study. The model incorporates quantitative genetic principles into a mixture-model framework in which various genetic effects, including additive, dominant, imprinting, and their interactions, are estimated by implementing the EM algorithm. Results Under the new model, a series of hypotheses tests are formulated to explain the pattern of the genetic control of cancer through aneuploid loci. Simulation studies were performed to investigate the statistical behavior of the model. Conclusions The model will provide a tool for estimating the effects of genetic loci on aneuploidy abnormality in genome-wide studies of cancer cells.

  15. Undetected sex chromosome aneuploidy by chromosomal microarray.

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    Markus-Bustani, Keren; Yaron, Yuval; Goldstein, Myriam; Orr-Urtreger, Avi; Ben-Shachar, Shay

    2012-11-01

    We report on a case of a female fetus found to be mosaic for Turner syndrome (45,X) and trisomy X (47,XXX). Chromosomal microarray analysis (CMA) failed to detect the aneuploidy because of a normal average dosage of the X chromosome. This case represents an unusual instance in which CMA may not detect chromosomal aberrations. Such a possibility should be taken into consideration in similar cases where CMA is used in a clinical setting.

  16. Phenotypic consequences of aneuploidy in Arabidopsis thaliana.

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    Henry, Isabelle M; Dilkes, Brian P; Miller, Eric S; Burkart-Waco, Diana; Comai, Luca

    2010-12-01

    Aneuploid cells are characterized by incomplete chromosome sets. The resulting imbalance in gene dosage has phenotypic consequences that are specific to each karyotype. Even in the case of Down syndrome, the most viable and studied form of human aneuploidy, the mechanisms underlying the connected phenotypes remain mostly unclear. Because of their tolerance to aneuploidy, plants provide a powerful system for a genome-wide investigation of aneuploid syndromes, an approach that is not feasible in animal systems. Indeed, in many plant species, populations of aneuploid individuals can be easily obtained from triploid individuals. We phenotyped a population of Arabidopsis thaliana aneuploid individuals containing 25 different karyotypes. Even in this highly heterogeneous population, we demonstrate that certain traits are strongly associated with the dosage of specific chromosome types and that chromosomal effects can be additive. Further, we identified subtle developmental phenotypes expressed in the diploid progeny of aneuploid parent(s) but not in euploid controls from diploid lineages. These results indicate long-term phenotypic consequences of aneuploidy that can persist after chromosomal balance has been restored. We verified the diploid nature of these individuals by whole-genome sequencing and discuss the possibility that trans-generational phenotypic effects stem from epigenetic modifications passed from aneuploid parents to their diploid progeny.

  17. Laboratory Exercises to Examine Recombination & Aneuploidy in "Drosophila"

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    Venema, Dennis R.

    2009-01-01

    Chromosomal aneuploidy, a deviation from an exact multiple of an organism's haploid chromosome number, is a difficult concept for students to master. Aneuploidy arising from chromosomal non-disjunction (NDJ) is particularly problematic for students, since it arises in the context of meiosis, itself a challenging subject. Students learning NDJ are…

  18. Mechanisms and chemical induction of aneuploidy in rodent germ cells

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    Mailhes, J B; Marchetti, F

    2004-10-15

    The objective of this review is to suggest that the advances being made in our understanding of the molecular events surrounding chromosome segregation in non-mammalian and somatic cell models be considered when designing experiments for studying aneuploidy in mammalian germ cells. Accurate chromosome segregation requires the temporal control and unique interactions among a vast array of proteins and cellular organelles. Abnormal function and temporal disarray among these, and others to be inidentified, biochemical reactions and cellular organelles have the potential for predisposing cells to aneuploidy. Although numerous studies have demonstrated that certain chemicals (mainly those that alter microtubule function) can induce aneuploidy in mammalian germ cells, it seems relevant to point out that such data can be influenced by gender, meiotic stage, and time of cell-fixation post-treatment. Additionally, a consensus has not been reached regarding which of several germ cell aneuploidy assays most accurately reflects the human condition. More recent studies have shown that certain kinase, phosphatase, proteasome, and topoisomerase inhibitors can also induce aneuploidy in rodent germ cells. We suggest that molecular approaches be prudently incorporated into mammalian germ cell aneuploidy research in order to eventually understand the causes and mechanisms of human aneuploidy. Such an enormous undertaking would benefit from collaboration among scientists representing several disciplines.

  19. Increased frequency of aneuploidy in long-lived spermatozoa.

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    You, Young-Ah; Park, Yoo-Jin; Kwon, Woo-Sung; Yoon, Sung-Jae; Ryu, Buom-Yong; Kim, Young Ju; Pang, Myung-Geol

    2014-01-01

    Aneuploidy commonly causes spontaneous abortions, stillbirths, and aneuploid births in humans. Notably, the majority of sex chromosome aneuploidies in live births have a paternal origin. An increased frequency of aneuploidy is also associated with male infertility. However, the dynamics and behavior of aneuploid spermatozoa during fertilization in humans have not been studied in detail. Therefore, we compared the frequency of aneuploidy and euploidy in live spermatozoa from normozoospermic men over a 3-day period. To assess the dynamics and behavior of aneuploid spermatozoa, we simultaneously evaluated sperm viability using the hypo-osmotic swelling test and sperm aneuploidy using fluorescence in situ hybridization. Whereas the frequency of viable euploid spermatozoa significantly decreased over 3 days, the frequency of viable spermatozoa with aneuploidy interestingly showed a time-dependent increase. In addition, spermatozoa with abnormal sex chromosomes survived longer. To compared with spermatozoa with other swelling patterns, those with tail-tip swelling patterns had a lower frequency of aneuploidy at all time points. This study revealed the novel finding that the frequency of aneuploid spermatozoa with fertilization capability significantly increased compared to that of euploid spermatozoa over 3 days, suggesting that aneuploid spermatozoa can survive longer than euploid spermatozoa and have a greater chance of fertilizing oocytes.

  20. Increased frequency of aneuploidy in long-lived spermatozoa.

    Directory of Open Access Journals (Sweden)

    Young-Ah You

    Full Text Available Aneuploidy commonly causes spontaneous abortions, stillbirths, and aneuploid births in humans. Notably, the majority of sex chromosome aneuploidies in live births have a paternal origin. An increased frequency of aneuploidy is also associated with male infertility. However, the dynamics and behavior of aneuploid spermatozoa during fertilization in humans have not been studied in detail. Therefore, we compared the frequency of aneuploidy and euploidy in live spermatozoa from normozoospermic men over a 3-day period. To assess the dynamics and behavior of aneuploid spermatozoa, we simultaneously evaluated sperm viability using the hypo-osmotic swelling test and sperm aneuploidy using fluorescence in situ hybridization. Whereas the frequency of viable euploid spermatozoa significantly decreased over 3 days, the frequency of viable spermatozoa with aneuploidy interestingly showed a time-dependent increase. In addition, spermatozoa with abnormal sex chromosomes survived longer. To compared with spermatozoa with other swelling patterns, those with tail-tip swelling patterns had a lower frequency of aneuploidy at all time points. This study revealed the novel finding that the frequency of aneuploid spermatozoa with fertilization capability significantly increased compared to that of euploid spermatozoa over 3 days, suggesting that aneuploid spermatozoa can survive longer than euploid spermatozoa and have a greater chance of fertilizing oocytes.

  1. Aneuploidy in Early Miscarriage and its Related Factors

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    Chan-Wei Jia

    2015-01-01

    Full Text Available Background: Genetic factors are the main cause of early miscarriage. This study aimed to investigate aneuploidy in spontaneous abortion by fluorescence in situ hybridization (FISH using probes for 13, 16, 18, 21, 22, X and Y chromosomes. Methods: A total of 840 chorionic samples from spontaneous abortion were collected and examined by FISH. We analyzed the incidence and type of abnormal cases and sex ratio in the samples. We also analyzed the relationship between the rate of aneuploidy and parental age, the rate of aneuploidy between recurrent abortion and sporadic abortion, the difference in incidence of aneuploidy between samples from previous artificial abortion and those from no previous induced abortion. Results: A total of 832 samples were finally analyzed. 368 (44.23% were abnormal, in which 84.24% (310/368 were aneuploidies and 15.76% (58/368 were polyploidies. The first was trisomy16 (121/310, followed by trisomy 22, and X monosomy. There was no significant difference in the rate of aneuploidy in the advanced maternal age group (≥35 years old and young maternal age group (<35 years old. However, the rate of trisomy 22 and the total rate of trisomies 21, 13, and 18 (the number of trisomy 21 plus trisomy 13 and trisomy 18 together showed significantly different in two groups. We found no skewed sex ratio. There was no significant difference in the rate of aneuploidy between recurrent miscarriage and sporadic abortion or between the samples from previous artificial abortion and those from no previous artificial abortion. Conclusions: Aneuploidy is a principal factor of miscarriage and total parental age is a risk factor. There is no skewed sex ratio in spontaneous abortion. There is also no difference in the rate of aneuploidy between recurrent abortion and sporadic abortion or between previous artificial abortion and no previous induced abortion.

  2. Chromosome X aneuploidy in Brazilian schizophrenic patients.

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    de Moraes, Leopoldo Silva; Khayat, André Salim; de Lima, Patrícia Danielle Lima; Lima, Eleonidas Moura; Pinto, Giovanny Rebouças; Leal, Mariana Ferreira; de Arruda Cardoso Smith, Marília; Burbano, Rommel Rodríguez

    2010-01-01

    The identification of cytogenetic abnormalities in schizophrenic patients may provide clues to the genes involved in this disease. For this reason, a chromosomal analysis of samples from 62 schizophrenics and 70 controls was performed with trypsin-Giemsa banding and fluorescence in situ hybridization of the X chromosome. A clonal pericentric inversion on chromosome 9 was detected in one male patient, and we also discovered mosaicism associated with X chromosome aneuploidy in female patients, primarily detected in schizophrenic and normal female controls over 40 years old. When compared with age-matched female controls, the frequency of X chromosome loss was not significantly different between schizophrenics and controls, except for the 40- to 49-year-old age group. Our findings suggest that the X chromosome loss seen in schizophrenic patients is inherent to the normal cellular aging process. However, our data also suggest that X chromosome gain may be correlated with schizophrenia in this Brazilian population.

  3. Microchimeric Cells, Sex Chromosome Aneuploidies and Cancer.

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    Korkmaz, Deniz Taştemir; Demirhan, Osman; Abat, Deniz; Demirberk, Bülent; Tunç, Erdal; Kuleci, Sedat

    2015-09-01

    The phenomenon of feta-maternal microchimerisms inspires numerous questions. Many questions remain to be answered regarding this new avenue of genetics. The X and Y chromosomes have been associated with malignancy in different types of human tumors. We aimed to investigate the numerical aberrations of chromosomes X and Y in lung cancer (LC) and bladder cancer (BC) and review recent evidence for possible roles of microchimeric cells (McCs) in these cancers. We carried out cytogenetic analysis of the tumor and blood sampling in 52 cases of people with BC and LC, and also with 30 healthy people. A total of 48 (92.3 %) of the patients revealed sex chromosome aneuploidies (SCAs). A total SCAs was found in 9.8 % of 2282 cells that were analyzed as one or more cells in each case. The 68 and 95 SCAs were found in the 1952 (8.4 %) cells in peripheral blood, and 41 and 19 SCAs in the 330 (18.2 %) cells in the tumoral tissues respectively. There was a significant difference in the frequencies of SCAs between the patients and the control groups determined by the Fischer's Exact Test (p chromosome monosomies. Largely a Y chromosome loss was present in 77.8 % of the men, and the 47, XXY karyotype was found in 33.3 % of them. The second most common SCA was monosomy X, and was found in 71.4 % of the women. McCs were observed in 26.9 % of the 52 patients, and the frequencies of McCs were higher in the blood than in the tissues (p aneuploidies of X and Y chromosomes play a role in the pathogenesis of cancers.

  4. Klinefelter syndrome and other sex chromosomal aneuploidies

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    Graham John M

    2006-10-01

    Full Text Available Abstract The term Klinefelter syndrome (KS describes a group of chromosomal disorder in which there is at least one extra X chromosome to a normal male karyotype, 46,XY. XXY aneuploidy is the most common disorder of sex chromosomes in humans, with prevalence of one in 500 males. Other sex chromosomal aneuploidies have also been described, although they are much less frequent, with 48,XXYY and 48,XXXY being present in 1 per 17,000 to 1 per 50,000 male births. The incidence of 49,XXXXY is 1 per 85,000 to 100,000 male births. In addition, 46,XX males also exist and it is caused by translocation of Y material including sex determining region (SRY to the X chromosome during paternal meiosis. Formal cytogenetic analysis is necessary to make a definite diagnosis, and more obvious differences in physical features tend to be associated with increasing numbers of sex chromosomes. If the diagnosis is not made prenatally, 47,XXY males may present with a variety of subtle clinical signs that are age-related. In infancy, males with 47,XXY may have chromosomal evaluations done for hypospadias, small phallus or cryptorchidism, developmental delay. The school-aged child may present with language delay, learning disabilities, or behavioral problems. The older child or adolescent may be discovered during an endocrine evaluation for delayed or incomplete pubertal development with eunuchoid body habitus, gynecomastia, and small testes. Adults are often evaluated for infertility or breast malignancy. Androgen replacement therapy should begin at puberty, around age 12 years, in increasing dosage sufficient to maintain age appropriate serum concentrations of testosterone, estradiol, follicle stimulating hormone (FSH, and luteinizing hormone (LH. The effects on physical and cognitive development increase with the number of extra Xs, and each extra X is associated with an intelligence quotient (IQ decrease of approximately 15–16 points, with language most affected

  5. Aneuploidy in Early Miscarriage and its Related Factors

    Institute of Scientific and Technical Information of China (English)

    Chan-Wei Jia; Li Wang; Yong-Lian Lan; Rui Song; Li-Yin Zhou; Lan Yu; Yang Yang

    2015-01-01

    Background:Genetic factors are the main cause of early miscarriage.This study aimed to investigate aneuploidy in spontaneous abortion by fluorescence in situ hybridization (FISH) using probes for 13,16,18,21,22,X and Y chromosomes.Methods:A total of 840 chorionic samples from spontaneous abortion were collected and examined by FISH.We analyzed the incidence and type of abnormal cases and sex ratio in the samples.We also analyzed the relationship between the rate of aneuploidy and parental age,the rate of aneuploidy between recurrent abortion and sporadic abortion,the difference in incidence of aneuploidy between samples from previous artificial abortion and those from no previous induced abortion.Results:A total of 832 samples were finally analyzed.368 (44.23%) were abnormal,in which 84.24% (310/368) were aneuploidies and 15.76% (58/368) were polyploidies.The first was trisomy16 (121/310),followed by trisomy 22,and X monosomy.There was no significant difference in the rate ofaneuploidy in the advanced maternal age group (≥35 years old) and young maternal age group (<35 years old).However,the rate oftrisomy 22 and the total rate oftrisomies 21,13,and 18 (the number oftrisomy 21 plus trisomy 13 and trisomy 18 together) showed significantly different in two groups.We found no skewed sex ratio.There was no significant difference in the rate of aneuploidy between recurrent miscarriage and sporadic abortion or between the samples from previous artificial abortion and those from no previous artificial abortion.Conclusions:Aneuploidy is a principal factor of miscarriage and total parental age is a risk factor.There is no skewed sex ratio in spontaneous abortion.There is also no difference in the rate of aneuploidy between recurrent abortion and sporadic abortion or between previous artificial abortion and no previous induced abortion.

  6. Aneuploidy: a report of an ECETOC task force.

    Science.gov (United States)

    Aardema, M J; Albertini, S; Arni, P; Henderson, L M; Kirsch-Volders, M; Mackay, J M; Sarrif, A M; Stringer, D A; Taalman, R D

    1998-02-01

    Aneuploidy plays a significant role in adverse human health conditions including birth defects, pregnancy wastage and cancer. Although there is clear evidence of chemically induced aneuploidy in experimental systems, to date there are insufficient data to determine with certainty if chemically induced aneuploidy contributes to human disease. However, since there is no reason to assume that chemically induced aneuploidy will not occur in human beings, it is prudent to address the aneugenic potential of chemicals in the safety assessment process. A wide range of methods has been described for the detection of chemically induced aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mammalian somatic and germ cell assays. However, none of these methods is sufficiently validated or widely used in routine screening. Underlying the efforts to develop aneuploidy-specific assays is the presumption that current genetic toxicology tests do not detected chemicals that have aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known or suspected aneugens. The conclusions from the review are listed below. 1. At present there are only nine chemicals that can be classified as definitive aneugens, as determined by positive results in in vivo rodent assays. 2. As expected, the majority of definitive and suspected aneugens are negative in the bacterial mutation assay. 3. The majority of definitive aneugens evaluated induce polyploidy in vitro. With few exception, they also induced structural chromosome aberrations in vitro. 4. All of the definitive aneugens that have been sufficiently tested induce micronuclei in rodent bone marrow cells in vivo. A number of these chemicals also induced structural chromosome aberrations in vivo. 5. There is no evidence for a unique germ cell aneugen, that is a chemical that induces aneuploidy in germ

  7. Frequency of aneuploidy related to age in porcine oocytes.

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    Hornak, Miroslav; Jeseta, Michal; Musilova, Petra; Pavlok, Antonin; Kubelka, Michal; Motlik, Jan; Rubes, Jiri; Anger, Martin

    2011-04-27

    It is generally accepted that mammalian oocytes are frequently suffering from chromosome segregation errors during meiosis I, which have severe consequences, including pregnancy loss, developmental disorders and mental retardation. In a search for physiologically more relevant model than rodent oocytes to study this phenomenon, we have employed comparative genomic hybridization (CGH), combined with whole genome amplification (WGA), to study the frequency of aneuploidy in porcine oocytes, including rare cells obtained from aged animals. Using this method, we were able to analyze segregation pattern of each individual chromosome during meiosis I. In contrast to the previous reports where conventional methods, such as chromosome spreads or FISH, were used to estimate frequency of aneuploidy, our results presented here show, that the frequency of this phenomenon was overestimated in porcine oocytes. Surprisingly, despite the results from human and mouse showing an increase in the frequency of aneuploidy with advanced maternal age, our results obtained by the most accurate method currently available for scoring the aneuploidy in oocytes indicated no increase in the frequency of aneuploidy even in oocytes from animals, whose age was close to the life expectancy of the breed.

  8. Frequency of aneuploidy related to age in porcine oocytes.

    Directory of Open Access Journals (Sweden)

    Miroslav Hornak

    Full Text Available It is generally accepted that mammalian oocytes are frequently suffering from chromosome segregation errors during meiosis I, which have severe consequences, including pregnancy loss, developmental disorders and mental retardation. In a search for physiologically more relevant model than rodent oocytes to study this phenomenon, we have employed comparative genomic hybridization (CGH, combined with whole genome amplification (WGA, to study the frequency of aneuploidy in porcine oocytes, including rare cells obtained from aged animals. Using this method, we were able to analyze segregation pattern of each individual chromosome during meiosis I. In contrast to the previous reports where conventional methods, such as chromosome spreads or FISH, were used to estimate frequency of aneuploidy, our results presented here show, that the frequency of this phenomenon was overestimated in porcine oocytes. Surprisingly, despite the results from human and mouse showing an increase in the frequency of aneuploidy with advanced maternal age, our results obtained by the most accurate method currently available for scoring the aneuploidy in oocytes indicated no increase in the frequency of aneuploidy even in oocytes from animals, whose age was close to the life expectancy of the breed.

  9. Host-induced aneuploidy and phenotypic diversification in the Sudden Oak Death pathogen Phytophthora ramorum

    Science.gov (United States)

    Aneuploidy can result in significant phenotypic changes, which can sometimes be selectively advantageous. For example, aneuploidy confers resistance to antifungal drugs in human pathogenic fungi. Aneuploidy has also been observed in invasive fungal and oomycete plant pathogens in the field. Environm...

  10. Aplastic Anemia in Two Patients with Sex Chromosome Aneuploidies.

    Science.gov (United States)

    Rush, Eric T; Schaefer, G Bradley; Sanger, Warren G; Coccia, Peter F

    2015-01-01

    Sex chromosome aneuploidies range in incidence from rather common to exceedingly rare and have a variable phenotype. We report 2 patients with sex chromosome aneuploidies who developed severe aplastic anemia requiring treatment. The first patient had tetrasomy X (48,XXXX) and presented at 9 years of age, and the second patient had trisomy X (47,XXX) and presented at 5 years of age. Although aplastic anemia has been associated with other chromosomal abnormalities, sex chromosome abnormalities have not been traditionally considered a risk factor for this condition. A review of the literature reveals that at least one other patient with a sex chromosome aneuploidy (45,X) has suffered from aplastic anemia and that other autosomal chromosomal anomalies have been described. Despite the uncommon nature of each condition, it is possible that the apparent association is coincidental. A better understanding of the genetic causes of aplastic anemia remains important.

  11. Molecular diagnosis of sex chromosome aneuploidy using quantitative PCR.

    Science.gov (United States)

    Mutter, G L; Pomponio, R J

    1991-08-11

    Numeric sex chromosome imbalances, or aneuploidies, are present in several pathological conditions including tumors, abnormal gestations, and clinical syndromes. Here we report a method to identify karyotypic imbalances of the X and Y chromosomes using the polymerase chain reaction (PCR). The polymerase chain reaction was used to quantitatively coamplify the sex chromosome linked genes ZFX and ZFY. Quantitation was facilitated by 1) use of a single primer set which recognizes both templates, 2) incorporation of radiolabelled nucleotides during amplification, and 3) use of amplification conditions which minimize heteroduplex formation. High accuracy of the method was confirmed by concordance with values expected from titrated male and female DNAs and cells from patients with sex chromosome aneuploidy. This approach provides a rapid and reproducible method of evaluating relative abundance of allelic genes, and might be applied to detection of autosomal aneuploidy.

  12. First trimester diagnosis and screening for fetal aneuploidy.

    Science.gov (United States)

    Driscoll, Deborah A; Gross, Susan J

    2008-01-01

    Maternal serum screening for neural tube defects and fetal aneuploidy in the second trimester has been incorporated into obstetrical practice over the past two decades. Now, as a result of several multicenter trials, first trimester screening between 11 and 14 weeks has been shown to be an effective and reliable screening test for Down syndrome and trisomy 18. Benefits of first trimester screening include earlier identification of the pregnancy at risk for fetal aneuploidy and anatomic defects, in particular, cardiac anomalies, and the option of earlier diagnosis by chorionic villus sampling, if available. This policy updates the American College of Medical Genetics policy statement entitled Second Trimester Maternal Serum Screening for Fetal Open Neural Tube Defects and Aneuploidy (2004) and complements the sections of American College of Medical Genetic's Standards and Guidelines for Clinical Genetics Laboratories entitled "Prenatal screening for Down syndrome that includes first trimester biochemistry and/or ultrasound measurements."

  13. Screening for fetal aneuploidy and neural tube defects.

    Science.gov (United States)

    Driscoll, Deborah A; Gross, Susan J

    2009-11-01

    Maternal serum screening for neural tube defects and fetal aneuploidy in the second trimester has been incorporated into obstetrical practice over the past two decades. Now, as a result of several multicenter trials, first trimester screening between 11 and 14 weeks has been shown to be an effective and reliable screening test for Down syndrome and trisomy 18. This policy updates the American College of Medical Genetics policy statement entitled Second Trimester Maternal Serum Screening for Fetal Open Neural Tube Defects and Aneuploidy (2004), incorporates First trimester diagnosis and screening for fetal aneuploidy (2008) and complements the sections of American College of Medical Genetic's Standards and Guidelines for Clinical Genetics Laboratories entitled Prenatal Screening for Down syndrome (2005) and Prenatal Screening for Open Neural Tube Defects (2005).

  14. Cell-free DNA screening and sex chromosome aneuploidies.

    Science.gov (United States)

    Mennuti, Michael T; Chandrasekaran, Suchitra; Khalek, Nahla; Dugoff, Lorraine

    2015-10-01

    Cell-free DNA (cfDNA) testing is increasingly being used to screen pregnant women for fetal aneuploidies. This technology may also identify fetal sex and can be used to screen for sex chromosome aneuploidies (SCAs). Physicians offering this screening will need to be prepared to offer comprehensive prenatal counseling about these disorders to an increasing number of patients. The purpose of this article is to consider the source of information to use for counseling, factors in parental decision-making, and the performance characteristics of cfDNA testing in screening for SCAs. Discordance between ultrasound examination and cfDNA results regarding fetal sex is also discussed.

  15. Refractory ceramic fibers (RCFs) induce germline aneuploidy in Drosophila oocytes.

    Science.gov (United States)

    Osgood, C J

    1994-06-01

    Mineral fibers are ubiquitous in the natural environment and are widely used in industry in such applications as insulators. We have previously shown that asbestos fibers induce aneuploidy in oocytes of Drosophila melanogaster; here we extend those studies by testing refractory ceramic fibers (RCFs) for their mutagenicity to germ cells. The results establish that the tested RCFs are inducers of aneuploidy following feeding of adult females. A subset of the RCFs were also effective following larval feeding. Our results suggest that RCFs, like certain asbestos fibers, may pose a hazard to germ cells.

  16. Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice

    Energy Technology Data Exchange (ETDEWEB)

    Leland, Shawn; Nagarajan, Prabakaran; Polyzos, Aris; Thomas, Sharon; Samaan, George; Donnell, Robert; Marchetti, Francesco; Venkatachalam, Sundaresan

    2009-06-24

    Aneuploidy, the most common chromosomal abnormality at birth and the main ascertained cause of pregnancy loss in humans, originates primarily from chromosome segregation errors during oogenesis. Here we report that heterozygosity for a mutation in the mitotic checkpoint kinase gene, Bub1, induces aneuploidy in female germ cells of mice, and that the effect increases with advancing maternal age. Analysis of Bub1 heterozygous oocytes showed that aneuploidy occurred primarily during the first meiotic division and involved premature sister chromatid separation. Furthermore, aneuploidy was inherited in zygotes and resulted in the loss of embryos after implantation. The incidence of aneuploidy in zygotes was sufficient to explain the reduced litter size in matings with Bub1 heterozygous females. No effects were seen in germ cells from heterozygous males. These findings show that Bub1 dysfunction is linked to inherited aneuploidy in female germ cells and may contribute to the maternal age-related increase in aneuploidy and pregnancy loss.

  17. SIGNIFICANCE OF ANEUPLOIDY IN MELANOMA OF THE EXTREMITY

    NARCIS (Netherlands)

    VANOVEN, MW; BAAS, PC; OOSTERHUIS, JW; KOOPS, HS; DAMMEIRING, A

    1992-01-01

    Tumor nuclear DNA content was determined by flow cytometry in routinely prepared paraffin blocks from 25 primary malignant melanomas of the extremities. Twelve of the tumors were aneuploid, and 13 were euploid. In this series the presence of aneuploidy appeared to have no prognostic value.

  18. Rapid diagnosis of aneuploidy using segmental duplication quantitative fluorescent PCR.

    Directory of Open Access Journals (Sweden)

    Xiangdong Kong

    Full Text Available The aim of this study was use a simple and rapid procedure, called segmental duplication quantitative fluorescent polymerase chain reaction (SD-QF-PCR, for the prenatal diagnosis of fetal chromosomal aneuploidies. This method is based on the co-amplification of segmental duplications located on two different chromosomes using a single pair of fluorescent primers. The PCR products of different sizes were subsequently analyzed through capillary electrophoresis, and the aneuploidies were determined based on the relative dosage between the two chromosomes. Each primer set, containing five pairs of primers, was designed to simultaneously detect aneuploidies located on chromosomes 21, 18, 13, X and Y in a single reaction. We applied these two primer sets to DNA samples isolated from individuals with trisomy 21 (n = 36; trisomy 18 (n = 6; trisomy 13 (n = 4; 45, X (n = 5; 47, XXX (n = 3; 48, XXYY (n = 2; and unaffected controls (n = 40. We evaluated the performance of this method using the karyotyping results. A correct and unambiguous diagnosis with 100% sensitivity and 100% specificity, was achieved for clinical samples examined. Thus, the present study demonstrates that SD-QF-PCR is a robust, rapid and sensitive method for the diagnosis of common aneuploidies, and these analyses can be performed in less than 4 hours for a single sample, providing a competitive alternative for routine use.

  19. Non-invasive prenatal testing for aneuploidy and beyond

    DEFF Research Database (Denmark)

    Dondorp, Wybo; de Wert, Guido; Bombard, Yvonne

    2015-01-01

    This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT ha...

  20. New insights on the origin and relevance of aneuploidy in human spermatozoa.

    Science.gov (United States)

    Templado, C; Uroz, L; Estop, A

    2013-10-01

    In humans, the most common chromosomal abnormality is aneuploidy. Because the majority of aneuploid conceptuses die during the early stages of embryonic development, an accurate estimate of the frequency of aneuploidy at conception can only be assessed by directly studying the gametes. The vast majority of aneuploidies arise de novo as a result of sporadic chromosome missegregation in paternal or maternal meiosis. In this review, we present the basic current knowledge about the incidence of aneuploidy in human spermatozoa in the general population and in patient populations where elevated levels of sperm aneuploidy are observed. These include infertile patients, patients with abnormal somatic karyotypes, and individuals exposed to certain environmental/lifestyle hazards. The clinical impact of increased levels of aneuploidy is discussed. We then focus on the non-disjunction mechanisms that cause aneuploidy during spermatogenesis and the factors that predispose to non-disjunction in male germ cells followed by an analysis of the sex differences in the incidence of gamete aneuploidy. Recent meiotic studies using multiplex-FISH on three fertile men have revealed that the frequency of conservative aneuploidy of metaphase II spermatocytes is similar to that observed in non-inseminated oocytes of young women. These findings suggest that the differences in the incidence of aneuploidy between spermatozoa and oocytes are not due to differences in chromosome segregation errors but rather to more effective checkpoint mechanisms in spermatogenesis than in oogenesis.

  1. Meiotic recombination errors, the origin of sperm aneuploidy and clinical recommendations.

    Science.gov (United States)

    Tempest, Helen G

    2011-02-01

    Since the early 1990s male infertility has successfully been treated by intracytoplasmic sperm injection (ICSI), nevertheless concerns have been raised regarding the genetic risk of ICSI. Chromosome aneuploidy (the presence of extra or missing chromosomes) is the leading cause of pregnancy loss and mental retardation in humans. While the majority of chromosome aneuploidies are maternal in origin, the paternal contribution to aneuploidy is clinically relevant particularly for the sex chromosomes. Given that it is difficult to study female gametes investigations are predominantly conducted in male meiotic recombination and sperm aneuploidy. Research suggests that infertile men have increased levels of sperm aneuploidy and that this is likely due to increased errors in meiotic recombination and chromosome synapsis within these individuals. It is perhaps counterintuitive but there appears to be no selection against chromosomally aneuploid sperm at fertilization. In fact the frequency of aneuploidy in sperm appears to be mirrored in conceptions. Given this information this review will cover our current understanding of errors in meiotic recombination and chromosome synapsis and how these may contribute to increased sperm aneuploidy. Frequencies of sperm aneuploidy in infertile men and individuals with constitutional karyotypic abnormalities are reviewed, and based on these findings, indications for clinical testing of sperm aneuploidy are discussed. In addition, the application of single nucleotide arrays for the analysis of meiotic recombination and identification of parental origin of aneuploidy are considered.

  2. Mosaic variegated aneuploidy with microcephaly: A rare cytogenetic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Meck, J.M.; Kozma, C.; Stratakis, C. [Georgetown Univ. Medical Center, Washington, DC (United States)] [and others

    1994-09-01

    The term {open_quotes}mosaic variegated aneuploidy with microcephaly{close_quotes} describes the finding of a variety of chromosomal aneuploidies within the same individual. This mutation affecting mitotic segregation has been reported previously in only 7 persons. We report here on male and female siblings with this condition. Proband 1 died at 57 days of age; proband 2 is 7 months old. Amniocentesis performed on the first sibling only revealed multiple aneuploidies (+2, +6, +X, tetrasomy 2, double trisomy X and 11, and deletion Xq); the majority of cells were normal and the abnormal cells did not constitute true mosaicism. Postnatally, blood on proband 1 had 20/50 cells (40%) with +18, single cells with +10 and +20, and 28/50 normal cells (56%). This was initially interpreted as trisomy 18 mosaicism not detected in amniocytes. Blood from proband 2 showed the following; after 48 hrs in culture, 4/50 trisomic cells (+3, +6, +18, XXY); after 72 hrs 3/50 trisomic cells (+5, +6, +18); after 96 hrs, 7/50 aneuploid cells (+2, +8, +9, +10, +18, double trisomy 11 and 18, tetrasomy 2 with +18). Skin biopsy on proband 2 revealed trisomy 2 in 5/140 cells (4%), one cell each +18 and +19, on cell tetrasomy 2, one cell XXY and +5; 131 cells (94%) were normal. Paternal skin fibroblasts had trisomy 6 in 2/100 cells and 1 cell trisomy 5; the remainder were normal. One trisomic cell (+18) in 100 was found in maternal skin fibroblasts. Trisomy 18 was the most common aneuploidy in the probands` blood. Aneuploidy for chromosomes 2 and X were more common in amniocytes and skin. No trisomies of chromosomes 1, 4, 12-17, 22 or Y were observed; acrocentrics rarely malsegregated. These findings are consistent with those of the other 7 reported patients, and constitute a distinct syndrome of multiple chromosomal aneuploidies associated with microcephaly. Although rare, cytogeneticists and clinical geneticists should be aware of this mitotic mutant.

  3. The epigenetic landscape of aneuploidy: constitutional mosaicism leading the way?

    Science.gov (United States)

    Davidsson, Josef

    2014-02-01

    The role of structural genetic changes in human disease has received substantial attention in recent decades, but surprisingly little is known about numerical chromosomal abnormalities, even though they have been recognized since the days of Boveri as partaking in different cellular pathophysiological processes such as cancer and genomic disorders. The current knowledge of the genetic and epigenetic consequences of aneuploidy is reviewed herein, with a special focus on using mosaic genetic syndromes to study the DNA methylation footprints and expressional effects associated with whole-chromosomal gains. Recent progress in understanding the debated role of aneuploidy as a driver or passenger in malignant transformation, as well as how the cell responds to and regulates excess genetic material in experimental settings, is also discussed in detail.

  4. Cognitive and neurological aspects of sex chromosome aneuploidies.

    Science.gov (United States)

    Hong, David S; Reiss, Allan L

    2014-03-01

    Sex chromosome aneuploidies are a common group of disorders that are characterised by an abnormal number of X or Y chromosomes. However, many individuals with these disorders are not diagnosed, despite established groups of core features that include aberrant brain development and function. Clinical presentations often include characteristic profiles of intellectual ability, motor impairments, and rates of neurological and psychiatric disorders that are higher than those of the general population. Advances in genetics and neuroimaging have substantially expanded knowledge of potential mechanisms that underlie these phenotypes, including a putative dose effect of sex chromosome genes on neuroanatomical structures and cognitive abilities. Continuing attention to emerging trends in research of sex chromosome aneuploidies is important for clinicians because it informs appropriate management of these common genetic disorders. Furthermore, improved understanding of underlying neurobiological processes has much potential to elucidate sex-related factors associated with neurological and psychiatric disease in general.

  5. Limitations of Aneuploidy and Anomaly Detection in the Obese Patient

    Directory of Open Access Journals (Sweden)

    Paula Zozzaro-Smith

    2014-07-01

    Full Text Available Obesity is a worldwide epidemic and can have a profound effect on pregnancy risks. Obese patients tend to be older and are at increased risk for structural fetal anomalies and aneuploidy, making screening options critically important for these women. Failure rates for first-trimester nuchal translucency (NT screening increase with obesity, while the ability to detect soft-markers declines, limiting ultrasound-based screening options. Obesity also decreases the chances of completing the anatomy survey and increases the residual risk of undetected anomalies. Additionally, non-invasive prenatal testing (NIPT is less likely to provide an informative result in obese patients. Understanding the limitations and diagnostic accuracy of aneuploidy and anomaly screening in obese patients can help guide clinicians in counseling patients on the screening options.

  6. Rapid screening for chromosomal aneuploidies using array-MLPA

    Directory of Open Access Journals (Sweden)

    van Beuningen Rinie

    2011-05-01

    Full Text Available Abstract Background Chromosome abnormalities, especially trisomy of chromosome 21, 13, or 18 as well as sex chromosome aneuploidy, are a well-established cause of pregnancy loss. Cultured cell karyotype analysis and FISH have been considered reliable detectors of fetal abnormality. However, results are usually not available for 3-4 days or more. Multiplex ligation-dependent probe amplification (MLPA has emerged as an alternative rapid technique for detection of chromosome aneuploidies. However, conventional MLPA does not allow for relative quantification of more than 50 different target sequences in one reaction and does not detect mosaic trisomy. A multiplexed MLPA with more sensitive detection would be useful for fetal genetic screening. Methods We developed a method of array-based MLPA to rapidly screen for common aneuploidies. We designed 116 universal tag-probes covering chromosomes 13, 18, 21, X, and Y, and 8 control autosomal genes. We performed MLPA and hybridized the products on a 4-well flow-through microarray system. We determined chromosome copy numbers by analyzing the relative signals of the chromosome-specific probes. Results In a blind study of 161 peripheral blood and 12 amniotic fluid samples previously karyotyped, 169 of 173 (97.7% including all the amniotic fluid samples were correctly identified by array-MLPA. Furthermore, we detected two chromosome X monosomy mosaic cases in which the mosaism rates estimated by array-MLPA were basically consistent with the results from karyotyping. Additionally, we identified five Y chromosome abnormalities in which G-banding could not distinguish their origins for four of the five cases. Conclusions Our study demonstrates the successful application and strong potential of array-MLPA in clinical diagnosis and prenatal testing for rapid and sensitive chromosomal aneuploidy screening. Furthermore, we have developed a simple and rapid procedure for screening copy numbers on chromosomes 13, 18

  7. Aneuploidy as a mechanism for stress-induced liver adaptation.

    Science.gov (United States)

    Duncan, Andrew W; Hanlon Newell, Amy E; Bi, Weimin; Finegold, Milton J; Olson, Susan B; Beaudet, Arthur L; Grompe, Markus

    2012-09-01

    Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question of whether this unusual somatic genetic variation evolved as an adaptive mechanism in response to hepatic injury. According to this model, hepatotoxic insults select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in the homogentisic acid dioxygenase (Hgd) gene located on chromosome 16. Loss of the remaining Hgd allele protects from fumarylacetoacetate hydrolase (Fah) deficiency, a genetic liver disease model. When adult mice heterozygous for Hgd and lacking Fah were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16-specific aneuploidy was approximately 50%. This result indicates that selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans remains under investigation.

  8. Chromosomal Instability, Aneuploidy, and Gene Mutations in Human Sporadic Colorectal Adenomas

    Directory of Open Access Journals (Sweden)

    Walter Giaretti

    2004-01-01

    Full Text Available Whether in vivo specific gene mutations lead to chromosomal instability (CIN and aneuploidy or viceversa is so far not proven. We hypothesized that aneuploidy among human sporadic colorectal adenomas and KRAS2 and APC mutations were not independent. Additionally, we investigated if 1p34–36 deletions by dual target FISH were associated with aneuploidy. Among 116 adenomas, 29 were DNA aneuploid by flow cytometry (25% and 29 were KRAS2 mutated (25%. KRAS2 mutations were associated with aneuploidy (P=0.02. However, while G–C and G–T transversions were strongly associated with DNA aneuploidy (P=0.007, G–A transitions were not. Within a second series of 61 adenomas, we found, instead, that APC mutational status and aneuploidy by flow cytometry were not associated. However, a statistically significant association was found with specific APC mutations, i.e., occurring in the mutation cluster region (MCR, codons 1200–1500 or downstream (P=0.016. Finally, the correlation of 1p34–36 deletions with flow cytometric and FISH detected aneuploidy was also significant (P=0.01. Specific KRAS2 and APC mutations and loss of genes in the 1p34–36 region appear associated with aneuploidy suggesting that these events are not independent and may cooperate in inducing human sporadic colorectal adenomas. A cause effect relationship between gene mutations and aneuploidy remains, however, to be demonstrated.

  9. No beneficial effect of preimplantation genetic screening in women of advanced maternal age with a high risk for embryonic aneuploidy

    NARCIS (Netherlands)

    Twisk, Moniek; Mastenbroek, Sebastiaan; Hoek, Annemieke; Heineman, Maas-Jan; van der Veen, Fulco; Bossuyt, Patrick M.; Repping, Sjoerd; Korevaar, Johanna C.

    2008-01-01

    Human preimplantation embryos generated through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments show a variable rate of numerical chromosome abnormalities or aneuploidies. Preimplantation genetic screening (PGS) has been designed to screen for aneuploidies in high

  10. Double aortic arch with double aneuploidy-rare anomaly in combined Down and Klinefelter syndrome

    NARCIS (Netherlands)

    Gerretsen, M.F.; Peelen, W.; Rammeloo, L.A.J.; Koolbergen, D.R.; Hruda, J.

    2009-01-01

    A 14-month-old boy with double aneuploidy and a double aortic arch suffered from frequently recurrent severe feeding and respiratory problems. Chromosomal analysis showed a 48,XXY + 21 karyotype: a double aneuploidy of Down syndrome (DS) and Klinefelter syndrome (KS). Only four cases of double aneup

  11. The contribution of germinal mosaicism to human aneuploidy.

    Science.gov (United States)

    Ghevaria, Harita; SenGupta, Sioban; Sarna, Urvashi; Sargeant, Susannah; Serhal, Paul; Delhanty, Joy

    2014-01-01

    Germinal mosaicism in a parent is considered to be a rare cause of aneuploidy in the offspring. The aim of this study was to assess the incidence of pre-meiotic errors, indicative of germinal mosaicism, leading to aneuploidy compared with those that occur at meiosis I. The material consisted of 126 oocytes, unexposed to sperm, donated by 57 women with an average maternal age of 35. The oocytes were at various stages of maturity and were analysed by array comparative genomic hybridisation. Of these, 102 gave conclusive results, comprising 47 that were immature, at the germinal vesicle (GV) or metaphase I stage (MI); 34 complete metaphase II-first polar body (MII-PB) complexes together with 21 incomplete complexes. Oocytes at the GV or MI stage provide direct evidence of pre-meiotic aneuploidy. Complete MII-PB complexes with the expected reciprocal gains/losses provide information on MI errors; those with non-reciprocal gains have pre-meiotic errors. Overall, 29 oocytes were aneuploid, and the source of the error was known for 21. In 8 (from 7 women) the error was pre-meiotic consisting of 4 MI oocytes and 4 MII-PB complexes with non-reciprocal gains. The remaining 13 were the result of errors at meiosis I. Although pre-meiotic errors occurred in only 10% of informative oocytes, most notable was the fact that for those oocytes where the source of the error was known, 38% were caused by germinal mosaicism compared with 62% that were the outcome of a meiosis I error. None of the women with germinal mosaicism were infertile.

  12. Rapid detection of autosomal aneuploidy using microsatellite markers

    Energy Technology Data Exchange (ETDEWEB)

    Ray, P.N.; Teshima, I.E. [Hospital for Sick Children, Ontario (Canada); Winsor, E.J.T. [Toronto Hospital, Ontario (Canada)] [and others

    1994-09-01

    Trisomy occurs in at least 4% of all clinically recognized pregnancies, making it the most common type of chromosome abnormality in humans. The most commonly occurring trisomies are those of chromosomes 13, 18, 21 and aneuploidy of X and Y, accounting for about 0.3% of all newborns and a much higher percentage of conceptuses. In Canada, prenatal chromosome analysis by amniocentesis is offered to those women {ge} 35 years of age at the time of delivery or equivalent risk by maternal serum screen. We are developing a rapid molecular diagnostic test to detect the most common autosomal aneuploidies in prenatal and neonatal samples. The tests makes use of highly polymorphic short tandem repeat markers labeled with fluorescent tags which allow analysis on a GENESCANNER automated fragment analyzer (ABI). Multiple polymorphic markers have been selected on each of chromosomes 13, 18 and 21. At a given locus, trisomic fetuses/neonates will have either three alleles or two alleles with one allele having twice the intensity of the other. Unaffected individuals have two equal intensity alleles. We are conducting a blind study that will compare the detection efficiencies of FISH analysis on uncultured cells and the molecular method on confirmation amniotic fluid samples collected at the time of termination of affected fetuses. Results on cultured amniocytes from one such patient confirmed that trisomy 21 can be detected. FISH was not done on this sample. In addition, detection efficiency of the molecular method in whole blood samples from affected neonates is also being studied. To date, two such samples have been tested, one with trisomy 13 and one with trisomy 18, and both samples were diagnosed correctly. Preliminary results suggest that this method may provide a valuable tool for the rapid diagnosis of aneuploidy.

  13. Natural and artefactual aneuploidy in human lymphocytes in extreme old age.

    Science.gov (United States)

    Lezhava, T; Khmaladze, E; Lokhadze, T; Buadze, T

    2008-04-01

    At present it is generally believed that aging is accompanied by an increase in the numbers of cells with altered chromosome sets. However, the problem of aneuploidy in extreme old age (80 years and over) has hardly been subjected to systematic investigation. The purpose of this study was to examine quantitative chromosome changes and relationship between "artefactual" and "natural" aneuploidy in subjects from 80 to 114 years of age using karyotype analyses. Chromosomes were studied in 1136 karyotypes of relatively round metaphases from 40 lymphocyte cultures obtained from 40 apparently normal subjects aged from 80 to 114 ( including 26 men and 14 women). 964 karyotypes from 48 donors aged 20 to 48 served as control. Lymphocytes were cultivation by modification method (Lezhava, 2006). It is suggested that the probability of natural aneuploidy rises substantially among elderly women; while that of artefactual aneuploidy is increased among elderly men; the problem of natural aneuploidy in males remains unclear.

  14. Japanese neuropathy patients with peripheral myelin protein-22 gene aneuploidy

    Energy Technology Data Exchange (ETDEWEB)

    Lebo, R.V.; Li, L.Y.; Flandermeyer, R.R. [Univ. of California, San Francisco, CA (United States)] [and others

    1994-09-01

    Peripheral myelin protein (PMP-22) gene aneuploidy results in Charcot-Marie-Tooth disease Type 1A (CMT1A) and the Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) in Japanese patients as well as Caucasian Americans. Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, results when expression of one of at least seven genes is defective. CMT1A, about half of all CMT mutations, is usually associated with a duplication spanning the peripheral myelin protein-22 gene on distal chromosome band 17p11.2. Autosomal dominant HNPP (hereditary pressure and sensory neuropathy, HPSN) results from a deletion of the CMT1A gene region. Multicolor in situ hybridization with PMP-22 gene region probe characterized HNPP deletion reliably and detected all different size duplications reported previously. In summary, 72% of 28 Japanese CMT1 (HMSNI) patients tested had the CMT1A duplication, while none of the CMT2 (HMSNII) or CMT3 (HMSNIII) patients had a duplication. Three cases of HNPP were identified by deletion of the CMT1A gene region on chromosome 17p. HNPP and CMT1A have been reported to result simultaneously from the same unequal recombination event. The lower frequency of HNPP compared to CMT1A suggests that HNPP patients have a lower reproductive fitness than CMT1A patients. This result, along with a CMT1A duplication found in an Asian Indian family, demonstrates the broad geographic distribution and high frequency of PMP-22 gene aneuploidy.

  15. Heritable alteration of DNA methylation induced by whole-chromosome aneuploidy in wheat.

    Science.gov (United States)

    Gao, Lihong; Diarso, Moussa; Zhang, Ai; Zhang, Huakun; Dong, Yuzhu; Liu, Lixia; Lv, Zhenling; Liu, Bao

    2016-01-01

    Aneuploidy causes changes in gene expression and phenotypes in all organisms studied. A previous study in the model plant Arabidopsis thaliana showed that aneuploidy-generated phenotypic changes can be inherited to euploid progenies and implicated an epigenetic underpinning of the heritable variations. Based on an analysis by amplified fragment length polymorphism and methylation-sensitive amplified fragment length polymorphism markers, we found that although genetic changes at the nucleotide sequence level were negligible, extensive changes in cytosine DNA methylation patterns occurred in all studied homeologous group 1 whole-chromosome aneuploid lines of common wheat (Triticum aestivum), with monosomic 1A showing the greatest amount of methylation changes. The changed methylation patterns were inherited by euploid progenies derived from the aneuploid parents. The aneuploidy-induced DNA methylation alterations and their heritability were verified at selected loci by bisulfite sequencing. Our data have provided empirical evidence supporting earlier suggestions that heritability of aneuploidy-generated, but aneuploidy-independent, phenotypic variations may have an epigenetic basis. That at least one type of aneuploidy - monosomic 1A - was able to cause significant epigenetic divergence of the aneuploid plants and their euploid progenies also lends support to recent suggestions that aneuploidy may have played an important and protracted role in polyploid genome evolution.

  16. Aneuploidy, the somatic mutation that makes cancer a species of its own.

    Science.gov (United States)

    Duesberg, P; Rasnick, D

    2000-10-01

    The many complex phenotypes of cancer have all been attributed to "somatic mutation." These phenotypes include anaplasia, autonomous growth, metastasis, abnormal cell morphology, DNA indices ranging from 0.5 to over 2, clonal origin but unstable and non-clonal karyotypes and phenotypes, abnormal centrosome numbers, immortality in vitro and in transplantation, spontaneous progression of malignancy, as well as the exceedingly slow kinetics from carcinogen to carcinogenesis of many months to decades. However, it has yet to be determined whether this mutation is aneuploidy, an abnormal number of chromosomes, or gene mutation. A century ago, Boveri proposed cancer is caused by aneuploidy, because it correlates with cancer and because it generates "pathological" phenotypes in sea urchins. But half a century later, when cancers were found to be non-clonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer although, (1) many carcinogens do not mutate genes, (2) there is no functional proof that mutant genes cause cancer, and (3) mutation is fast but carcinogenesis is exceedingly slow. Intrigued by the enormous mutagenic potential of aneuploidy, we undertook biochemical and biological analyses of aneuploidy and gene mutation, which show that aneuploidy is probably the only mutation that can explain all aspects of carcinogenesis. On this basis we can now offer a coherent two-stage mechanism of carcinogenesis. In stage one, carcinogens cause aneuploidy, either by fragmenting chromosomes or by damaging the spindle apparatus. In stage two, ever new and eventually tumorigenic karyotypes evolve autocatalytically because aneuploidy destabilizes the karyotype, ie. causes genetic instability. Thus, cancer cells derive their unique and complex phenotypes from random chromosome number mutation, a process that is similar to regrouping assembly lines

  17. Rapid-prenatal diagnosis through fluorescence in situ hybridization for preventing aneuploidy related birth defects

    Directory of Open Access Journals (Sweden)

    Ashish Fauzdar

    2013-01-01

    Conclusion: Rapid FISH is a reliable and prompt method for detecting numerical chromosomal aberrations and has now been implemented as a routine diagnostic procedure for detection of fetal aneuploidy in India.

  18. Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia

    OpenAIRE

    Simpson, N.; Addis, L; Brandler, W.; Slonims, V.; Clark, A.; Watson, J.; Scerri, T.; Hennessy, E.; Stein, J.; Talcott, J.; Conti-Ramsden, G.; O'Hare, A.; Baird, G.; Fairfax, B.; Knight, J

    2014-01-01

    Aim Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. Method Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 mal...

  19. Double and multiple chromosomal aneuploidies in spontaneous abortions: A single institutional experience

    Directory of Open Access Journals (Sweden)

    Shivakumar Subramaniyam

    2014-01-01

    Full Text Available Objective: To characterize double and multiple aneuploidies in spontaneous abortions (SAB. Materials and Methods: Retrospective analysis of cytogenetics data obtained by culturing/harvesting products of the conception material at our center from 2006 to 2009 was performed. The abnormal cytogenetic results, maternal age, gestational age, and previous pregnancy history were recorded and compared. Results: Double and multiple aneuploidies are rare, however, a high percentage of double (4.6% and multiple (0.4% chromosomal aneuploidies were observed in our study of 1502 cases of SAB. Of 1502 cases of SAB evaluated, 70 cases (4.6% showed double aneuploidy, whereas 6 cases (0.4% had multiple aneuploidies. The chromosomes most frequently involved in double aneuploidy in the decreasing order were 21, 16, ± X, 22, 18, 13, and 15. The most frequent chromosome combinations observed were: Loss of X/21 (8.5%, 21/22 (4.4%, 16/21 (4.4%, and 7/16 (4.4%. The chromosome combinations in multiple aneuploidy included trisomy of chromosomes X/5/8, 8/20/22, 16/20/22, 14/21/22, and loss of X with 21/21 and 7/21. These abnormalities were significantly observed in women between the age group 40-44 years (59.2%. A high success rate (94% of obtaining metaphase cells was observed in this study mainly due to the use of direct and long-term cultures. Conclusions: We observed a high percentage of double (4.6% and multiple (0.4% aneuploidies, frequently involving the acrocentic chromosomes 13, 15, 21, and 22 and nonacrocentric chromosomes X, 16, and 18.

  20. Molecular diagnostic testing for Klinefelter syndrome and other male sex chromosome aneuploidies

    OpenAIRE

    Hager Karl; Jennings Kori; Hosono Seiyu; Howell Susan; Gruen Jeffrey R; Rivkees Scott A; Tartaglia Nicole R; Rinder Henry M

    2012-01-01

    Abstract Background Male sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations. Objective To develop a non-invasive, rapid and high-throughput molecular diagnostic assay for detection of male sex chromosome aneuploidies, including 47,XXY (Klinefelter), 47,XYY, 48,XXYY and 48,XXXY syndromes. Methods The assay utilizes three XYM and four XA markers to interrogate Y:X and X:autosome ratios, respectively. The seven markers were PCR amplified usi...

  1. A comparison of ejaculated and testicular spermatozoa aneuploidy rates in patients with high sperm DNA damage.

    Science.gov (United States)

    Moskovtsev, Sergey I; Alladin, Naazish; Lo, Kirk C; Jarvi, Keith; Mullen, J Brendan M; Librach, Clifford L

    2012-06-01

    Testicular spermatozoa are utilized to achieve pregnancy in couples with severe male factor infertility. Several studies suggest that aneuploidy rates in spermatozoa are elevated at the testicular level in infertile patients compared to ejaculates of normal controls. However, essential data regarding aneuploidy rates between ejaculated and testicular spermatozoa in the same individuals is lacking. The purpose of our study was to compare aneuploidy rates at the testicular and post-testicular level from the same patients with persistently high sperm DNA damage. Ejaculates and testicular biopsies were obtained from eight patients with persistently high DNA damage (>30%). Both ejaculated and testicular samples were analyzed for sperm DNA damage and sperm aneuploidy for chromosomes 13, 18, 21, X, and Y. In addition, semen samples from ten normozoospermic men presenting for fertility evaluation served as a control group. A strong correlation between the alteration of spermatogenesis and chromatin deterioration was observed in our study. In the same individuals, testicular samples showed a significantly lower DNA damage compared to ejaculated spermatozoa (14.9% ± 5.0 vs. 40.6% ± 14.8, P<0.05), but significantly higher aneuploidy rates for the five analyzed chromosomes (12.41% ± 3.7 vs. 5.77% ± 1.2, P<0.05). While testicular spermatozoa appear favourable for ICSI in terms of lower DNA damage, this potential advantage could be offset by the higher aneuploidy rates in testicular spermatozoa.

  2. Is metal contamination responsible for increasing aneuploidy levels in the Manila clam Ruditapes philippinarum?

    KAUST Repository

    Piló, D.

    2016-11-03

    The present study assessed the metal genotoxicity potential at chromosome-level in the bivalve Ruditapes philippinarum collected along different areas of the Tagus estuary. Higher levels of aneuploidy on gill cells were detected at the most sediment contaminated area both in May (31.7%) and October (36.0%) when compared to a less contaminated area over the same periods (20.3% and 29.0% respectively). Interestingly, metal bioaccumulation in gills was higher in the specimens collected at the least contaminated area with the exception of Pb. Indeed, the multivariate analysis revealed a stronger relation between aneuploidy and sediment contamination than between aneuploidy and the bioaccumulation of the metals. The temporal and spatial inconsistency found for the bioaccumulation of metals in R. philippinarum and the positive correlation between sediment contamination and aneuploidy at the most contaminated area suggest that these chromosome-level effects might be due to chronic metal contamination occurring in the Tagus estuary, rather than a direct result of the temporal variation of bioavailable contaminants. The vertical transmission phenomenon of bivalve aneuploidy levels may then be perpetuating those levels on clams from the most contaminated area. The present results shed light about the effect of metal toxicity at the chromosome-level in species inhabiting chronic contaminated areas and highlight the use of aneuploidy as an effective tool to identify persistent contamination in worldwide transitional waters.

  3. Double aneuploidy in three Egyptian patients: Down-Turner and Down-Klinefelter syndromes.

    Science.gov (United States)

    Zaki, M S; Kamel, A A; El-Ruby, M

    2005-01-01

    The co-occurrence of two numerical chromosomal abnormalities in same individual (double aneuploidy) is relatively rare and its clinical presentations are variable depending on the predominating aneuploidy or a combination effect of both. Furthermore, double aneuploidy involving both autosomal and sex chromosomes is seldom described. In this study, we present three patients with double aneuploidy involving chromosome 21 and sex chromosomes. They all had the classical non disjunction trisomy 21; that was associated with monosomy X in two of them and double X in the other. Clinically, they had most of the phenotypic features of Down syndrome as well as variable features characteristic of Turner or Klinefelter syndrome. Cytogenetic studies and fluorescence in situ hybridization (FISH) analysis were carried out for all patients and their parents. The first patient was a male, mosaic with 2 cell lines (45,X/47,XY,+21) by regular banding techniques and had an affected sib with Down syndrome (47,XY,+21). The second was a female, mosaic (46,X,+21/47,XX,+21) where monosomy X was detected only by FISH in 15 percentages of cells, nevertheless, stigmata of Turner syndrome was more obvious in this patient. The third patient had non mosaic double trisomy; Down-Klinefelter (48,XXY,+21) presented with Down syndrome phenotype. Parental karyotypes and FISH studies for these patients were normal with no evidence of mosaicism. In this report, we review the variable clinical presentations among the few reported cases with the same aneuploidy in relation to ours. Also, the proposed mechanisms of double aneuploidy and the occurrence of non-disjunction in more than one family member are discussed. This study emphasizes the importance of molecular cytogenetics studies for more than one tissue in cases with atypical features of characteristic chromosomal aberration syndromes. To our knowledge, this is the first report of double aneuploidy, Down-Turner and Down-Klinefelter syndromes in

  4. Fluorescence in situ hybridization in uncultured amniocytes for detection of aneuploidy in 4210 prenatal cases

    Institute of Scientific and Technical Information of China (English)

    JIA Chan-wei; WANG Shu-yu; MA Yan-min; LAN Yong-lian; SI Yan-mei; YU Lan; ZHOU Li-ying

    2011-01-01

    Background Almost all reported fluorescence in situ hybridization (FISH) kits for prenatal diagnosis use probes from foreign (non-Chinese) countries. The aim of this study was to analyze the reliability of domestic (Chinese) FISH probe sets to detect aneuploidies of chromosomes 13, 18, 21, X, and Y related to prenatal diagnosis in 4210 cases.Methods Cytogenetic karyotyping was carded out as a standard prenatal diagnostic test, and amniotic fluid cell interphase FISH analysis was performed using two sets of probes (centromeric probes for chromosomes 18, X, and Y,and locus-specific probes for chromosomes 13 and 21) provided by GP Medical Technologies, Beijing, China. Then we compared the two results and found the performance characteristics for informative FISH results of aneuploidies by the domestic kit probes.Results In 4210 cases, 4126 cases generated karyotype results and 133 abnormal karyotypes (including 97 aneuploidies) were found. The FISH results of 98 cases (among them, 31 cases gave normal cytogenetic results) were uninformative. The rate of abnormal cases was 3.2% (133/4126). For the abnormal karyotypes, the rate of aneuploidy was 72.9% (97/133). Among the 97 aneuploidies, there were 58 cases of trisomy 21 (58/97, 59.8%), four cases of trisomy 13, 23 cases of trisomy 18, and 12 cases of sex chromosomal aneuploidies. The total concordance of the two methods was 97.9% (95/97; two cases were mosaics that had a low percentage of abnormal cells), and the concordance of trisomy 21, 13, and 18 by the two methods was 100%.Conclusions The two sets of the domestic FISH kit probes are reliable for prenatal diagnosis. The results demonstrate that FISH is a rapid and accurate clinical method for prenatal identification of chromosome aneuploidies.

  5. The influence of sex chromosome aneuploidy on brain asymmetry.

    Science.gov (United States)

    Rezaie, Roozbeh; Daly, Eileen M; Cutter, William J; Murphy, Declan G M; Robertson, Dene M W; DeLisi, Lynn E; Mackay, Clare E; Barrick, Thomas R; Crow, Timothy J; Roberts, Neil

    2009-01-05

    The cognitive deficits present in individuals with sex chromosome aneuploidies suggest that hemispheric differentiation of function is determined by an X-Y homologous gene [Crow (1993); Lancet 342:594-598]. In particular, females with Turner's syndrome (TS) who have only one X-chromosome exhibit deficits of spatial ability whereas males with Klinefelter's syndrome (KS) who possess a supernumerary X-chromosome are delayed in acquiring words. Since spatial and verbal abilities are generally associated with right and left hemispheric function, such deficits may relate to anomalies of cerebral asymmetry. We therefore applied a novel image analysis technique to investigate the relationship between sex chromosome dosage and structural brain asymmetry. Specifically, we tested Crow's prediction that the magnitude of the brain torque (i.e., a combination of rightward frontal and leftward occipital asymmetry) would, as a function of sex chromosome dosage, be respectively decreased in TS women and increased in KS men, relative to genotypically normal controls. We found that brain torque was not significantly different in TS women and KS men, in comparison to controls. However, TS women exhibited significantly increased leftward brain asymmetry, restricted to the posterior of the brain and focused on the superior temporal and parietal-occipital association cortex, while KS men showed a trend for decreased brain asymmetry throughout the frontal lobes. The findings suggest that the number of sex chromosomes influences the development of brain asymmetry not simply to modify the torque but in a complex pattern along the antero-posterior axis.

  6. Aneuploidy involving chromosome 1 may be an early predictive marker of intestinal type gastric cancer

    Energy Technology Data Exchange (ETDEWEB)

    Williams, L. [Royal Glamorgan Hospital, Ynysmaerdy, Llantrisant CF72 8XR (United Kingdom); Somasekar, A. [Institute of Life Science, Swansea School of Medicine, Swansea University, Swansea SA28PP (United Kingdom); Neath Port Talbot Hospital, Abertawe Bro Morgannwg University NHS Trust, Baglan Way, Port Talbot SA12 7BX (United Kingdom); Davies, D.J.; Cronin, J.; Doak, S.H. [Institute of Life Science, Swansea School of Medicine, Swansea University, Swansea SA28PP (United Kingdom); Alcolado, R. [Royal Glamorgan Hospital, Ynysmaerdy, Llantrisant CF72 8XR (United Kingdom); Williams, J.G. [Neath Port Talbot Hospital, Abertawe Bro Morgannwg University NHS Trust, Baglan Way, Port Talbot SA12 7BX (United Kingdom); Griffiths, A.P. [Department of Histopathology, Morriston Hospital, Abertawe Bro Morgannwg University NHS Trust, Morriston, SA66NL (United Kingdom); Baxter, J.N. [Department of Surgery, Morriston Hospital, Abertawe Bro Morgannwg University NHS Trust, Morriston, SA66NL (United Kingdom); Jenkins, G.J.S., E-mail: g.j.jenkins@swansea.ac.uk [Institute of Life Science, Swansea School of Medicine, Swansea University, Swansea SA28PP (United Kingdom)

    2009-10-02

    Intestinal type gastric cancer is a significant cause of mortality, therefore a better understanding of its molecular basis is required. We assessed if either aneuploidy or activity of the oncogenic transcription factor nuclear factor kappa B (NF-{kappa}B), increased incrementally during pre-malignant gastric histological progression and also if they correlated with each other in patient samples, as they are both induced by oxygen free radicals. In a prospective study of 54 (aneuploidy) and 59 (NF-{kappa}B) consecutive patients, aneuploidy was assessed by interphase fluorescent in situ hybridisation (FISH) for chromosome 1. NF-{kappa}B was assessed by expression of interleukin-8 (IL-8), and in a subset, by immunohistochemistry (IHC) for active p65. Aneuploidy levels increased incrementally across the histological series. 2.76% of cells with normal histology (95% CI, 2.14-3.38%) showed background levels of aneuploidy, this increased to averages of 3.78% (95% CI, 3.21-4.35%), 5.89% (95% CI, 3.72-8.06%) and 7.29% (95% CI, 4.73-9.85%) of cells from patients with gastritis, Helicobacter pylori positive gastritis and atrophy/intestinal metaplasia (IM) respectively. IL-8 expression was only increased in patients with current H. pylori infection. NF-{kappa}B analysis showed some increased p65 activity in inflamed tissues. IL-8 expression and aneuploidy level were not linked in individual patients. Aneuploidy levels increased incrementally during histological progression; were significantly elevated at very early stages of neoplastic progression and could well be linked to cancer development and used to assess cancer risk. Reactive oxygen species (ROS) induced in early gastric cancer are presumably responsible for the stepwise accumulation of this particular mutation, i.e. aneuploidy. Hence, aneuploidy measured by fluorescent in situ hybridisation (FISH) coupled to brush cytology, would be worthy of consideration as a predictive marker in gastric cancer and could be

  7. Detection of sex chromosome aneuploidy in dog spermatozoa by triple color fluorescence in situ hybridization.

    Science.gov (United States)

    Komaki, Haruna; Oi, Maya; Suzuki, Hiroshi

    2014-09-01

    With the development of a direct visualization of sex chromosome in a single sperm by fluorescence in situ hybridization (FISH) technique, the frequency of aberration (aneuploidy) in spermatozoa in several mammals has been investigated. However, there is no report in the incidence of X-Y aneuploidy in the sperm population of dogs. Therefore, in this study, the aneuploidy in dog spermatozoa was examined by multicolor FISH using specific molecular probes for canine sex chromosomes and autosome. Semen from eight male Labrador retrievers was used as specimen. For decondensation of sperm nuclei, the specimen was treated with 1 M NaOH for 4 minutes at room temperature. Probes for chromosomes X, Y, and 1, labeled with SpectrumGreen, Cy3 and Cy5, respectively, were hybridized with decondensed spermatozoa. Fluorescence in situ hybridization signals in sperm heads were clearly detected in each specimen, regardless of the sperm donor. The FISH signal of at least one of the three probes was detected in all sperm heads examined. There was no significant difference between the theoretical ratio (50:50) and the observed ratio of X and Y chromosomes in spermatozoa of all the eight dogs. Mean percentage of sex chromosome aneuploidy was 0.127% (ranged between 0% and 0.316%). This percentage of canine sex chromosome aneuploidy was lower than the one reported in cattle, horses, river buffalo, and goats sperm, but higher than that observed in mice and sheep.

  8. The association between environmental exposure to pyrethroids and sperm aneuploidy.

    Science.gov (United States)

    Radwan, Michał; Jurewicz, Joanna; Wielgomas, Bartosz; Piskunowicz, Marta; Sobala, Wojciech; Radwan, Paweł; Jakubowski, Lucjusz; Hawuła, Wanda; Hanke, Wojciech

    2015-06-01

    The aim of the present study is to determine whether the environmental exposure to pyrethroids was associated with males sperm chromosome disomy. The study population consisted of 195 men who attended the infertility clinic for diagnostic purposes and who had normal semen concentration of 20-300×10(6) mL(-1) or slight oligozoospermia (semen concentration of 15-20×10(6) mL(-1)) (WHO, 1999). Participants were interviewed and provided a semen sample. The pyrethroids metabolites: 3-phenoxybenzoic acid (3PBA), cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (CDCCA), trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (TDCCA) and cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA) were analysed in the urine using a validated gas chromatography ion-tap mass spectrometry method. Sperm aneuploidy was assessed using multicolor FISH (DNA probes specific for chromosomes X, Y, 18, 13, 21). Our results showed that CDCCA >50th percentile was associated with disomy of chromosome 18 (p=0.05) whereas the level of TDCCA in urine >50th percentile was related to XY disomy (p=0.04) and disomy of chromosome 21 (p=0.05). Urinary 3PBA level ⩽50 and >50 percentile was related to disomy of sex chromosomes: XY disomy (p=0.05 and p=0.02 respectively), Y disomy (p=0.04 and 0.02 respectively), disomy of chromosome 21 (p=0.04 and p=0.04 respectively) and total disomy (p=0.03 and p=0.04 respectively). Additionally disomy of chromosome 18 was positively associated with urinary level of 3PBA >50 percentile (p=0.03). The results reported here are found that pyrethroids may be a sperm aneugens. These findings may be of concern due to increased pyrethroid use and prevalent human exposure.

  9. Retinoic acid-treated pluripotent stem cells undergoing neurogenesis present increased aneuploidy and micronuclei formation.

    Directory of Open Access Journals (Sweden)

    Rafaela C Sartore

    Full Text Available The existence of loss and gain of chromosomes, known as aneuploidy, has been previously described within the central nervous system. During development, at least one-third of neural progenitor cells (NPCs are aneuploid. Notably, aneuploid NPCs may survive and functionally integrate into the mature neural circuitry. Given the unanswered significance of this phenomenon, we tested the hypothesis that neural differentiation induced by all-trans retinoic acid (RA in pluripotent stem cells is accompanied by increased levels of aneuploidy, as previously described for cortical NPCs in vivo. In this work we used embryonal carcinoma (EC cells, embryonic stem (ES cells and induced pluripotent stem (iPS cells undergoing differentiation into NPCs. Ploidy analysis revealed a 2-fold increase in the rate of aneuploidy, with the prevalence of chromosome loss in RA primed stem cells when compared to naïve cells. In an attempt to understand the basis of neurogenic aneuploidy, micronuclei formation and survivin expression was assessed in pluripotent stem cells exposed to RA. RA increased micronuclei occurrence by almost 2-fold while decreased survivin expression by 50%, indicating possible mechanisms by which stem cells lose their chromosomes during neural differentiation. DNA fragmentation analysis demonstrated no increase in apoptosis on embryoid bodies treated with RA, indicating that cell death is not the mandatory fate of aneuploid NPCs derived from pluripotent cells. In order to exclude that the increase in aneuploidy was a spurious consequence of RA treatment, not related to neurogenesis, mouse embryonic fibroblasts were treated with RA under the same conditions and no alterations in chromosome gain or loss were observed. These findings indicate a correlation amongst neural differentiation, aneuploidy, micronuclei formation and survivin downregulation in pluripotent stem cells exposed to RA, providing evidence that somatically generated chromosomal

  10. BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer

    DEFF Research Database (Denmark)

    López-García, Carlos; Sansregret, Laurent; Domingo, Enric

    2016-01-01

    Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, ...... contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution....

  11. Mutations in MAPT give rise to aneuploidy in animal models of tauopathy.

    Science.gov (United States)

    Rossi, Giacomina; Conconi, Donatella; Panzeri, Elena; Paoletta, Laura; Piccoli, Elena; Ferretti, Maria Giulia; Mangieri, Michela; Ruggerone, Margherita; Dalprà, Leda; Tagliavini, Fabrizio

    2014-03-01

    Tau is a major microtubule-associated protein in brain neurons. Its misfolding and accumulation cause neurodegenerative diseases characterized by brain atrophy and dementia, named tauopathies. Genetic forms are caused by mutations of microtubule-associated protein tau gene (MAPT). Tau is expressed also in nonneural tissues such as lymphocytes. Tau has been recently recognized as a multifunctional protein, and in particular, some findings supported a role in genome stability. In fact, peripheral cells of patients affected by frontotemporal dementia carrying different MAPT mutations showed structural and numerical chromosome aberrations. The aim of this study was to assess chromosome stability in peripheral cell from two animal models of genetic tauopathy, JNPL3 and PS19 mouse strains expressing the human tau carrying the P301L and P301S mutations, respectively, to confirm the previous data on humans. After demonstrating the presence of mutated tau in spleen, we performed standard cytogenetic analysis of splenic lymphocytes from homozygous and hemizygous JNPL3, hemizygous PS19, and relevant controls. Losses and gains of chromosomes (aneuploidy) were evaluated. We detected a significantly higher level of aneuploidy in JNPL3 and PS19 than in control mice. Moreover, in JNPL3, the aneuploidy was higher in homozygotes than in hemizygotes, demonstrating a gene dose effect, which appeared also to be age independent. Our results show that mutated tau is associated with chromosome instability. It is conceivable to hypothesize that in genetic tauopathies the aneuploidy may be present also in central nervous system, possibly contributing to neurodegeneration.

  12. Impact of type 1 diabetes and glycemic control on fetal aneuploidy biochemical markers

    DEFF Research Database (Denmark)

    Madsen, Helen Nordahl; Ekelund, Charlotte Kvist; Tørring, Niels;

    2012-01-01

    Objective: To determine the influence of type 1 diabetes mellitus (T1DM) on the first trimester serum markers of fetal aneuploidy; pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (free β-hCG) and to evaluate the influence of glycemic control on...

  13. Effects of Sex Chromosome Aneuploidies on Brain Development: Evidence from Neuroimaging Studies

    Science.gov (United States)

    Lenroot, Rhoshel K.; Lee, Nancy Raitano; Giedd, Jay N.

    2009-01-01

    Variation in the number of sex chromosomes is a relatively common genetic condition, affecting as many as 1/400 individuals. The sex chromosome aneuploidies (SCAs) are associated with characteristic behavioral and cognitive phenotypes, although the degree to which specific individuals are affected can fall within a wide range. Understanding the…

  14. Incidental prenatal diagnosis of sex chromosome aneuploidies: health, behavior, and fertility.

    NARCIS (Netherlands)

    Pieters, J.J.; Kooper, A.J.A.; Geurts van Kessel, A.H.M.; Braat, D.D.M.; Smits, A.P.T.

    2011-01-01

    Objective. To assess the diagnostic relevance of incidental prenatal findings of sex chromosome aneuploidies. Methods. We searched with medical subject headings (MeSHs) and keywords in Medline and the Cochrane Library and systematically screened publications on postnatally diagnosed sex chromosomal

  15. Could sperm aneuploidy rate determination be used as a predictive test before intracytoplasmic sperm injection?

    Science.gov (United States)

    Petit, François M; Frydman, Nelly; Benkhalifa, Moncef; Le Du, Anne; Aboura, Azzedine; Fanchin, Renato; Frydman, Rene; Tachdjian, Gerard

    2005-01-01

    Chromosome abnormalities in embryos are a major cause of implantation and development failures. Some couples with normal karyotypes have repeated implantation failures after intracytoplasmic sperm injection (ICSI). In order to value patients at risk for genetic ICSI failures and the validity of sperm aneuploidy analysis, we have studied cytogenetic abnormalities in sperm from ICSI patients. Twenty-nine patients with normal karyotypes were included. Ten patients had at least 4 ICSI treatments without pregnancy (group A). Nine patients had a pregnancy after 1 to 3 ICSI treatments (group B). Ten fertile men with normal semen parameters were studied as controls (group C). Fluorescent in situ hybridization (FISH) was used for sperm nucleus cytogenetic analysis using chromosomes 8, 9, 13, 18, 21, X, and Y specific probes. Aneuploidy for each chromosome and diploidy rates were significantly higher in group A than in group B and in group B than in group C (P < .05). Considering each patient in groups A and B, aneuploidy rate for each chromosome was too variable to be considered as a significant test. We proposed analysis of the total sperm aneuploidy. Chromosomal sperm nuclei profile could be used as a predictive biological test before ICSI in order to improve genetic counseling for oligoasthenoteratozoospermia patients.

  16. Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm.

    Science.gov (United States)

    Robbins, W A; Meistrich, M L; Moore, D; Hagemeister, F B; Weier, H U; Cassel, M J; Wilson, G; Eskenazi, B; Wyrobek, A J

    1997-05-01

    Each year more than 20,000 children and young persons of reproductive age are exposed to known mutagens in the form of chemo- and/or radiotherapy for cancer in the States. As more of these treatments are effective there is growing concern that genetic defects are introduced in the germ cells of these young patients. It is well documented for male rodents that treatment with chemo- and radio-therapeutic agents before mating can cause genetic damage in the germ line, and the magnitude of heritable effects depends on the spermatogenic cell stage treated. Similar germinal effects are suspected to occur in humans but remain unproven. Hodgkin's disease (HD) is an example of a malignancy which is typically diagnosed during a patient's reproductive years. In our study we observed eight male HD patients who were treated with NOVP (Novanthrone, Oncovin, Vinblastine, Prednisone) chemotherapy. We evaluated sperm aneuploidy using multi-colour fluorescence in situ hybridization (FISH), and found approximately 5-fold increases in sperm with disomies, diploidies and complex genotypes involving chromosome X, Y and 8. Increases in sex chromosome aneuploidies arose from segregation errors at meiosis I as well as meiosis II. The aneuploidy effects were transient, however, declining to pretreatment levels within approximately 100 days after the end of the therapy. When compared with normal men, some HD patients showed higher proportions of certain sperm aneuploidy types even before their first therapy.

  17. Re: Fluorescence In Situ Hybridization Detects Increased Sperm Aneuploidy in Men with Recurrent Pregnancy Loss

    Directory of Open Access Journals (Sweden)

    Ranjith Ramasamy,

    2015-06-01

    Full Text Available Male factor infertility can be overcome with the use of assisted reproductive technologies and for this purpose the mostly intracytoplasmic sperm injection (ICSI was used. Although using sperm from men with relatively normal semen parameters with high-tech methods, many couples fail to achieve pregnancy or face recurrent pregnancy loss (RPL. In this study, the authors tried to find an answer for potential causes of RPL and in vitro fertilization (IVF failure by using fluorescence in situ hybridization (FISH analysis. FISH analysis was used to detect numerical abnormalities in sex chromosomes (X,Y and autosomes (13,18, 21 in ejaculated sperm. Significantly higher percentage of sperm aneuploidy was found in men with RPL within the sex chromosomes and chromosomes 18,13 and 21. Although men with normal sperm parameter, 40% of abnormal sperm aneuploidy was found in all the chromosomes analyzed. In addition to that, men with abnormal sperm density and motility had a higher percentage of sex chromosome aneuploidy than men with normal density and motility. In conclusion, sperm FISH analysis can be suggested in men with RPL and normal sperm density/motility to understand the reason of pregnancy failure. Also, this study showed that men with oligoasthenoteratozoospermia (OAT might have a greater percentage of sperm aneuploidy compared to those with normal sperm parameters.

  18. Same-day prenatal diagnosis of common chromosomal aneuploidies using microfluidics-fluorescence in situ hybridization.

    Science.gov (United States)

    Ho, Sherry S Y; Chua, Cuiwen; Gole, Leena; Biswas, Arijit; Koay, Evelyn; Choolani, Mahesh

    2012-04-01

    Rapid molecular prenatal diagnostic methods, such as fluorescence in situ hybridization (FISH), quantitative fluorescence-PCR, and multiplex ligation-dependent probe amplification, can detect common fetal aneuploidies within 24 to 48 h. However, specific diagnosis or aneuploidy exclusion should be ideally available within the same day as fetal sampling to alleviate parental anxiety. Microfluidic technologies integrate different steps into a microchip, saving time and costs. We have developed a cost-effective, same-day prenatal diagnostic FISH assay using microfluidics. Amniotic fluids (1-4 mL from 40 pregnant women at 15-22 weeks of gestation) were fixed with Carnoy's before loading into the microchannels of a microfluidic FISH-integrated nanostructured device. The glass slides were coated with nanostructured titanium dioxide to facilitate cell adhesion. Pretreatment and hybridization were performed within the microchannels. Fifty nuclei were counted by two independent analysts, and all results were validated with their respective karyotypes. Of the 40 samples, we found three cases of fetal aneuploidies (trisomies 13, 18, and 21), whereas the remaining 37 cases were normal. Results were concordant with their karyotypes and ready to be released within 3 h of sample receipt. Microfluidic FISH, using 20-fold less than the recommended amount of probe, is a cost-effective method to diagnose common fetal aneuploidies within the same day of fetal sampling.

  19. Mapping the Stability of Human Brain Asymmetry across Five Sex-Chromosome Aneuploidies

    Science.gov (United States)

    Lin, Amy; Clasen, Liv; Lee, Nancy Raitano; Wallace, Gregory L.; Lalonde, Francois; Blumenthal, Jonathan; Giedd, Jay N.

    2015-01-01

    The human brain displays stereotyped and early emerging patterns of cortical asymmetry in health. It is unclear if these asymmetries are highly sensitive to genetic and environmental variation or fundamental features of the brain that can survive severe developmental perturbations. To address this question, we mapped cortical thickness (CT) asymmetry in a group of genetically defined disorders known to impact CT development. Participants included 137 youth with one of five sex-chromosome aneuploidies [SCAs; XXX (n = 28), XXY (n = 58), XYY (n = 26), XXYY (n = 20), and XXXXY (n = 5)], and 169 age-matched typically developing controls (80 female). In controls, we replicated previously reported rightward inferior frontal and leftward lateral parietal CT asymmetry. These opposing frontoparietal CT asymmetries were broadly preserved in all five SCA groups. However, we also detected foci of shifting CT asymmetry with aneuploidy, which fell almost exclusively within regions of significant CT asymmetry in controls. Specifically, X-chromosome aneuploidy accentuated normative rightward inferior frontal asymmetries, while Y-chromosome aneuploidy reversed normative rightward medial prefrontal and lateral temporal asymmetries. These findings indicate that (1) the stereotyped normative pattern of opposing frontoparietal CT asymmetry arises from developmental mechanisms that can withstand gross chromosomal aneuploidy and (2) X and Y chromosomes can exert focal, nonoverlapping and directionally opposed influences on CT asymmetry within cortical regions of significant asymmetry in health. Our study attests to the resilience of developmental mechanisms that support the global patterning of CT asymmetry in humans, and motivates future research into the molecular bases and functional consequences of sex chromosome dosage effects on CT asymmetry. PMID:25568109

  20. Mapping the stability of human brain asymmetry across five sex-chromosome aneuploidies.

    Science.gov (United States)

    Lin, Amy; Clasen, Liv; Lee, Nancy Raitano; Wallace, Gregory L; Lalonde, Francois; Blumenthal, Jonathan; Giedd, Jay N; Raznahan, Armin

    2015-01-07

    The human brain displays stereotyped and early emerging patterns of cortical asymmetry in health. It is unclear if these asymmetries are highly sensitive to genetic and environmental variation or fundamental features of the brain that can survive severe developmental perturbations. To address this question, we mapped cortical thickness (CT) asymmetry in a group of genetically defined disorders known to impact CT development. Participants included 137 youth with one of five sex-chromosome aneuploidies [SCAs; XXX (n = 28), XXY (n = 58), XYY (n = 26), XXYY (n = 20), and XXXXY (n = 5)], and 169 age-matched typically developing controls (80 female). In controls, we replicated previously reported rightward inferior frontal and leftward lateral parietal CT asymmetry. These opposing frontoparietal CT asymmetries were broadly preserved in all five SCA groups. However, we also detected foci of shifting CT asymmetry with aneuploidy, which fell almost exclusively within regions of significant CT asymmetry in controls. Specifically, X-chromosome aneuploidy accentuated normative rightward inferior frontal asymmetries, while Y-chromosome aneuploidy reversed normative rightward medial prefrontal and lateral temporal asymmetries. These findings indicate that (1) the stereotyped normative pattern of opposing frontoparietal CT asymmetry arises from developmental mechanisms that can withstand gross chromosomal aneuploidy and (2) X and Y chromosomes can exert focal, nonoverlapping and directionally opposed influences on CT asymmetry within cortical regions of significant asymmetry in health. Our study attests to the resilience of developmental mechanisms that support the global patterning of CT asymmetry in humans, and motivates future research into the molecular bases and functional consequences of sex chromosome dosage effects on CT asymmetry.

  1. Screening of Fetal Chromosome Aneuploidies in the First and Second Trimester of 125,170 Iranian Pregnant Women

    Directory of Open Access Journals (Sweden)

    Elham SEYYED-KAVOOSI

    2015-10-01

    Full Text Available Background: Aneuploidy is one of the main causes of congenital anomalies, mental and physical disabilities, in new-borns. The aim of this study was to determine various chromosomal aneuploidies in the first and second trimester screening of pregnant women, in Iran.Methods: A descriptive retrospective study was conducted on 125,170 pregnant women referred to a major referral medical diagnostic laboratory (Niloo Laboratory, Tehran for prenatal screening tests (2010-2013. Patients were di-vided into 3 groups: first trimester screening (FTS, second trimester screening (STS, and combined screening groups. In positive and borderline cases, and amniocentesis and cytogenetic analysis were carried out.Results: Total prevalence of aneuploidy in 125,170 pregnant women was one in 491, (Detection Rate=82.7% for Down syndrome. The DR for DS in three groups was as follow: 87.5% for FTS (25783 women, 80.9% for STS (91345 women, and 94.7% for combined tests (8042 women. Total number of cases with Edward's syndrome was 18, Patau's syndrome six, Klinefelter syndrome six, triploidy three, and Cri-du-chat syndrome one.Conclusion: The present study shows the frequency of aneuploidy in the first and second trimester screenings in a major medical laboratory in Tehran. The prevalence of aneuploidies grows with increased maternal age. The rate of aneuploidy in first trimester is higher than second.

  2. Screening of Fetal Chromosome Aneuploidies in the First and Second Trimester of 125,170 Iranian Pregnant Women

    Science.gov (United States)

    SEYYED KAVOOSI, Elham; YOUNESSI, Sarang; FARHUD, Dariush D.

    2015-01-01

    Background: Aneuploidy is one of the main causes of congenital anomalies, mental and physical disabilities, in newborns. The aim of this study was to determine various chromosomal aneuploidies in the first and second trimester screening of pregnant women, in Iran. Methods: A descriptive retrospective study was conducted on 125,170 pregnant women referred to a major referral medical diagnostic laboratory (Niloo Laboratory, Tehran) for prenatal screening tests (2010–2013). Patients were divided into 3 groups: first trimester screening (FTS), second trimester screening (STS), and combined screening groups. In positive and borderline cases, and amniocentesis and cytogenetic analysis were carried out. Results: Total prevalence of aneuploidy in 125,170 pregnant women was one in 491, (Detection Rate=82.7% for Down syndrome). The DR for DS in three groups was as follow: 87.5% for FTS (25783 women), 80.9% for STS (91345 women), and 94.7% for combined tests (8042 women). Total number of cases with Edward's syndrome was 18, Patau's syndrome six, Klinefelter syndrome six, triploidy three, and Cri-du-chat syndrome one. Conclusion: The present study shows the frequency of aneuploidy in the first and second trimester screenings in a major medical laboratory in Tehran. The prevalence of aneuploidies grows with increased maternal age. The rate of aneuploidy in first trimester is higher than second. PMID:26258091

  3. Copy-number variation and false positive prenatal aneuploidy screening results.

    Science.gov (United States)

    Snyder, Matthew W; Simmons, LaVone E; Kitzman, Jacob O; Coe, Bradley P; Henson, Jessica M; Daza, Riza M; Eichler, Evan E; Shendure, Jay; Gammill, Hilary S

    2015-04-23

    Investigations of noninvasive prenatal screening for aneuploidy by analysis of circulating cell-free DNA (cfDNA) have shown high sensitivity and specificity in both high-risk and low-risk cohorts. However, the overall low incidence of aneuploidy limits the positive predictive value of these tests. Currently, the causes of false positive results are poorly understood. We investigated four pregnancies with discordant prenatal test results and found in two cases that maternal duplications on chromosome 18 were the likely cause of the discordant results. Modeling based on population-level copy-number variation supports the possibility that some false positive results of noninvasive prenatal screening may be attributable to large maternal copy-number variants. (Funded by the National Institutes of Health and others.).

  4. Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo.

    Science.gov (United States)

    Pfau, Sarah J; Silberman, Rebecca E; Knouse, Kristin A; Amon, Angelika

    2016-06-15

    Aneuploidy, an imbalanced karyotype, is a widely observed feature of cancer cells that has long been hypothesized to promote tumorigenesis. Here we evaluate the fitness of cells with constitutional trisomy or chromosomal instability (CIN) in vivo using hematopoietic reconstitution experiments. We did not observe cancer but instead found that aneuploid hematopoietic stem cells (HSCs) exhibit decreased fitness. This reduced fitness is due at least in part to the decreased proliferative potential of aneuploid hematopoietic cells. Analyses of mice with CIN caused by a hypomorphic mutation in the gene Bub1b further support the finding that aneuploidy impairs cell proliferation in vivo. Whereas nonregenerating adult tissues are highly aneuploid in these mice, HSCs and other regenerative adult tissues are largely euploid. These findings indicate that, in vivo, mechanisms exist to select against aneuploid cells.

  5. Incidence of X and Y Chromosomal Aneuploidy in a Large Child Bearing Population

    OpenAIRE

    Samango-Sprouse, Carole; Kırkızlar, Eser; Hall, Megan P.; Lawson, Patrick; Demko, Zachary; Zneimer, Susan M.; Curnow, Kirsten J.; Gross, Susan; Gropman, Andrea

    2016-01-01

    Background X&Y chromosomal aneuploidies are among the most common human whole-chromosomal copy number changes, but the population-based incidence and prevalence in the child-bearing population is unclear. Methods This retrospective analysis of prospectively collected data leveraged a routine non-invasive prenatal test (NIPT) using parental genotyping to estimate the population-based incidence of X&Y chromosome variations in this population referred for NIPT (generally due to advanced maternal...

  6. Detection of human aneuploidies in prenatal and postnatal diagnosis using molecular cytogenetics

    Directory of Open Access Journals (Sweden)

    Kucheria Kiran

    2002-01-01

    Full Text Available Chromosomal aneuploidies especially trisomies 13, 18, 21, monosomy X and 47, XXY account for up to 95% of live born cytogenetic abnormalities. The diagnosis of aneuploidies usually done by conventional cytogenetic analysis (CCA is associated with technical difficulties and requires about 1-3 weeks for providing a result, especially in prenatal diagnosis. In the present study, Fluorescence In Situ Hybridization (FISH was used on interphase cells for rapid prenatal and postnatal detection of aneuploidies. The frequent indications of high pregnancies included for prenatal diagnosis were previous child with chromosomal abnormalities, abnormal ultrasound scan and advanced maternal age (> 35 years. Interphase FISH was done using probes specific for chromosomes 13, 18, 21, X and Y on uncultured chorionic villi and amniotic fluid samples. All samples were analyzed subsequently using conventional cytogenetics. The analysis of aneuploidies for chromosomes 13, 15, 16, 18, 21, 22, X and Y using FISH was extended to abortuses from spontaneous abortion cases. In cases where cytogenetics was not informative, a diagnosis could be made using interphase FISH. For postnatal diagnosis, interphase FISH was done to confirm low-level mosaicism in patients with primary amenorrhea, suspected cases of Klinefelter syndrome, and mental retardation using probes specific for various autosomes, X and Y chromosomes. FISH was also done using probe specific for the sex-determining region (SRY on the Y chromosome in cases with ambiguous genitalia. The SRY region could be identified in cases that lacked the Y chromosome on conventional cytogenetic analysis thereby emphasizing on the high resolution of FISH technique in detecting sub-microscopic rearrangements. To conclude, interphase FISH decreases the time interval between sampling and diagnosis. This is of tremendous value in prenatal diagnosis of urgent high-risk pregnancies, management of ambiguous genitalia and low

  7. Spontaneous aneuploidy and clone formation in adipose tissue stem cells during different periods of culturing.

    Science.gov (United States)

    Buyanovskaya, O A; Kuleshov, N P; Nikitina, V A; Voronina, E S; Katosova, L D; Bochkov, N P

    2009-07-01

    Cytogenetic analysis of 13 mesenchymal stem cell cultures isolated from normal human adipose tissue was carried out at different stages of culturing. The incidence of chromosomes 6, 8, 11, and X aneuploidy and polyploidy was studied by fluorescent in situ hybridization. During the early passages, monosomal cells were more often detected than trisomal ones. A clone with chromosome 6 monosomy was detected in three cultures during late passages.

  8. Mosaic double aneuploidy (45,X/47,XX,+8) with aortic dissection.

    Science.gov (United States)

    Lee, M N; Choi, K H; Kim, D K; Kim, S H

    2014-01-01

    Chromosomal aneuploidy is considerably frequent and may involve either autosomes or sex chromosomes. While double aneuploidy involving both autosomal and sex chromosomes is rare, several reports described the cases of sex chromosomal aneuploidies in combination with trisomy 21, such as Down-Klinefelter and Down-Turner syndrome. However, trisomy 8-Turner syndrome has been rarely described to date. Here we report a case of a 28-year-old female with mosaic trisomy 8-Turner syndrome. The patient was referred to our hospital for aortic dissection. On physical evaluation, features of her phenotype, which included short stature, webbed neck and cubitus valgus, suggested congenital anomalies such as Turner syndrome. Chest CT revealed aortic dissection with bicuspid aortic valve and coarctation. G-banding cytogenetic analysis of peripheral blood showed mosaicism with two cell lines (45,X[17]/47,XX,+8[33]). FISH analysis indicated that 15% of the cells were of monosomy X karyotype and 85% of the cells were with XX karyotype and trisomy 8 was detected only in XX cells. Though the patient exhibited clinical features of Turner syndrome, somatic stigmas present were not clearly distinguishable from those of trisomy 8, such as short stature, skeletal and cardiac abnormalities. Observations from most of the double aneuploidy cases indicated that the patient's phenotype was not necessarily in correlation to the ratio of autosomal and sex chromosomal aberrations. Mosaicism in trisomy 8-Turner syndrome was rarely documented and we believe this is the first reported case of mosaicism in trisomy 8-Turner syndrome presenting with aortic dissection and surviving into adulthood.

  9. Assessment of aneuploidy in human oocytes and preimplantation embryos by chromosome painting

    Energy Technology Data Exchange (ETDEWEB)

    Rougier, N.; Viegas-Pequignot, E.; Plachot, M. [Hospital Necker, Paris (France)] [and others

    1994-09-01

    The poor quality of chromosome preparations often observed after fixation of oocytes and embryos did not usually allow accurate identification of chromosomes involved in non-disjunctions. We, therefore, used chromosome painting to determine the incidence of abnormalities for chromosomes 1 and 7. A total of 50 oocytes inseminated for IVF and showing no signs of fertilization as well as 37 diploid embryos donated for research were fixed according to the Dyban`s technique. Fluorescence in situ hybridization was carried out using whole chromosome painting DNA probes specific for human chromosome 1 and 7. The incidence of aneuploidy was 28%, 10% and 60% for metaphase II, polar body and sperm chromosomes, respectively. The high incidence of aneuploidy observed in sperm prematurely condensed sperm chromosomes is due to the fact that usually far less than 23 sperm chromatids are observed, maybe as a consequence of incomplete chromosome condensation. Thirty seven embryos were analyzed with the same probes. 48% of early embryos were either monosomic 1 or 7 or mosaics comprising blastomeres with 1, 2 or 3 signals. Thus, 8 among the 11 abnormal embryos had hypodiploid cells (25 to 37 chromosomes) indicating either an artefactual loss of chromosomes or a complex anomaly of nuclear division (maltinucleated blastomeres, abnormal migration of chromosomes at anaphase). We therefore calculated a {open_quotes}corrected{close_quotes} incidence of aneuploidy for chromosomes 1 or 7 in early embryos: 18%. 86% of the blastocysts showed mosaicism 2n/3 or 4n as a consequence of the formation of the syncitiotrophoblast. To conclude, chromosome painting is an efficient method to accurately identify chromosomes involved in aneuploidy. This technique should allow us to evaluate the incidence of non-disjunction for all chromosome pairs. Our results confirm the high incidence of chromosome abnormalities occurring as a consequence of meiotic or mitotic non-disjunctions in human oocytes and embryos.

  10. Noninvasive prenatal testing for fetal aneuploidy: clinical assessment and a plea for restraint.

    Science.gov (United States)

    Norton, Mary E; Rose, Nancy C; Benn, Peter

    2013-04-01

    The recent introduction of clinical tests to detect fetal aneuploidy by analysis of cell-free DNA in maternal plasma represents a tremendous advance in prenatal diagnosis and the culmination of many years of effort by researchers in the field. The development of noninvasive prenatal testing for clinical application by commercial industry has allowed much faster introduction into clinical care, yet also presents some challenges regarding education of patients and health care providers struggling to keep up with developments in this rapidly evolving area. It is important that health care providers recognize that the test is not diagnostic; rather, it represents a highly sensitive and specific screening test that should be expected to result in some false-positive and false-negative diagnoses. Although currently being integrated in some settings as a primary screening test for women at high risk of fetal aneuploidy, from a population perspective, a better option for noninvasive prenatal testing may be as a second-tier test for those patients who screen positive by conventional aneuploidy screening. How noninvasive prenatal testing will ultimately fit with the current prenatal testing algorithms remains to be determined. True cost-utility analyses will be needed to determine the actual clinical efficacy of this approach in the general prenatal population.

  11. Aneuploidy in sperm of Hodgkin`s disease patients receiving NOVP chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Robbins, W.A.; Cassel, M.J.; Wyrobek, A.J. [Lawrence Livermore National Lab., CA (United States)] [and others

    1994-09-01

    Induction of genetic damage in germ cells of young patients receiving chemo- or radiotherapy for cancers with probable cure, such as Hodgkin`s disease, is cause for concern. These young patients may someday desire children, and germ cell alterations presenting as numerical chromosomal abnormalities in sperm may place their future offspring at risk. To address this concern, we measured aneuploidy in sperm from eight young Hodgkin`s disease patients: four pre-treatment, four during treatment, and three over a 45 month period following treatment with NOVP (Novantrone, Oncovin, Vinblastine and Prednisone). Patients ranged in stage of disease from IA-IIEB and none had received prior radiation or chemotherapy. Using multi-chromosome sperm FISH with repetitive sequence probes specific for chromosomes X, Y and 8, we found a significant 2-4 fold increase in particular numerical chromosomal abnormalities during treatment which were limited in persistence post-treatment. Additionally, pre-treatment Hodgkin`s disease patients showed elevations in some numerical chromosomal abnormalities when compared to a healthy reference group. In several men, the fraction of aneuploid sperm did not return to healthy reference group levels even after completion of therapy. These results show that elevated sperm aneuploidy occurs in germ cells of young cancer patients during chemotherapy and suggest caution to prevent conceptions during this period. The elevated sperm aneuploidy appears transient, but in some cases never returns to healthy reference group levels.

  12. Effects of cadmium on aneuploidy and hemocyte parameters in the Pacific oyster, Crassostrea gigas

    Energy Technology Data Exchange (ETDEWEB)

    Bouilly, Karine [IFREMER, Laboratoire de Genetique et Pathologie, La Tremblade 17390 (France); Gagnaire, Beatrice [IFREMER, Laboratoire de Genetique et Pathologie, La Tremblade 17390 (France); Bonnard, Marc [IFREMER, Laboratoire de Genetique et Pathologie, La Tremblade 17390 (France); Thomas-Guyon, Helene [Laboratoire de Biologie et Environnement Marins, FRE-CNRS, 2727, Universite de La Rochelle, 22 Avenue Michel Crepeau, La Rochelle 17042 (France); Renault, Tristan [IFREMER, Laboratoire de Genetique et Pathologie, La Tremblade 17390 (France); Miramand, Pierre [Laboratoire de Biologie et Environnement Marins, FRE-CNRS, 2727, Universite de La Rochelle, 22 Avenue Michel Crepeau, La Rochelle 17042 (France); Lapegue, Sylvie [IFREMER, Laboratoire de Genetique et Pathologie, La Tremblade 17390 (France)]. E-mail: slapegue@ifremer.fr

    2006-06-15

    Pacific oysters, Crassostrea gigas, are commonly reared in estuaries where they are exposed to anthropogenic pollution. Much research has been made on the toxicity of cadmium to aquatic organisms because the compound recurrently contaminates their environment. Our study examined the influence of cadmium on aneuploidy level (lowered chromosome number in a percentage of somatic cells) and hemocyte parameters in C. gigas at different stages of life. Adults and juveniles were exposed to two different concentrations of cadmium. The first concentration applied was equivalent to a peak value found in Marennes-Oleron bay (Charente-Maritime, France; 50 ng L{sup -1}) and the second was 10 times higher (500 ng L{sup -1}). Exposure to 50 ng L{sup -1} cadmium caused a significant decrease in the survival time of C. gigas, but exposure to 500 ng L{sup -1} surprisingly affected the survival time positively. Significant differences in aneuploidy level were observed between the cadmium treatments and the control in adults but not in juveniles or the offspring of the adult groups. The effects of cadmium on hemocyte parameters were analyzed by flow cytometry. Several hemocyte parameters increased significantly after 21 days of cadmium exposure and subsequently decreased. Phenoloxidase-like activity, evaluated by spectrophotometry, varied over the time of the experiment and increased after 66 days of contact with 500 ng L{sup -1} cadmium. Taken together, cadmium at environmentally relevant concentrations seems to have only moderate effects on aneuploidy and hemocyte parameters.

  13. Abnormal meiotic recombination in infertile men and its association with sperm aneuploidy.

    Science.gov (United States)

    Ferguson, Kyle A; Wong, Edgar Chan; Chow, Victor; Nigro, Mark; Ma, Sai

    2007-12-01

    Defects in early meiotic events are thought to play a critical role in male infertility; however, little is known regarding the relationship between early meiotic events and the chromosomal constitution of human sperm. Thus, we analyzed testicular tissue from 26 men (9 fertile and 17 infertile men), using immunofluorescent techniques to examine meiotic chromosomes, and fluorescent in situ hybridization to assess sperm aneuploidy. Based on a relatively small sample size, we observed that 42% (5/12) of men with impaired spermatogenesis displayed reduced genome-wide recombination when compared to the fertile men. Analysis of individual chromosomes showed chromosome-specific defects in recombination: chromosome 13 and 18 bivalents with only a single crossover and chromosome 21 bivalents lacking a crossover were more frequent among the infertile men. We identified two infertile men who displayed a novel meiotic defect in which the sex chromosomes failed to recombine: one man had an absence of sperm in the testes, while the other displayed increased sex chromosome aneuploidy in the sperm, resulting in a 45,X abortus after intracytoplasmic sperm injection. When all men were pooled, we observed an inverse correlation between the frequency of sex chromosome recombination and XY disomy in the sperm. Recombination between the sex chromosomes may be a useful indicator for identifying men at risk of producing chromosomally abnormal sperm. An understanding of the molecular mechanisms that contribute to sperm aneuploidy in infertile men could aid in risk assessment for couples undergoing assisted reproduction.

  14. Dosage Effects of X and Y Chromosomes on Language and Social Functioning in Children with Supernumerary Sex Chromosome Aneuploidies: Implications for Idiopathic Language Impairment and Autism Spectrum Disorders

    Science.gov (United States)

    Lee, Nancy Raitano; Wallace, Gregory L.; Adeyemi, Elizabeth I.; Lopez, Katherine C.; Blumenthal, Jonathan D.; Clasen, Liv S.; Giedd, Jay N.

    2012-01-01

    Background: Supernumerary sex chromosome aneuploidies (X/Y-aneuploidies), the presence of extra X and/or Y chromosomes, are associated with heightened rates of language impairments and social difficulties. However, no single study has examined different language domains and social functioning in the same sample of children with tri-, tetra-, and…

  15. Screening for fetal aneuploidies at 11 to 13 weeks%"妊娠11~13周胎儿非整倍体的筛查"点评

    Institute of Scientific and Technical Information of China (English)

    韩瑾; 李东至

    2011-01-01

    @@ Effective screening for major aneuploidies can be provided in the first trimester of pregnancy.Screening by a combination of fetal nuchal translucency and maternal serum fre-β-human chorionic gonadotrophin and pregnancy associated plasma protein-A can identify about 90%of fetuses with trisomy 21 and other major aneuploidies for a false positive rate of 5%.

  16. The fragile Y hypothesis: Y chromosome aneuploidy as a selective pressure in sex chromosome and meiotic mechanism evolution.

    Science.gov (United States)

    Blackmon, Heath; Demuth, Jeffery P

    2015-09-01

    Loss of the Y-chromosome is a common feature of species with chromosomal sex determination. However, our understanding of why some lineages frequently lose Y-chromosomes while others do not is limited. The fragile Y hypothesis proposes that in species with chiasmatic meiosis the rate of Y-chromosome aneuploidy and the size of the recombining region have a negative correlation. The fragile Y hypothesis provides a number of novel insights not possible under traditional models. Specifically, increased rates of Y aneuploidy may impose positive selection for (i) gene movement off the Y; (ii) translocations and fusions which expand the recombining region; and (iii) alternative meiotic segregation mechanisms (achiasmatic or asynaptic). These insights as well as existing evidence for the frequency of Y-chromosome aneuploidy raise doubt about the prospects for long-term retention of the human Y-chromosome despite recent evidence for stable gene content in older non-recombining regions.

  17. Effects of aneuploidy on genome structure, expression, and interphase organization in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Bruno Huettel

    2008-10-01

    Full Text Available Aneuploidy refers to losses and/or gains of individual chromosomes from the normal chromosome set. The resulting gene dosage imbalance has a noticeable affect on the phenotype, as illustrated by aneuploid syndromes, including Down syndrome in humans, and by human solid tumor cells, which are highly aneuploid. Although the phenotypic manifestations of aneuploidy are usually apparent, information about the underlying alterations in structure, expression, and interphase organization of unbalanced chromosome sets is still sparse. Plants generally tolerate aneuploidy better than animals, and, through colchicine treatment and breeding strategies, it is possible to obtain inbred sibling plants with different numbers of chromosomes. This possibility, combined with the genetic and genomics tools available for Arabidopsis thaliana, provides a powerful means to assess systematically the molecular and cytological consequences of aberrant numbers of specific chromosomes. Here, we report on the generation of Arabidopsis plants in which chromosome 5 is present in triplicate. We compare the global transcript profiles of normal diploids and chromosome 5 trisomics, and assess genome integrity using array comparative genome hybridization. We use live cell imaging to determine the interphase 3D arrangement of transgene-encoded fluorescent tags on chromosome 5 in trisomic and triploid plants. The results indicate that trisomy 5 disrupts gene expression throughout the genome and supports the production and/or retention of truncated copies of chromosome 5. Although trisomy 5 does not grossly distort the interphase arrangement of fluorescent-tagged sites on chromosome 5, it may somewhat enhance associations between transgene alleles. Our analysis reveals the complex genomic changes that can occur in aneuploids and underscores the importance of using multiple experimental approaches to investigate how chromosome numerical changes condition abnormal phenotypes and

  18. Molecular diagnostic testing for Klinefelter syndrome and other male sex chromosome aneuploidies

    Directory of Open Access Journals (Sweden)

    Hager Karl

    2012-04-01

    Full Text Available Abstract Background Male sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations. Objective To develop a non-invasive, rapid and high-throughput molecular diagnostic assay for detection of male sex chromosome aneuploidies, including 47,XXY (Klinefelter, 47,XYY, 48,XXYY and 48,XXXY syndromes. Methods The assay utilizes three XYM and four XA markers to interrogate Y:X and X:autosome ratios, respectively. The seven markers were PCR amplified using genomic DNA isolated from a cohort of 323 males with aneuploid (n = 117 and 46,XY (n = 206 karyotypes. The resulting PCR products were subjected to Pyrosequencing, a quantitative DNA sequencing method. Results Receiver operator characteristic (ROC curves were used to establish thresholds for the discrimination of aneuploid from normal samples. The XYM markers permitted the identification of 47,XXY, 48,XXXY and 47,XYY syndromes with 100% sensitivity and specificity in both purified DNA and buccal swab samples. The 48,XXYY karyotype was delineated by XA marker data from 46,XY; an X allele threshold of 43% also permitted detection of 48,XXYY with 100% sensitivity and specificity. Analysis of X chromosome-specific biallelic SNPs demonstrated that 43 of 45 individuals (96% with 48,XXYY karyotype had two distinct X chromosomes, while 2 (4% had a duplicate X, providing evidence that 48,XXYY may result from nondisjunction during early mitotic divisions of a 46,XY embryo. Conclusions Quantitative Pyrosequencing, with high-throughput potential, can detect male sex chromosome aneuploidies with 100% sensitivity.

  19. Short exposure to paclitaxel induces multipolar spindle formation and aneuploidy through promotion of acentrosomal pole assembly

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Paclitaxel is a widely used microtubule drug and cancer medicine. Here we report that by short exposure to paclitaxel at a low dose, multipolar spindles were induced in mitotic cells without centrosome amplification. Both TPX2 depletion and Aurora-A overexpression antagonized the multipolarity. Live cell imaging showed that some paclitaxel-treated cells accomplished multipolar cell division and a portion of the daughter cells went on to the next round of mitosis. The surviving cells grew into clones with varied genome content. The results indicated that an aneuploidy population could be induced by short exposure to paclitaxel at a low dose, implicating potential side effects of paclitaxel.

  20. Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis

    DEFF Research Database (Denmark)

    Friis-Ottessen, Mariann; Bendix, Laila; Kølvraa, Steen;

    2014-01-01

    Ulcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. Short telomeres have been reported in mucosal cells of UC patients. Telomeres are repetitive base sequences capping the ends of linear chromosomes......, and protect them from erosion and subsequent wrongful recombination and end-to-end joining during cell division. Short telomeres are associated with the development of chromosomal instability and aneuploidy, the latter being risk factors for development of dysplasia and cancer. Specifically, the abrupt...... shortening of one or more telomeres to a critical length, rather than bulk shortening of telomeres, seems to be associated with chromosomal instability....

  1. Correction of Down syndrome and Edwards syndrome aneuploidies in human cell cultures.

    Science.gov (United States)

    Amano, Tomokazu; Jeffries, Emiko; Amano, Misa; Ko, Akihiro C; Yu, Hong; Ko, Minoru S H

    2015-10-01

    Aneuploidy, an abnormal number of chromosomes, has previously been considered irremediable. Here, we report findings that euploid cells increased among cultured aneuploid cells after exposure to the protein ZSCAN4, encoded by a mammalian-specific gene that is ordinarily expressed in preimplantation embryos and occasionally in stem cells. For footprint-free delivery of ZSCAN4 to cells, we developed ZSCAN4 synthetic mRNAs and Sendai virus vectors that encode human ZSCAN4. Applying the ZSCAN4 biologics to established cultures of mouse embryonic stem cells, most of which had become aneuploid and polyploid, dramatically increased the number of euploid cells within a few days. We then tested the biologics on non-immortalized primary human fibroblast cells derived from four individuals with Down syndrome—the most frequent autosomal trisomy of chromosome 21. Within weeks after ZSCAN4 application to the cells in culture, fluorescent in situ hybridization with a chromosome 21-specific probe detected the emergence of up to 24% of cells with only two rather than three copies. High-resolution G-banded chromosomes further showed up to 40% of cells with a normal karyotype. These findings were confirmed by whole-exome sequencing. Similar results were obtained for cells with the trisomy 18 of Edwards syndrome. Thus a direct, efficient correction of aneuploidy in human fibroblast cells seems possible in vitro using human ZSCAN4.

  2. Prediction model for aneuploidy in early human embryo development revealed by single-cell analysis

    Science.gov (United States)

    Vera-Rodriguez, Maria; Chavez, Shawn L.; Rubio, Carmen; Pera, Renee A. Reijo; Simon, Carlos

    2015-01-01

    Aneuploidies are prevalent in the human embryo and impair proper development, leading to cell cycle arrest. Recent advances in imaging and molecular and genetic analyses are postulated as promising strategies to unveil the mechanisms involved in aneuploidy generation. Here we combine time-lapse, complete chromosomal assessment and single-cell RT–qPCR to simultaneously obtain information from all cells that compose a human embryo until the approximately eight-cell stage (n=85). Our data indicate that the chromosomal status of aneuploid embryos (n=26), including those that are mosaic (n=3), correlates with significant differences in the duration of the first mitotic phase when compared with euploid embryos (n=28). Moreover, gene expression profiling suggests that a subset of genes is differentially expressed in aneuploid embryos during the first 30 h of development. Thus, we propose that the chromosomal fate of an embryo is likely determined as early as the pronuclear stage and may be predicted by a 12-gene transcriptomic signature. PMID:26151134

  3. SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy

    Science.gov (United States)

    Samango-Sprouse, Carole; Banjevic, Milena; Ryan, Allison; Sigurjonsson, Styrmir; Zimmermann, Bernhard; Hill, Matthew; Hall, Megan P.; Westemeyer, Margaret; Saucier, Jennifer; Demko, Zachary; Rabinowitz, Matthew

    2013-01-01

    Objective To develop a single nucleotide polymorphism- and informatics-based non-invasive prenatal test that detects sex chromosome aneuploidies early in pregnancy. Methods Fifteen aneuploid samples, including thirteen 45,X, two 47,XXY, and one 47,XYY, along with 185 euploid controls, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex PCR assay that targeted 19,488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y, and sequenced. Sequencing results were analyzed using a Bayesian-based maximum likelihood statistical method to determine copy number of interrogated chromosomes, calculating sample-specific accuracies. Results Of the samples that passed a stringent quality control metric (93%), the algorithm correctly identified copy number at all five chromosomes in all 187 samples, for 934/935 correct calls as early as 9.4 weeks of gestation. We detected 45,X with 91.7% sensitivity (CI: 61.5-99.8%) and 100% specificity (CI: 97.9-100%), and 47,XXY and 47,XYY. The average calculated accuracy was 99.78%. Conclusion This method non-invasively detected 45,X, 47,XXY, and 47,XYY fetuses from cfDNA isolated from maternal plasma with high calculated accuracies, and thus offers a non-invasive method with the potential to function as a routine screen allowing for early prenatal detection of rarely diagnosed yet commonly occurring sex aneuploidies. PMID:23712453

  4. Human germ cell formation in xenotransplants of induced pluripotent stem cells carrying X chromosome aneuploidies.

    Science.gov (United States)

    Dominguez, Antonia A; Chiang, H Rosaria; Sukhwani, Meena; Orwig, Kyle E; Reijo Pera, Renee A

    2014-09-22

    Turner syndrome is caused by complete or partial loss of the second sex chromosome and is characterized by spontaneous fetal loss in >90% of conceptions. Survivors possess an array of somatic and germline clinical characteristics. Induced pluripotent stem cells (iPSCs) offer an opportunity for insight into genetic requirements of the X chromosome linked to Turner syndrome. We derived iPSCs from Turner syndrome and control individuals and examined germ cell development as a function of X chromosome composition. We demonstrate that two X chromosomes are not necessary for reprogramming or maintenance of pluripotency and that there are minimal differences in gene expression, at the single cell level, linked to X chromosome aneuploidies. Formation of germ cells, as assessed in vivo through a murine xenotransplantation model, indicated that undifferentiated iPSCs, independent of X chromosome composition, are capable of forming germ-cell-like cells (GCLCs) in vivo. In combination with clinical data regarding infertility in women with X chromosome aneuploidies, results suggest that two intact X chromosomes are not required for human germ cell formation, qualitatively or quantitatively, but rather are likely to be required for maintenance of human germ cells to adulthood.

  5. NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy.

    Science.gov (United States)

    Wilson, K L; Czerwinski, J L; Hoskovec, J M; Noblin, S J; Sullivan, C M; Harbison, A; Campion, M W; Devary, K; Devers, P; Singletary, C N

    2013-02-01

    The BUN and FASTER studies, two prospective multicenter trials in the United States, validated the accuracy and detection rates of first and second trimester screening previously reported abroad. These studies, coupled with the 2007 release of the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin that endorsed first trimester screening as an alternative to traditional second trimester multiple marker screening, led to an explosion of screening options available to pregnant women. ACOG also recommended that invasive diagnostic testing for chromosome aneuploidy be made available to all women regardless of maternal age. More recently, another option known as Non-invasive Prenatal Testing (NIPT) became available to screen for chromosome aneuploidy. While screening and testing options may be limited due to a variety of factors, healthcare providers need to be aware of the options in their area in order to provide their patients with accurate and reliable information. If not presented clearly, patients may feel overwhelmed at the number of choices available. The following guideline includes recommendations for healthcare providers regarding which screening or diagnostic test should be offered based on availability, insurance coverage, and timing of a patient's entry into prenatal care, as well as a triage assessment so that a general process can be adapted to unique situations.

  6. Proteomic profile determination of autosomal aneuploidies by mass spectrometry on amniotic fluids

    Directory of Open Access Journals (Sweden)

    Desmetz Caroline

    2008-01-01

    Full Text Available Abstract Background Prenatal diagnosis of chromosomal abnormalities by cytogenetic analysis is time-consuming, expensive, and requires highly qualified technicians. Rapid diagnosis of aneuploidies followed by reassurance of women with normal results can be performed by molecular analysis of uncultured foetal cells. In the present study, we developed a proteomic fingerprinting approach coupled with a statistical classification method to improve diagnosis of aneuploidies, including trisomies 13, 18, and 21, in amniotic fluid samples. Results The proteomic spectra obtained from 52 pregnant women were compiled, normalized, and mass peaks with mass-to-charge ratios between 2.5 and 50 kDa identified. Peak information was combined together and analysed using univariate statistics. Among the 208 expressed protein peaks, 40 differed significantly between aneuploid and non aneuploid samples, with AUC diagnostic values ranging from 0.71 to 0.91. Hierarchical clustering, principal component analysis and support vector machine (SVM analysis were performed. Two class predictor models were defined from the training set, which resulted in a prediction accuracy of 92.3% and 96.43%, respectively. Using an external and independent validation set, diagnostic accuracies were maintained at 87.5% and 91.67%, respectively. Conclusion This pilot study demonstrates the potential interest of protein expression signature in the identification of new potential biological markers that might be helpful for the rapid clinical management of high-risk pregnancies.

  7. Analysis of micronuclei and microtubule arrangement to identify aneuploidy-inducing agents in cultured mammalian cells

    Energy Technology Data Exchange (ETDEWEB)

    Degrassi, F.; Pisano, C. [Centre di Genetica Evoluzionistica, Rome (Italy); Tanzarella, C.; Antoccia, A.; Battistoni, A. [Universita La Sapienza, Rome (Italy)

    1993-12-31

    The development of in vitro test methods to detect environmental agents that might induce aneuploidy is of crucial importance in genotoxicity testing. Chromosome numerical changes may arise from damage to various cell structures and activities such as spindle components or kinetochore proteins as well as from damage to the chromosomes. Therefore, the development of effective assays to identify chromosome misdistribution in mammalian cell cultures requires the contribution of different research areas such as cytogenetics, molecular biology and cell biology. Recently, we have been working at the development of an in vitro test for aneuploidy-inducing agents combining the micronucleus assay with the immunofluorescent staining of kinetochores in micronuclei (MN). The assay has been standardized by analyzing the induction of MN containing kinetochores (CREST-positive MN) after a number of agents with different mechanism of action. Subsequently, the optimization of the assay has been carried out by introducing cytochalasin-B (cyt-B) in the test protocol in order to score MN in cells that have undergone one cell cycle. Finally, with the aim of providing an understanding of the mechanisms responsible for the production of CREST-positive MN we have analyzed the cellular structures involved in mitotic division by using specific antibodies in immunofluorescence studies.

  8. Prenatal detection of aneuploidy and imbalanced chromosomal arrangements by massively parallel sequencing.

    Directory of Open Access Journals (Sweden)

    Shan Dan

    Full Text Available Fetal chromosomal abnormalities are the most common reasons for invasive prenatal testing. Currently, G-band karyotyping and several molecular genetic methods have been established for diagnosis of chromosomal abnormalities. Although these testing methods are highly reliable, the major limitation remains restricted resolutions or can only achieve limited coverage on the human genome at one time. The massively parallel sequencing (MPS technologies which can reach single base pair resolution allows detection of genome-wide intragenic deletions and duplication challenging karyotyping and microarrays as the tool for prenatal diagnosis. Here we reported a novel and robust MPS-based method to detect aneuploidy and imbalanced chromosomal arrangements in amniotic fluid (AF samples. We sequenced 62 AF samples on Illumina GAIIx platform and with averagely 0.01× whole genome sequencing data we detected 13 samples with numerical chromosomal abnormalities by z-test. With up to 2× whole genome sequencing data we were able to detect microdeletion/microduplication (ranged from 1.4 Mb to 37.3 Mb of 5 samples from chorionic villus sampling (CVS using SeqSeq algorithm. Our work demonstrated MPS is a robust and accurate approach to detect aneuploidy and imbalanced chromosomal arrangements in prenatal samples.

  9. Haplotype mapping of a diploid non-meiotic organism using existing and induced aneuploidies.

    Directory of Open Access Journals (Sweden)

    Melanie Legrand

    2008-01-01

    Full Text Available Haplotype maps (HapMaps reveal underlying sequence variation and facilitate the study of recombination and genetic diversity. In general, HapMaps are produced by analysis of Single-Nucleotide Polymorphism (SNP segregation in large numbers of meiotic progeny. Candida albicans, the most common human fungal pathogen, is an obligate diploid that does not appear to undergo meiosis. Thus, standard methods for haplotype mapping cannot be used. We exploited naturally occurring aneuploid strains to determine the haplotypes of the eight chromosome pairs in the C. albicans laboratory strain SC5314 and in a clinical isolate. Comparison of the maps revealed that the clinical strain had undergone a significant amount of genome rearrangement, consisting primarily of crossover or gene conversion recombination events. SNP map haplotyping revealed that insertion and activation of the UAU1 cassette in essential and non-essential genes can result in whole chromosome aneuploidy. UAU1 is often used to construct homozygous deletions of targeted genes in C. albicans; the exact mechanism (trisomy followed by chromosome loss versus gene conversion has not been determined. UAU1 insertion into the essential ORC1 gene resulted in a large proportion of trisomic strains, while gene conversion events predominated when UAU1 was inserted into the non-essential LRO1 gene. Therefore, induced aneuploidies can be used to generate HapMaps, which are essential for analyzing genome alterations and mitotic recombination events in this clonal organism.

  10. BACs-on-Beads Technology: A Reliable Test for Rapid Detection of Aneuploidies and Microdeletions in Prenatal Diagnosis

    Science.gov (United States)

    Martínez-Conejero, José Antonio; Serra, Vicente; Olmo, Inés; Lara, Coral; Simón, Carlos

    2014-01-01

    The risk of fetal aneuploidies is usually estimated based on high resolution ultrasound combined with biochemical determination of criterion in maternal blood, with invasive procedures offered to the population at risk. The purpose of this study was to investigate the effectiveness of a new rapid aneuploidy screening test on amniotic fluid (AF) or chorionic villus (CV) samples based on BACs-on-Beads (BoBs) technology and to compare the results with classical karyotyping by Giemsa banding (G-banding) of cultured cells in metaphase as the gold standard technique. The prenatal-BoBs kit was used to study aneuploidies involving chromosomes 13, 18, 21, X, and Y as well as nine microdeletion syndromes in 321 AF and 43 CV samples. G-banding of metaphase cultured cells was performed concomitantly for all prenatal samples. A microarray-based comparative genomic hybridization (aCGH) was also carried out in a subset of samples. Prenatal-BoBs results were widely confirmed by classical karyotyping. Only six karyotype findings were not identified by Prenatal-BoBs, all of them due to the known limitations of the technique. In summary, the BACs-on-Beads technology was an accurate, robust, and efficient method for the rapid diagnosis of common aneuploidies and microdeletion syndromes in prenatal samples. PMID:24795887

  11. Social Deficits in Male Children and Adolescents with Sex Chromosome Aneuploidy: A Comparison of XXY, XYY, and XXYY Syndromes

    Science.gov (United States)

    Cordeiro, Lisa; Tartaglia, Nicole; Roeltgen, David; Ross, Judith

    2012-01-01

    We compare social skills in three groups of males with sex chromosome aneuploidies (SCAs) using the Social Responsiveness Scale (SRS). Participants included males with XXY (N = 102, M = 10.08 years), XYY (N = 40, M = 9.93 years), and XXYY (N = 32, M = 11.57 years). XXY had lower (better) SRS scores compared to XYY and XXYY. Scores were not…

  12. Drug resistance in colorectal cancer cell lines is partially associated with aneuploidy status in light of profiling gene expression

    DEFF Research Database (Denmark)

    Guo, Jiao; Xu, Shaohang; Huang, Xuanlin

    2016-01-01

    colorectal cancer cells, HCT116 and LoVo, were cultured with the chemotherapeutic drugs irinotecan (SN38) or oxaliplatin (QxPt), and the non- and drug-resistant cell lines were selected. Whole exome sequencing (WES) was employed to evaluate the aneuploidy status of these cells, and RNAseq and LC-MS/MS were...

  13. BACs-on-Beads technology: a reliable test for rapid detection of aneuploidies and microdeletions in prenatal diagnosis.

    Science.gov (United States)

    García-Herrero, Sandra; Campos-Galindo, Inmaculada; Martínez-Conejero, José Antonio; Serra, Vicente; Olmo, Inés; Lara, Coral; Simón, Carlos; Rubio, Carmen

    2014-01-01

    The risk of fetal aneuploidies is usually estimated based on high resolution ultrasound combined with biochemical determination of criterion in maternal blood, with invasive procedures offered to the population at risk. The purpose of this study was to investigate the effectiveness of a new rapid aneuploidy screening test on amniotic fluid (AF) or chorionic villus (CV) samples based on BACs-on-Beads (BoBs) technology and to compare the results with classical karyotyping by Giemsa banding (G-banding) of cultured cells in metaphase as the gold standard technique. The prenatal-BoBs kit was used to study aneuploidies involving chromosomes 13, 18, 21, X, and Y as well as nine microdeletion syndromes in 321 AF and 43 CV samples. G-banding of metaphase cultured cells was performed concomitantly for all prenatal samples. A microarray-based comparative genomic hybridization (aCGH) was also carried out in a subset of samples. Prenatal-BoBs results were widely confirmed by classical karyotyping. Only six karyotype findings were not identified by Prenatal-BoBs, all of them due to the known limitations of the technique. In summary, the BACs-on-Beads technology was an accurate, robust, and efficient method for the rapid diagnosis of common aneuploidies and microdeletion syndromes in prenatal samples.

  14. BACs-on-Beads Technology: A Reliable Test for Rapid Detection of Aneuploidies and Microdeletions in Prenatal Diagnosis

    Directory of Open Access Journals (Sweden)

    Sandra García-Herrero

    2014-01-01

    Full Text Available The risk of fetal aneuploidies is usually estimated based on high resolution ultrasound combined with biochemical determination of criterion in maternal blood, with invasive procedures offered to the population at risk. The purpose of this study was to investigate the effectiveness of a new rapid aneuploidy screening test on amniotic fluid (AF or chorionic villus (CV samples based on BACs-on-Beads (BoBs technology and to compare the results with classical karyotyping by Giemsa banding (G-banding of cultured cells in metaphase as the gold standard technique. The prenatal-BoBs kit was used to study aneuploidies involving chromosomes 13, 18, 21, X, and Y as well as nine microdeletion syndromes in 321 AF and 43 CV samples. G-banding of metaphase cultured cells was performed concomitantly for all prenatal samples. A microarray-based comparative genomic hybridization (aCGH was also carried out in a subset of samples. Prenatal-BoBs results were widely confirmed by classical karyotyping. Only six karyotype findings were not identified by Prenatal-BoBs, all of them due to the known limitations of the technique. In summary, the BACs-on-Beads technology was an accurate, robust, and efficient method for the rapid diagnosis of common aneuploidies and microdeletion syndromes in prenatal samples.

  15. Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer's disease neurons

    NARCIS (Netherlands)

    van den Bos, Hilda; Spierings, Diana C J; Taudt, Aaron S; Bakker, Bjorn; Porubský, David; Falconer, Ester; Novoa, Carolina; Halsema, Nancy; Kazemier, Hinke G; Hoekstra-Wakker, Karina; Guryev, Victor; den Dunnen, Wilfred F A; Foijer, Floris; Tatché, Maria Colomé; Boddeke, Hendrikus W G M; Lansdorp, Peter M

    2016-01-01

    BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease of the brain and the most common form of dementia in the elderly. Aneuploidy, a state in which cells have an abnormal number of chromosomes, has been proposed to play a role in neurodegeneration in AD patients. Several studies using

  16. Individualized choice in prenatal diagnosis : the impact of karyotyping and standalone rapid aneuploidy detection on quality of life

    NARCIS (Netherlands)

    Boormans, E. M. A.; Birnie, E.; Oepkes, D.; Boekkooi, P. F.; Bonsel, G. J.; van Lith, J. M. M.

    2010-01-01

    Objective To assess the reasons and perceptions of women who are offered a choice between karyotyping and standalone rapid aneuploidy detection (RAD) and to compare the impact of both tests on anxiety and health-related quality of life Methods In this prospective comparative study, women undergoing

  17. Cell-free fetal DNA and cell-free total DNA levels in spontaneous abortion with fetal chromosomal aneuploidy.

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    Ji Hyae Lim

    Full Text Available BACKGROUND: Cell-free fetal DNA and cell-free total DNA in maternal circulation have been proposed as potential markers for noninvasive monitoring of the placental condition during the pregnancy. However, the correlation of and change in cell-free fetal DNA and cell-free total DNA in spontaneous abortion (SA with fetal chromosomal aneuploidy have not yet been reported. Therefore, we investigated cell-free fetal DNA and cell-free total DNA levels in SA women with fetal chromosomal aneuploidy. METHODOLOGY/PRINCIPAL FINDINGS: A nested case-control study was conducted with maternal plasma collected from 268 women in their first trimester of pregnancy. Subjects included 41 SA with normal fetal karyotype, 26 SA with fetal chromosomal aneuploidy, and 201 normal controls. The unmethylated PDE9A gene was used to measure the maternal plasma levels of cell-free fetal DNA. The GAPDH gene was used to measure the maternal plasma levels of cell-free total DNA. The diagnostic accuracy was measured using receiver-operating characteristic (ROC curves. Levels of cell-free fetal DNA and cell-free total DNA were significantly higher in both SA women with normal fetal karyotype and SA women with fetal chromosomal aneuploidy in comparison with the normal controls (P<0.001 in both. The correlation between cell-free fetal DNA and cell-free total DNA levels was stronger in the normal controls (r = 0.843, P<0.001 than in SA women with normal karyotype (r = 0.465, P = 0.002 and SA women with fetal chromosomal aneuploidy (r = 0.412, P = 0.037. The area under the ROC curve for cell-free fetal DNA and cell-free total DNA was 0.898 (95% CI, 0.852-0.945 and 0.939 (95% CI, 0.903-0.975, respectively. CONCLUSIONS: Significantly high levels of cell-free fetal DNA and cell-free total DNA were found in SA women with fetal chromosomal aneuploidy. Our findings suggest that cell-free fetal DNA and cell-free total DNA may be useful biomarkers for the prediction of SA

  18. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.

    Science.gov (United States)

    Dondorp, Wybo; de Wert, Guido; Bombard, Yvonne; Bianchi, Diana W; Bergmann, Carsten; Borry, Pascal; Chitty, Lyn S; Fellmann, Florence; Forzano, Francesca; Hall, Alison; Henneman, Lidewij; Howard, Heidi C; Lucassen, Anneke; Ormond, Kelly; Peterlin, Borut; Radojkovic, Dragica; Rogowski, Wolf; Soller, Maria; Tibben, Aad; Tranebjærg, Lisbeth; van El, Carla G; Cornel, Martina C

    2015-11-01

    This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non

  19. Correlation study between sperm concentration, hyaluronic acid-binding capacity and sperm aneuploidy in Hungarian patients.

    Science.gov (United States)

    Mokánszki, Attila; Molnár, Zsuzsanna; Ujfalusi, Anikó; Balogh, Erzsébet; Bazsáné, Zsuzsa Kassai; Varga, Attila; Jakab, Attila; Oláh, Éva

    2012-12-01

    Infertile men with low sperm concentration and/or less motile spermatozoa have an increased risk of producing aneuploid spermatozoa. Selecting spermatozoa by hyaluronic acid (HA) binding may reduce genetic risks such as chromosomal rearrangements and numerical aberrations. Fluorescence in-situ hybridization (FISH) has been used to evaluate the presence of aneuploidies. This study examined spermatozoa of 10 oligozoospermic, 9 asthenozoospermic, 9 oligoasthenozoospermic and 17 normozoospermic men by HA binding and FISH. Mean percentage of HA-bound spermatozoa in the normozoospermic group was 81%, which was significantly higher than in the oligozoospermic (Psex chromosomes (P=0.014) and chromosome 17 (P=0.0019), diploidy (P=0.03) and estimated numerical chromosome aberrations (P=0.004) were significantly higher in the oligoasthenozoospermic group compared with the other groups. There were statistically significant relationships (Pchromosome aberrations (r=-0.668) and between HA binding and estimated numerical chromosome aberrations (r=-0.682). HA binding and aneuploidy studies of spermatozoa in individual cases allow prediction of reproductive prognosis and provision of appropriate genetic counselling. Infertile men with normal karyotypes and low sperm concentrations and/or less motile spermatozoa have significantly increased risks of producing aneuploid (diminished mature) spermatozoa. Selecting spermatozoa by hyaluronic acid (HA) binding, based on a binding between sperm receptors for zona pellucida and HA, may reduce the potential genetic risks such as chromosomal rearrangements and numerical aberrations. In the present study we examined sperm samples of 45 men with different sperm parameters by HA-binding assay and fluorescence in-situ hybridization (FISH). Mean percentage of HA-bound spermatozoa in the normozoospermic group was significantly higher than the oligozoospermic, the asthenozoospermic and the oligoasthenozoospermic groups. Using FISH, disomy of sex

  20. Non-invasive prenatal chromosomal aneuploidy testing--clinical experience: 100,000 clinical samples.

    Directory of Open Access Journals (Sweden)

    Ron M McCullough

    Full Text Available OBJECTIVE: As the first laboratory to offer massively parallel sequencing-based noninvasive prenatal testing (NIPT for fetal aneuploidies, Sequenom Laboratories has been able to collect the largest clinical population experience data to date, including >100,000 clinical samples from all 50 U.S. states and 13 other countries. The objective of this study is to give a robust clinical picture of the current laboratory performance of the MaterniT21 PLUS LDT. STUDY DESIGN: The study includes plasma samples collected from patients with high-risk pregnancies in our CLIA-licensed, CAP-accredited laboratory between August 2012 to June 2013. Samples were assessed for trisomies 13, 18, 21 and for the presence of chromosome Y-specific DNA. Sample data and ad hoc outcome information provided by the clinician was compiled and reviewed to determine the characteristics of this patient population, as well as estimate the assay performance in a clinical setting. RESULTS: NIPT patients most commonly undergo testing at an average of 15 weeks, 3 days gestation; and average 35.1 years of age. The average turnaround time is 4.54 business days and an overall 1.3% not reportable rate. The positivity rate for Trisomy 21 was 1.51%, followed by 0.45% and 0.21% rate for Trisomies 18 and 13, respectively. NIPT positivity rates are similar to previous large clinical studies of aneuploidy in women of maternal age ≥ 35 undergoing amniocentesis. In this population 3519 patients had multifetal gestations (3.5% with 2.61% yielding a positive NIPT result. CONCLUSION: NIPT has been commercially offered for just over 2 years and the clinical use by patients and clinicians has increased significantly. The risks associated with invasive testing have been substantially reduced by providing another assessment of aneuploidy status in high-risk patients. The accuracy and NIPT assay positivity rate are as predicted by clinical validations and the test demonstrates improvement in the

  1. DNA aneuploidy and breast cancer: a meta-analysis of 141,163 cases

    Science.gov (United States)

    Li, Jun

    2016-01-01

    Background & Aims DNA ploidy, a DNA flow cytometry parameter, reflects tumor cell cycle. In breast cancer (BC), ploidy status characterizes genotypic stability and potential metastatic capacity. It is suggested that aneuploidy is an independent prognosticator for BC patients and could aid for individualized medicine. There are extensive studies concerning the prognostic significance of DNA aneuploidy, however, its clinical utility remains controversial. Herein we conducted a meta-analysis to determine the correlation between DNA ploidy status and BC characteristics and survival. Methods The electronic databases PubMed, EMBASE, and Web of Science were searched for relevant studies. The major investigated parameters were the BC aneuploidy rates in relation to tumor stage, size, lymph node metastasis, grading, estrogen receptor (ER) status, disease-free survival (DFS), and overall survival (OS). Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for DFS and OS were extracted from each study before meta-analyzed. Risk ratios (RRs) were computed using the fixed-effect or random-effects model according to data heterogeneity, and the Mantel-Haenszel or the inverse-variance method was adopted where appropriate to obtain pooled estimates using RevMan 5.3. The Egger's test was conducted with Stata 11. Results Pooled analyses of data from 29 studies involving a total of 141,163 cases showed that BC patients with more advanced tumors (stage I vs. stages II-IV, RR=0.84; 95% CI, 0.74 to 0.96; P=0.01), larger tumors (≤2 cm vs. >2 cm: RR=0.82; 95% CI, 0.77 to 0.87; P<0.00001), lymph node metastasis (pN0 vs. pN1-3: RR=0.85; 95% CI, 0.83 to 0.87, P<0.00001), poorer tumor proliferation (G2 vs. G1: RR=1.58; 95% CI, 1.40 to 1.79; P<0.00001; G3 vs. G1: RR=2.17; 95% CI, 1.77 to 2.67; P<0.00001; G3 vs. G2: RR=1.41; 95% CI, 1.25 to 1.60; P<0.00001), and ER− status (ER− vs. ER+: RR=1.32; 95% CI, 1.22 to 1.43; P<0.00001) were significantly more frequently

  2. Suppression of allelic recombination and aneuploidy by cohesin is independent of Chk1 in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Shay Covo

    Full Text Available Sister chromatid cohesion (SCC, which is established during DNA replication, ensures genome stability. Establishment of SCC is inhibited in G2. However, this inhibition is relived and SCC is established as a response to DNA damage, a process known as Damage Induced Cohesion (DIC. In yeast, Chk1, which is a kinase that functions in DNA damage signal transduction, is considered an activator of SCC through DIC. Nonetheless, here we show that, unlike SCC mutations, loss of CHK1 did not increase spontaneous or damage-induced allelic recombination or aneuploidy. We suggest that Chk1 has a redundant role in the control of DIC or that DIC is redundant for maintaining genome stability.

  3. [Next generation sequencing and its applications in non-invasive prenatal testing of aneuploidies].

    Science.gov (United States)

    Babay, Lilla Éva; Horányi, Dániel; Rigó, János; Nagy, Gyula Richárd

    2015-06-28

    The development of the new generation sequencing techniques brought a new era in the field of DNA sequencing, that also revolutionized the prenatal screening for aneuploidy. In order to provide a more complete view, the authors describe some first generation methods as well as the theoretical and technical background of the next generation methods. In the second part of this review, the authors focuse on non-invasive prenatal testing, which is a fetal cell-free DNA based method requiring advanced sequencing procedures. After discussing the theoretical and technical background, the authors review current application and utility of non-invasive prenatal testing. They conclude that non-invasive prenatal testing is the most effective screening test in high risk pregnancies and its efficiency can be justified in studies involving low risk pregnancies as well.

  4. Suppression of Allelic Recombination and Aneuploidy by Cohesin Is Independent of Chk1 in Saccharomyces cerevisiae

    Science.gov (United States)

    Gordenin, Dmitry A.; Resnick, Michael A.

    2014-01-01

    Sister chromatid cohesion (SCC), which is established during DNA replication, ensures genome stability. Establishment of SCC is inhibited in G2. However, this inhibition is relived and SCC is established as a response to DNA damage, a process known as Damage Induced Cohesion (DIC). In yeast, Chk1, which is a kinase that functions in DNA damage signal transduction, is considered an activator of SCC through DIC. Nonetheless, here we show that, unlike SCC mutations, loss of CHK1 did not increase spontaneous or damage-induced allelic recombination or aneuploidy. We suggest that Chk1 has a redundant role in the control of DIC or that DIC is redundant for maintaining genome stability. PMID:25551702

  5. Rapid detection of chromosome 18 aneuploidies in amniocytes by using primed in situ labeling (PRINS) technique

    Institute of Scientific and Technical Information of China (English)

    杨建滨; 郑树

    2002-01-01

    This paper presents a feasible method for rapid detection of the interphase nuclei of uncultured amniocytes for chromosomes 18 by using our modified primed in situ labeling (PRINS) technique. A total of 262 independent, uncultured amniotic fluid samples were analysed in a blind fashion before the karyotype was available. In addition, 62 samples were examined by fluorescence in situ hybridization (FISH) for comparison. In more than 95% of the samples PRINS reactions with primer 18cen were successfully induced. Two samples were properly identified and correctly scored as trisomic 18. PRINS reaction could be performed automatically in less than one hour with a programmable thermocycler. Our studies showed that the PRINS technique is simple, rapid and cost-effective. It is as sensitive and specific as FISH; can enhance the accuracy of standard cytogenetic analysis; and allows identification of chromosomes 18 aneuploidies in uncultured amniocytes in significantly less time.

  6. Incidence of X and Y Chromosomal Aneuploidy in a Large Child Bearing Population

    Science.gov (United States)

    Kırkızlar, Eser; Hall, Megan P.; Demko, Zachary; Zneimer, Susan M.; Curnow, Kirsten J.; Gross, Susan; Gropman, Andrea

    2016-01-01

    Background X&Y chromosomal aneuploidies are among the most common human whole-chromosomal copy number changes, but the population-based incidence and prevalence in the child-bearing population is unclear. Methods This retrospective analysis of prospectively collected data leveraged a routine non-invasive prenatal test (NIPT) using parental genotyping to estimate the population-based incidence of X&Y chromosome variations in this population referred for NIPT (generally due to advanced maternal age). Results From 141,916 women and 29,336 men, 119 X&Y chromosomal abnormalities (prevalence: 1 in 1,439) were identified. Maternal findings include: 43 cases of 45,X (40 mosaic); 30 cases of 47,XXX (12 mosaic); 3 cases of 46,XX uniparental disomy; 2 cases of 46,XY/46,XX; 23 cases of mosaicism of unknown type; 2 cases of 47,XX,i(X)(q10). Paternal findings include: 2 cases of 47,XXY (1 mosaic); 10 cases of 47,XYY (1 mosaic); 4 partial Y deletions. Conclusions Single chromosome aneuploidy was present in one of every 1,439 individuals considered in this study, showing 47,XXX; 47,XX,i(X)(q10); 47,XYY; 47,XXY, partial Y deletions, and a high level of mosaicism for 45,X. This expands significantly our understanding of X&Y chromosomal variations and fertility issues, and is critical for families and adults affected by these disorders. This current and extensive information on fertility will be beneficial for genetic counseling on prenatal diagnoses as well as for newly diagnosed postnatal cases. PMID:27512996

  7. Fen1 mutations that specifically disrupt its interaction with PCNA cause aneuploidy-associated cancer

    Institute of Scientific and Technical Information of China (English)

    Li Zheng; Sankar Mitra; Qin Huang; Kemp H Kernstine; Gerd P Pfeifer; Binghui Shen; Huifang Dai; Muralidhar L Hegde; Mian Zhou; Zhigang Guo; Xiwei Wu; Jun WU; Lei Su; Xueyan Zhong

    2011-01-01

    DNA replication and repair are critical processes for all living organisms to ensure faithful duplication and transmission of genetic information. Flap endonuclease 1 (Feni), a structure-specific nuclease, plays an important role in multiple DNA metabolic pathways and maintenance of genome stability. Human FEN1 mutations that impair its exonuclease activity have been linked to cancer development. FEN1 interacts with multiple proteins, including proliferation cell nuclear antigen (PCNA), to form various functional complexes. Interactions with these proteins are considered to be the key molecular mechanisms mediating FEN1's key biological functions. The current challenge is to experimentally demonstrate the biological consequence of a specific interaction without compromising other functions of a desired protein. To address this issue, we established a mutant mouse model harboring a FEN1 point mutation (F343A/F344A, FFAA), which specifically abolishes the FEN1/PCNA interaction. We show that the FFAA mutation causes defects in RNA primer removal and long-patch base excision repair, even in the heterozygous state, resulting in numerous DNA breaks. These breaks activate the G2/M checkpoint protein, Chk1, and induce neartetraploid aneuploidy, commonly observed in human cancer, consequently elevating the transformation frequency. Consistent with this, inhibition of aneupioidy formation by a Chk1 inhibitor significantly suppressed the cellular transformation. WT/FFAA FEN1 mutant mice develop aneuploidy-associated cancer at a high frequency. Thus, this study establishes an exemplary case for investigating the biological significance of protein-protein interactions by knock-in of a point mutation rather than knock-out of a whole gene.

  8. Reduction in sperm aneuploidy levels in severe oligoasthenoteratospermic patients after medical therapy: a preliminary report

    Institute of Scientific and Technical Information of China (English)

    Giorgio Cavallini; Maria Cristina Magli; Andor Crippa; Anna Pia Ferraretti; Luca Gianaroli

    2012-01-01

    The objective of this study was to investigate whether medical therapy can reduce sperm aneuploidy levels and improve the results of intracytoplasmic sperm injection (ICSI) in patients with severe idiopathic oligoasthenoteratospermia (OAT).Thirty-three infertile couples requiring ICSI because of severe idiopathic OAT after at least one unsuccessful ICSI cycle were considered.Semen parameters (concentration,motility and morphology),the percentage of aneuploid sperm and the results of ICSI (the number of oocytes fertilized,embryos transferred,biochemical pregnancies,clinical pregnancies and live births) were compared before and after a 3-month course of treatment with L-carnitine 1 g given twice per day+acetyl-L-carnitine 500 mg given twice per day+one 30-mg cinnoxicam tablet every 4 days.Aneuploidy was assessed using fluorescent in situ hybridisation (FISH) performed on chromosomes X,Y,13,15,16,17,18,21 and 22.The results showed that 22 of the 33 patients had a reduced frequency of aneuploid sperm and improved sperm morphology after treatment (group 1),and 11 showed no change (group 2).The numbers of biochemical pregnancies,clinical pregnancies and live births were significantly higher in group 1 than in group 2.No significant difference was found between the groups regarding the numbers of oocytes fertilized and embryos transferred.The side effects were negligible.The numbers of ICSI pregnancies and live births in severe idiopathic OAT patients improved with a course of L-carnitine,acetyI-L-carnitine and cinnoxicam.

  9. Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death

    Directory of Open Access Journals (Sweden)

    Anne-Laure Bougé

    2016-03-01

    Full Text Available In neurodegenerative diseases such as Alzheimer's disease (AD, cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown, in particular with respect to the microtubule (MT-binding protein Tau, which is found in excess in the brain and cerebrospinal fluid of affected individuals. Although it has long been known that Tau is phosphorylated during mitosis to generate a lower affinity for MTs, there is, to our knowledge, no indication that an excess of this protein could affect mitosis. Here, we studied the effect of an excess of human Tau (hTau protein on cell mitosis in vivo. Using the Drosophila developing wing disc epithelium as a model, we show that an excess of hTau induces a mitotic arrest, with the presence of monopolar spindles. This mitotic defect leads to aneuploidy and apoptotic cell death. We studied the mechanism of action of hTau and found that the MT-binding domain of hTau is responsible for these defects. We also demonstrate that the effects of hTau occur via the inhibition of the function of the kinesin Klp61F, the Drosophila homologue of kinesin-5 (also called Eg5 or KIF11. We finally show that this deleterious effect of hTau is also found in other Drosophila cell types (neuroblasts and tissues (the developing eye disc, as well as in human HeLa cells. By demonstrating that MT-bound Tau inhibits the Eg5 kinesin and cell mitosis, our work provides a new framework to consider the role of Tau in neurodegenerative diseases.

  10. Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death.

    Science.gov (United States)

    Bougé, Anne-Laure; Parmentier, Marie-Laure

    2016-03-01

    In neurodegenerative diseases such as Alzheimer's disease (AD), cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown, in particular with respect to the microtubule (MT)-binding protein Tau, which is found in excess in the brain and cerebrospinal fluid of affected individuals. Although it has long been known that Tau is phosphorylated during mitosis to generate a lower affinity for MTs, there is, to our knowledge, no indication that an excess of this protein could affect mitosis. Here, we studied the effect of an excess of human Tau (hTau) protein on cell mitosis in vivo. Using the Drosophila developing wing disc epithelium as a model, we show that an excess of hTau induces a mitotic arrest, with the presence of monopolar spindles. This mitotic defect leads to aneuploidy and apoptotic cell death. We studied the mechanism of action of hTau and found that the MT-binding domain of hTau is responsible for these defects. We also demonstrate that the effects of hTau occur via the inhibition of the function of the kinesin Klp61F, the Drosophila homologue of kinesin-5 (also called Eg5 or KIF11). We finally show that this deleterious effect of hTau is also found in other Drosophila cell types (neuroblasts) and tissues (the developing eye disc), as well as in human HeLa cells. By demonstrating that MT-bound Tau inhibits the Eg5 kinesin and cell mitosis, our work provides a new framework to consider the role of Tau in neurodegenerative diseases.

  11. Adaptive aneuploidy protects against thiol peroxidase deficiency by increasing respiration via key mitochondrial proteins.

    Science.gov (United States)

    Kaya, Alaattin; Gerashchenko, Maxim V; Seim, Inge; Labarre, Jean; Toledano, Michel B; Gladyshev, Vadim N

    2015-08-25

    Aerobic respiration is a fundamental energy-generating process; however, there is cost associated with living in an oxygen-rich environment, because partially reduced oxygen species can damage cellular components. Organisms evolved enzymes that alleviate this damage and protect the intracellular milieu, most notably thiol peroxidases, which are abundant and conserved enzymes that mediate hydrogen peroxide signaling and act as the first line of defense against oxidants in nearly all living organisms. Deletion of all eight thiol peroxidase genes in yeast (∆8 strain) is not lethal, but results in slow growth and a high mutation rate. Here we characterized mechanisms that allow yeast cells to survive under conditions of thiol peroxidase deficiency. Two independent ∆8 strains increased mitochondrial content, altered mitochondrial distribution, and became dependent on respiration for growth but they were not hypersensitive to H2O2. In addition, both strains independently acquired a second copy of chromosome XI and increased expression of genes encoded by it. Survival of ∆8 cells was dependent on mitochondrial cytochrome-c peroxidase (CCP1) and UTH1, present on chromosome XI. Coexpression of these genes in ∆8 cells led to the elimination of the extra copy of chromosome XI and improved cell growth, whereas deletion of either gene was lethal. Thus, thiol peroxidase deficiency requires dosage compensation of CCP1 and UTH1 via chromosome XI aneuploidy, wherein these proteins support hydroperoxide removal with the reducing equivalents generated by the electron transport chain. To our knowledge, this is the first evidence of adaptive aneuploidy counteracting oxidative stress.

  12. Comprehensive embryo analysis of advanced maternal age-related aneuploidies and mosaicism by short comparative genomic hybridization.

    Science.gov (United States)

    Rius, Mariona; Daina, Gemma; Obradors, Albert; Ramos, Laia; Velilla, Esther; Fernández, Sílvia; Martínez-Passarell, Olga; Benet, Jordi; Navarro, Joaquima

    2011-01-01

    The short comparative genomic hybridization (short-CGH) method was used to perform a comprehensive cytogenetic study of isolated blastomeres from advanced maternal age embryos, discarded after fluorescent in situ hybridization (FISH) preimplantation genetic screening (PGS), detecting aneuploidies (38.5% of which corresponded to chromosomes not screened by 9-chromosome FISH), structural aberrations (31.8%), and mosaicism (77.3%). The short-CGH method was subsequently applied in one PGS, achieving a twin pregnancy.

  13. Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy

    DEFF Research Database (Denmark)

    Ottesen, Anne-Marie; Aksglaede, Lise; Garn, Inger

    2010-01-01

    chromosome aneuploidy and (2) to determine the number of SHOX copies in a subgroup of these patients (n = 255) these patients and 74 healthy controls. Median height standard deviation scores in 46,XX males (n = 6) were -1.2 (-2.8 to 0.3), +0.9 (-2.2 to +4.6) in 47,XXY (n = 129), +1.3 (-1.8 to +4.9) in 47,XYY...

  14. Investigation of the frequency of chromosomal aneuploidy using triple fluorescence in situ hybridization in 12 Chinese infertile men

    Institute of Scientific and Technical Information of China (English)

    张群芳; 卢光琇

    2004-01-01

    Background Chromosomal aberrations are the major cause of pre-and post-implantation embryo wastage and some studies suggest that half of all human conceptions have a chromosomal abnormality. A chromosomal aberration in human sperms is also one of the causes of failure of in vitro fertilization. This study was designed to ascertain whether chromosomal aneuploidy in spermatozoa is a risk factor for male infertility.Methods Twelve infertile men were divided into two groups: 10 with oligoasthenoteratozoospermia (OAT, Group A) and two with a normal semen analysis (Group B). Two normal healthy sperm donors acted as controls (Group C). We used fluorescence in situ hybridization (FISH) and probes for chromosomes X, Y and 18 to determine the frequency of aneuploidy.Results The frequencies of spermatozoa disomy for chromosomes X, Y and 18 were 0.30% and 0.30%, respectively, in Group B. The percentages were not significantly different from those of Group C (0.15% and 0. 16%). The frequencies of nullisomy for chromosomes X, Y and 18 were 0.15%and 0 for Group B, and 0 and 0.15% for Group C (P>0.05). In Group A, the incidences of disomy were 1.13% and 0. 96% and the frequencies of nullisomy were 1.13% and 1.60%. In these three groups, the incidences of diploidy were 0.60%, 1.00%, and 0.30%, respectively. Both the frequencies of disomic and nullisomic spermatozoa for chromosomes X, Y, and 18 and of diploid spermatozoa were significantly higher in Group A than in Groups B and C. The estimated total aneuploidy rates in the sperm from the three groups were 42.44%, 6.05%, and 2.59%,respectively.Conclusion These results indicate that chromosomal aneuploidy in spermatozoa may be a risk factor for infertility.

  15. Establishment of a 10-Plex Quantitative Fluorescent-PCR Assay for rapid diagnosis of sex chromosome aneuploidies.

    Directory of Open Access Journals (Sweden)

    Xingmei Xie

    Full Text Available Sex chromosome aneuploidies occur commonly in the general population, with an incidence of 1 in 400 newborns. However, no tests specifically targeting sex chromosomes have been carried out in prenatal diagnosis or newborn screening, resulting in late recognition of these diseases. In this study, a rapid diagnostic method for sex chromosome aneuploidies was established using Quantitative Fluorescent-PCR (QF-PCR. Ten markers were included in one multiplex QF-PCR assay, including two sex determination genes (AMXY and SRY, five X-linked short tandem repeats (STRs; DXS1053, DXS981, DXS6809, DXS1187, and DXS8377, one X/Y-common STR (X22, and two autosomal STRs (D13S305 and D21S11. Retrospective tests of 70 cases with known cytogenetic results indicated that the 10-plex QF-PCR assay could well determine sex chromosome copy numbers by both allelic peak numbers and a sex chromosome dosage calculation with the autosomal STRs as internal controls. Prospective comparison with cytogenetic karyotyping on 534 cases confirmed that the 10-plex QF-PCR assay could be well employed for sex chromosome aneuploidy diagnosis in at least the Chinese Han population. This is the first QF-PCR test for the diagnosis of sex chromosome aneuploidies in the Chinese population. This test is superior to previous designs by including up to 8 sex-linked markers covering different parts of sex chromosomes as well as employing internal controls for copy number dosage calculation in a single PCR reaction. Due to simple technique and data analysis, as well as easy implementation within routine clinical services, this method is of great clinical application value and could be widely applied.

  16. An adaptive detection method for fetal chromosomal aneuploidy using cell-free DNA from 447 Korean women

    Directory of Open Access Journals (Sweden)

    Sunshin Kim

    2016-10-01

    Full Text Available Abstract Background Noninvasive prenatal testing (NIPT using massively parallel sequencing of cell-free DNA (cfDNA is increasingly being used to predict fetal chromosomal abnormalities. However, concerns over erroneous predictions which occur while performing NIPT still exist in pregnant women at high risk for fetal aneuploidy. We performed the largest-scale clinical NIPT study in Korea to date to assess the risk of false negatives and false positives using next-generation sequencing. Methods A total of 447 pregnant women at high risk for fetal aneuploidy were enrolled at 12 hospitals in Korea. They underwent definitive diagnoses by full karyotyping by blind analysis and received aneuploidy screening at 11–22 weeks of gestation. Three steps were employed for cfDNA analyses. First, cfDNA was sequenced. Second, the effect of GC bias was corrected using normalization of samples as well as LOESS and linear regressions. Finally, statistical analysis was performed after selecting a set of reference samples optimally adapted to a test sample from the whole reference samples. We evaluated our approach by performing cfDNA testing to assess the risk of trisomies 13, 18, and 21 using the sets of extracted reference samples. Results The adaptive selection algorithm presented here was used to choose a more optimized reference sample, which was evaluated by the coefficient of variation (CV, demonstrated a lower CV and higher sensitivity than standard approaches. Our adaptive approach also showed that fetal aneuploidies could be detected correctly by clearly splitting the z scores obtained for positive and negative samples. Conclusions We show that our adaptive reference selection algorithm for optimizing trisomy detection showed improved reliability and will further support practitioners in reducing both false negative and positive results.

  17. Establishment of a 10-Plex Quantitative Fluorescent-PCR Assay for rapid diagnosis of sex chromosome aneuploidies.

    Science.gov (United States)

    Xie, Xingmei; Liang, Qiaoyi

    2014-01-01

    Sex chromosome aneuploidies occur commonly in the general population, with an incidence of 1 in 400 newborns. However, no tests specifically targeting sex chromosomes have been carried out in prenatal diagnosis or newborn screening, resulting in late recognition of these diseases. In this study, a rapid diagnostic method for sex chromosome aneuploidies was established using Quantitative Fluorescent-PCR (QF-PCR). Ten markers were included in one multiplex QF-PCR assay, including two sex determination genes (AMXY and SRY), five X-linked short tandem repeats (STRs; DXS1053, DXS981, DXS6809, DXS1187, and DXS8377), one X/Y-common STR (X22), and two autosomal STRs (D13S305 and D21S11). Retrospective tests of 70 cases with known cytogenetic results indicated that the 10-plex QF-PCR assay could well determine sex chromosome copy numbers by both allelic peak numbers and a sex chromosome dosage calculation with the autosomal STRs as internal controls. Prospective comparison with cytogenetic karyotyping on 534 cases confirmed that the 10-plex QF-PCR assay could be well employed for sex chromosome aneuploidy diagnosis in at least the Chinese Han population. This is the first QF-PCR test for the diagnosis of sex chromosome aneuploidies in the Chinese population. This test is superior to previous designs by including up to 8 sex-linked markers covering different parts of sex chromosomes as well as employing internal controls for copy number dosage calculation in a single PCR reaction. Due to simple technique and data analysis, as well as easy implementation within routine clinical services, this method is of great clinical application value and could be widely applied.

  18. Unisexual and heterosexual meiotic reproduction generate aneuploidy and phenotypic diversity de novo in the yeast Cryptococcus neoformans.

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    Min Ni

    2013-09-01

    Full Text Available Aneuploidy is known to be deleterious and underlies several common human diseases, including cancer and genetic disorders such as trisomy 21 in Down's syndrome. In contrast, aneuploidy can also be advantageous and in fungi confers antifungal drug resistance and enables rapid adaptive evolution. We report here that sexual reproduction generates phenotypic and genotypic diversity in the human pathogenic yeast Cryptococcus neoformans, which is globally distributed and commonly infects individuals with compromised immunity, such as HIV/AIDS patients, causing life-threatening meningoencephalitis. C. neoformans has a defined a-α opposite sexual cycle; however, >99% of isolates are of the α mating type. Interestingly, α cells can undergo α-α unisexual reproduction, even involving genotypically identical cells. A central question is: Why would cells mate with themselves given that sex is costly and typically serves to admix preexisting genetic diversity from genetically divergent parents? In this study, we demonstrate that α-α unisexual reproduction frequently generates phenotypic diversity, and the majority of these variant progeny are aneuploid. Aneuploidy is responsible for the observed phenotypic changes, as chromosome loss restoring euploidy results in a wild-type phenotype. Other genetic changes, including diploidization, chromosome length polymorphisms, SNPs, and indels, were also generated. Phenotypic/genotypic changes were not observed following asexual mitotic reproduction. Aneuploidy was also detected in progeny from a-α opposite-sex congenic mating; thus, both homothallic and heterothallic sexual reproduction can generate phenotypic diversity de novo. Our study suggests that the ability to undergo unisexual reproduction may be an evolutionary strategy for eukaryotic microbial pathogens, enabling de novo genotypic and phenotypic plasticity and facilitating rapid adaptation to novel environments.

  19. Meiotic behaviour and sperm aneuploidy in an infertile man with a mosaic 45,X/46,XY karyotype.

    Science.gov (United States)

    Ren, He; Chow, Victor; Ma, Sai

    2015-12-01

    The meiotic behaviour of the germ cells in 45,X/46,XY men has not been extensively studied. This study investigated the meiotic events and sperm aneuploidy in an azoospermic man with a 45,X/46,XY (50/50) mosaic karyotype to better understand the fate of the 45,X cells and the production of chromosomally abnormal spermatozoa. Combining immunofluorescence techniques and fluorescence in-situ hybridization, meiotic recombination, synapsis, meiotic sex chromosome inactivation (MSCI) and configuration were analysed, as well as sperm aneuploidy in the patient and 10 normal, fertile men. Despite the 50:50 somatic mosaicism in the patient, 25% of pachytene cells analysed were 45,X. Furthermore, 63% of pachytene cells were 46,XY with paired sex chromosomes, and 12% were 46,XY with unpaired sex chromosomes, which displayed abnormal MCSI patterns. Although the patient's testicular spermatozoa showed increased aneuploidy, the majority were of normal constitution. The X:Y sperm ratio was significantly increased compared with the controls (P < 0.001), which may indicate that some 45,X cells gave rise to X-bearing spermatozoa. The findings provide insight into the fate of 45,X/46,XY cells in meiosis, supporting the hypothesis that stringent checkpoints ensure the favourable production of spermatozoa with normal chromosomal constitution despite an individual's abnormal karyotype.

  20. Noninvasive Fetal Trisomy (NIFTY test: an advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies

    Directory of Open Access Journals (Sweden)

    Jiang Fuman

    2012-12-01

    Full Text Available Abstract Background Conventional prenatal screening tests, such as maternal serum tests and ultrasound scan, have limited resolution and accuracy. Methods We developed an advanced noninvasive prenatal diagnosis method based on massively parallel sequencing. The Noninvasive Fetal Trisomy (NIFTY test, combines an optimized Student’s t-test with a locally weighted polynomial regression and binary hypotheses. We applied the NIFTY test to 903 pregnancies and compared the diagnostic results with those of full karyotyping. Results 16 of 16 trisomy 21, 12 of 12 trisomy 18, two of two trisomy 13, three of four 45, X, one of one XYY and two of two XXY abnormalities were correctly identified. But one false positive case of trisomy 18 and one false negative case of 45, X were observed. The test performed with 100% sensitivity and 99.9% specificity for autosomal aneuploidies and 85.7% sensitivity and 99.9% specificity for sex chromosomal aneuploidies. Compared with three previously reported z-score approaches with/without GC-bias removal and with internal control, the NIFTY test was more accurate and robust for the detection of both autosomal and sex chromosomal aneuploidies in fetuses. Conclusion Our study demonstrates a powerful and reliable methodology for noninvasive prenatal diagnosis.

  1. Rapid and simultaneous detection of common aneuploidies by quadruplex real-time polymerase chain reaction combined with melting curve analysis

    Science.gov (United States)

    Lou, Jiwu; Sun, Manna; Zhao, Ying; Ji, Zhisong; Liu, Fenghua; Li, Dongzhi; Xu, Wanfang; Lin, Yangyang; Liu, Yanhui

    2017-01-01

    Background During the prenatal period, the number variation of chromosomes 13, 18, 21, X and Y accounts for more than 80% of the clinically significant chromosomal abnormalities diagnosed. Rapid tests for prenatal diagnosis of these abnormalities can improve pregnancy management and alleviate parental anxiety. Here, we present a molecular alternative method for detecting common aneuploidies. Methods This method is based on co-amplification of segmental duplications located on two different chromosomes using a single pair of primers. Segmental duplications have a high degree of sequence identity, but have single-nucleotide differences in some regions. These sequence differences can be quantified using melting curve analysis of dual-labeled probes to estimate the relative dosages of different chromosomes. We designed two quadruplex real-time PCR assays to detect aneuploidies of chromosomes 13, 18, 21, X and Y. Results We examined 75 aneuploid DNA samples and 56 unaffected DNA control samples using these two assays and correctly identified all samples. Four cases of unbalanced translocation were also accurately detected. The observed averaged ratio for each chromosomal disorder was similar to the theoretically expected value. Conclusions Our real-time assay is a robust, rapid, and easy to conduct technique for prenatal diagnosis of common aneuploidies, representing a competitive alternative for use in diagnostic laboratories. PMID:28241016

  2. Possible risk factors for Down syndrome and sex chromosomal aneuploidy in Mysore, South India

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    Malini Suttur

    2007-01-01

    Full Text Available Background: Down syndrome (DS and sex chromosomal aneuploidy (SA are common chromosomal anomalies causing congenital malformations and mental retardation in humans. The well-established risk factor, advanced maternal age, was not found in many of the DS and SA cases in India, while the other possible risk factors have not been well studied. In view of this, the present study has been made. Materials and Methods: During the last 5 years, 150 clinically suspected DS and 25 SA cases were referred to our laboratory for chromosome investigation from major hospitals of Mysore city. Chromosome preparations were made from these patients after informed consent was obtained. Well-spread G-banded metaphase plates were analyzed by automated LEICA KARYO software. Two hundred and 100 randomly selected families belonging to different religions were used as controls for the DS and SA cases, respectively. Statistical analysis was carried out using logistic regression Results: Out of the 150 cases of DS, 122 had free trisomy 21, two were mosaic trisomy 21, and one had translocation. Logistic regression of case-control study of DS children revealed that the odds ratio of uncle-niece marriages, or second cousin marriages, or parents lived in rural region, or exposure of the parents to chemicals, or parents education status, or habits (tobacco/ alcohol used of father, or mother not undergone prenatal scanning, or mothers with previous abortions were significant when all the variables of that category were used one at a time. Exposure of the parents to chemicals, parents′ educational status, habits (tobacco/alcohol use of the father, mother not undergone prenatal scanning, and history of previous abortions were significant when all the variables of that category were used one at a time. Similarly, except for consanguinity, history of previous abortions, and mother not undergone prenatal scanning, all other factors showed significant odds ratios in SA cases

  3. In vivo studies on chemically induced aneuploidy in mouse somatic and germinal cells.

    Science.gov (United States)

    Leopardi, P; Zijno, A; Bassani, B; Pacchierotti, F

    1993-05-01

    Within the context of a coordinated program to study aneuploidy induction sponsored by the European Community, nine chemicals were tested in mouse bone marrow and spermatocytes after intraperitoneal injection. In somatic cells, cell progression delay, hyperploidy, polyploidy induction and induction of micronucleated polychromatic erythrocyte (MnPCE) were studied. In germ cells hyperploidy induction was evaluated. The chemicals selected were: colchicine (COL), econazole (EZ), hydroquinone (HQ), thiabendazole (TB), diazepam (DZ), chloral hydrate (CH), cadmium chloride (CD), pyrimethamine (PY) and thimerosal (TM). Using literature data on c-mitotic effects in bone marrow as a reference, the same doses were tested in somatic and germ cells in order to compare the effects induced. Bone marrow cells were sampled 18 or 24 h after treatment. Germ cells were sampled 6, 8 or 18 h after treatment. Effects of COL and HQ in bone marrow have been reported elsewhere. Somatic effects were induced by CH (hyperploidy and cell cycle lengthening), TB (MnPCEs and cell cycle lengthening) and by PY (MnPCEs). EZ, DZ, CD and TM did not induce any kind of somatic effects. An increase in the incidence of hyperploid spermatocytes was induced by COL, at three dose levels, and by one dose of HQ and TB. All the other chemicals did not induce germinal aneuploidy at any dose or time tested. The hyperploidy control frequency ranged between 0.4 and 1.0% in somatic cells and from 0.3 to 0.9% in germ cells. In both somatic and germ cells, the maximum yield of induced hyperploidy did not exceed 3.5%. The time period of target cell sensitivity is probably restricted and this, associated with the heterogeneity and the asynchrony of cellular maturation processes, may account for our data. Under these circumstances, the negative data should be interpreted with some caution, particularly in germ cells, where additional indicators of chemical-cell interaction and cell cycle effects were not provided by

  4. Screening for aneuploidies by maternal age, fetal nuchal translucency and maternal serum biochemistry at 11-13+6 gestational weeks

    Directory of Open Access Journals (Sweden)

    Karadžov-Orlić Nataša

    2012-01-01

    Full Text Available Introduction. Aneuploidies are the major cause of perinatal death and early psychophysical disorders. Objective. In this study, we analyzed detection and false-positive rates of screening for aneuploidies in the first trimester by the combination of maternal age, fetal nuchal translucency (NT thickness and maternal serum free beta-human chorionic gonadotrophin (β-hCG, and pregnancy-associated plasma protein-A (PAPP-A at 11-13+6 weeks of gestation, using the appropriate software developed by the Fetal Medicine Foundation. Methods. Our screening study for aneuploidies analyzed 4172 singleton pregnancies from January 2006 to December 2010. The sensitivities and false-positive rates using the combined aneuploidies determination for the risk cut-off of 1:275 were evaluated. Results. In the trisomy 21 pregnancies, the fetal NT was higher than 95th centile, in 72.8%, serum free b-hCG concentration it was above the 95th centile in 55% and serum PAPP-A was below the 5th centile in 47% of the cases. In the trisomy 18 and 13, the fetal NT was above 95th centile in 66.6% and 44.4% of the cases, respectively. The serum free b-hCG concentration was above the 95th centile in 0 and 10%, but serum PAPP-A was below 5th centile in 80.9% and 88.8% of pregnancies. In the trisomy 21 pregnancies the median free beta-hCG was 2.3 MoM and the median PAPP-A was 0.45 MoM. Chromosomal abnormalities were detected in 169 fetuses: trisomy 21 (97, Turner syndrome (19, trisomy 18 (28, trisomy 13 (11 and others (14. Detection rate of combined screening for aneuploides were 86.0% with false positive rate of 5.3% (mean age 33±4.9 years, >35 years in 35% of pregnancies. Conclusion. Our study suggests that the strategy of first-trimester combined screening of biochemical values and ultrasonographic parameters at 12 gestational weeks identifies higher percentage of aneuploidies with a lower false-positive rate than a single parameter strategy.

  5. Sex chromosome aneuploidy in cytogenetic findings of referral patients from south of Iran

    Directory of Open Access Journals (Sweden)

    Najmeh Jouyan

    2012-01-01

    Full Text Available Background: Chromosome abnormality (CA including Sex chromosomes abnormality (SCAs is one of the most important causes of disordered sexual development and infertility. SCAs formed by numerical or structural alteration in X and Y chromosomes, are the most frequently CA encountered at both prenatal diagnosis and at birth. Objective: This study describes cytogenetic findings of cases suspected with CA referred for cytogenetic study. Materials and Methods: Blood samples of 4151 patients referred for cytogenetic analysis were cultured for chromosome preparation. Karyotypes were prepared for all samples and G-Banded chromosomes were analyzed using x100 objective lens. Sex chromosome aneuploidy cases were analyzed and categorized in two groups of Turners and Klinefelter’s syndrome (KFS. Results: Out of 230 (5.54% cases with chromosomally abnormal karyotype, 122 (30% cases suspected of sexual disorder showed SCA including 46% Turner’s syndrome, 46% KFS and the remaining other sex chromosome abnormalities. The frequency of classic and mosaic form of Turner’s syndrome was 33% and 67%, this was 55% and 45% for KFS, respectively. Conclusion: This study shows a relatively high sex chromosome abnormality in this region and provides cytogenetic data to assist clinicians and genetic counselors to determine the priority of requesting cytogenetic study. Differences between results from various reports can be due to different genetic background or ethnicity.

  6. Prenatal detection of chromosome aneuploidies in uncultured chorionic villus samples by FISH

    Energy Technology Data Exchange (ETDEWEB)

    Bryndorf, T.; Christensen, B.; Vad, M.; Philip, J. [Univ. of Copenhagen (Denmark)] [and others

    1996-10-01

    We developed a 1-d FISH assay for detection of numerical chromosome abnormalities in uncultured chorionic villus samples (CVS). Probes specific for chromosomes 13, 18, 21, X, and Y were used to determine ploidy by analysis of signal number in hybridized nuclei. Aneuploidy detection using this assay was directly compared with the results obtained by conventional cytogenetic analysis in a consecutive, clinical study of 2,709 CVS and placental samples. The FISH assay yielded discrete differences in the signal profiles between cytogenetically normal and abnormal samples. On the basis of these results, we generated FISH-assay cutoff values that discriminated between karyotypically normal and aneuploid samples. Samples with mosaicism and a single sample with possible heritable small chromosome X probe target were exceptions and showed poor agreement between FISH results and conventional cytogenetics. We conclude that the FISH assay may act as a more accurate and less labor-demanding alternative to {open_quotes}direct{close_quotes} CVS analysis. 22 refs., 1 fig., 4 tabs.

  7. Mosaic variegated aneuploidy associated with a dysmorphic syndrome and mental handicap

    Energy Technology Data Exchange (ETDEWEB)

    Mehta, L.; Babu, A.; Willner, J. [Sount Sinai Sachool of Medicine, New York, NY (United States)] [and others

    1994-09-01

    A 41-year-old woman was evaluated for dysmorphic features and mental handicap. Prior karyotyping had revealed 7% mosaicism for trisomy 18 in skin fibroblasts with normal blood chromosomes. Clinical features consisted of short stature, mild mental retardation, sensorineural deafness and the following dysmorphic features: short, broad neck, low posterior hairline, small palpebral fissures with iris coloboma on the right, epicanthic folds, small mouth, high palate and prominent mandible, short metacarpals and digits, particularly the fifth, with bilateral simian creases. Medical problems included non-insulin dependent diabetes mellitus, hypertension, oligomenorrhea and recent onset of diabetic neuropathy and retinal exudates. Head size and brain MRI were within normal limits. Peripheral blood chromosomes revealed: 46,XX (45 cells), 46,XX,t(7;16)(q21;q21) in 1 cell, 45,X (1 cell), 48,XXXX (1 cell), 47,XX,+mar (1 cell), 48,XX,+mar,+mar (1 cell). Skin fibroblasts revealed the following karyotypes: 46,XX (25 cells), 45,X (14 cells), 47,XX,+2 (10 cells) and 47,X,+2,+7 (1 cell). Previously reported cases of mosaic variegated aneuploidy include microcephaly as a prominent feature. Chromosomes involved in the abnormality are variable. Clinical presentations in such patients are not consistent and do not appear to correlate with specific chromosome defects. This patient represents an interesting example of probable mitotic instability disrupting normal developmental processes.

  8. Meiotic recombination, synapsis, meiotic inactivation and sperm aneuploidy in a chromosome 1 inversion carrier.

    Science.gov (United States)

    Kirkpatrick, Gordon; Chow, Victor; Ma, Sai

    2012-01-01

    Disrupted meiotic behaviour of inversion carriers may be responsible for suboptimal sperm parameters in these carriers. This study investigated meiotic recombination, synapsis, transcriptional silencing and chromosome segregation effects in a pericentric inv(1) carrier. Recombination (MLH1), synapsis (SYCP1, SYCP3) and transcriptional inactivation (γH2AX, BRCA1) were examined by fluorescence immunostaining. Chromosome specific rates of recombination were determined by fluorescence in-situ hybridization. Furthermore, testicular sperm was examined for aneuploidy and segregation of the inv(1). Our findings showed that global recombination rates were similar to controls. Recombination on the inv(1) and the sex chromosomes were reduced. The inv(1) associated with the XY body in 43.4% of cells, in which XY recombination was disproportionately absent, and 94.3% of cells displayed asynapsed regions which displayed meiotic silencing regardless of their association with the XY body. Furthermore, a low frequency of chromosomal imbalance was observed in spermatozoa (3.4%). Our results suggest that certain inversion carriers may display unimpaired global recombination and impaired recombination on the involved and the sex chromosomes during meiosis. Asynapsis or inversion-loop formation in the inverted region may be responsible for impaired spermatogenesis and may prevent sperm-chromosome imbalance.

  9. Tetraploid cells from cytokinesis failure induce aneuploidy and spontaneous transformation of mouse ovarian surface epithelial cells.

    Science.gov (United States)

    Lv, Lei; Zhang, Tianwei; Yi, Qiyi; Huang, Yun; Wang, Zheng; Hou, Heli; Zhang, Huan; Zheng, Wei; Hao, Qiaomei; Guo, Zongyou; Cooke, Howard J; Shi, Qinghua

    2012-08-01

    Most ovarian cancers originate from the ovarian surface epithelium and are characterized by aneuploid karyotypes. Aneuploidy, a consequence of chromosome instability, is an early event during the development of ovarian cancers. However, how aneuploid cells are evolved from normal diploid cells in ovarian cancers remains unknown. In the present study, cytogenetic analyses of a mouse syngeneic ovarian cancer model revealed that diploid mouse ovarian surface epithelial cells (MOSECs) experienced an intermediate tetraploid cell stage, before evolving to aneuploid (mainly near-tetraploid) cells. Using long-term live-cell imaging followed by fluorescence in situ hybridization (FISH), we demonstrated that tetraploid cells originally arose from cytokinesis failure of bipolar mitosis in diploid cells, and gave rise to aneuploid cells through chromosome mis-segregation during both bipolar and multipolar mitoses. Injection of the late passage aneuploid MOSECs resulted in tumor formation in C57BL/6 mice. Therefore, we reveal a pathway for the evolution of diploid to aneuploid MOSECs and elucidate a mechanism for the development of near-tetraploid ovarian cancer cells.

  10. Impact of type 1 diabetes and glycemic control on fetal aneuploidy biochemical markers

    DEFF Research Database (Denmark)

    Madsen, Helen Nordahl; Ekelund, Charlotte K; Tørring, Niels;

    2012-01-01

    Objective. To determine the influence of type 1 diabetes mellitus (T1DM) on the first trimester serum markers of fetal aneuploidy; pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (free β-hCG) and to evaluate the influence of glycemic control...... on these parameters in the pregnant diabetic women. Design. Retrospective study. Setting. Data were extracted from electronic obstetric and laboratory databases at two Danish University Hospitals. Population. Based on 36 415 pregnancies without T1DM (non-T1DM) and 331 pregnancies with T1DM; β-hCG and PAPP-A were...... obtained at 8+0 to 14+2 gestational weeks. Methods. Medians for PAPP-A and free β-hCG were generated and multiple of the normal gestation-specific median (MoM) values were calculated for each separate pregnancy. After adjustment for maternal weight, ethnicity and smoking status, MoM values were compared...

  11. Multipolar mitosis and aneuploidy after chrysotile treatment: a consequence of abscission failure and cytokinesis regression.

    Science.gov (United States)

    Cortez, Beatriz Araujo; Rezende-Teixeira, Paula; Redick, Sambra; Doxsey, Stephen; Machado-Santelli, Glaucia Maria

    2016-02-23

    Chrysotile, like other types of asbestos, has been associated with mesothelioma, lung cancer and asbestosis. However, the cellular abnormalities induced by these fibers involved in cancer development have not been elucidated yet. Previous works show that chrysotile fibers induce features of cancer cells, such as aneuploidy, multinucleation and multipolar mitosis. In the present study, normal and cancer derived human cell lines were treated with chrysotile and the cellular and molecular mechanisms related to generation of aneuploid cells was elucidated. The first alteration observed was cytokinesis regression, the main cause of multinucleated cells formation and centrosome amplification. The multinucleated cells formed after cytokinesis regression were able to progress through cell cycle and generated aneuploid cells after abnormal mitosis. To understand the process of cytokinesis regression, localization of cytokinetic proteins was investigated. It was observed mislocalization of Anillin, Aurora B, Septin 9 and Alix in the intercellular bridge, and no determination of secondary constriction and abscission sites. Fiber treatment also led to overexpression of genes related to cancer, cytokinesis and cell cycle. The results show that chrysotile fibers induce cellular and molecular alterations in normal and tumor cells that have been related to cancer initiation and progression, and that tetraploidization and aneuploid cell formation are striking events after fiber internalization, which could generate a favorable context to cancer development.

  12. Induction of micronuclei and aneuploidy by the quinone-forming agents benzene and o-phenylphenol.

    Science.gov (United States)

    Eastmond, D A

    1993-04-01

    A number of carcinogens appear to exert their tumorigenic effects through the formation of quinone metabolites. These quinone-forming carcinogens are generally inactive or weakly active in standard gene mutation assays. Accumulating evidence indicates that this class of compounds may exert their genotoxic and carcinogenic effects through the induction of large-scale gene alterations. This article presents an overview of work that has been performed using recently developed molecular cytogenic techniques to investigate the aneuploidy-inducing and clastogenic properties of the major quinone-forming metabolites of benzene, a widely used industrial chemical, and o-phenylphenol, a fungicide and disinfectant. These metabolites of benzene (hydroquinone, catechol, and benzenetriol) and o-phenylphenol (phenylhydroquinone) have each been shown to be capable of interfering with chromosome segregation and inducing chromosomal breakage. These results indicate that both numerical and structural chromosomal aberrations induced by the quinone metabolites of benzene and o-phenylphenol may play a role in the carcinogenic effects of these two agents.

  13. Beyond Trisomy 21: Additional Chromosomal Anomalies Detected through Routine Aneuploidy Screening

    Directory of Open Access Journals (Sweden)

    Amy Metcalfe

    2014-04-01

    Full Text Available Prenatal screening is often misconstrued by patients as screening for trisomy 21 alone; however, other chromosomal anomalies are often detected. This study aimed to systematically review the literature and use diagnostic meta-analysis to derive pooled detection and false positive rates for aneuploidies other than trisomy 21 with different prenatal screening tests. Non-invasive prenatal testing had the highest detection (DR and lowest false positive (FPR rates for trisomy 13 (DR: 90.3%; FPR: 0.2%, trisomy 18 (DR: 98.1%; FPR: 0.2%, and 45,X (DR: 92.2%; FPR: 0.1%; however, most estimates came from high-risk samples. The first trimester combined test also had high DRs for all conditions studied (trisomy 13 DR: 83.1%; FPR: 4.4%; trisomy 18 DR: 91.9%; FPR: 3.5%; 45,X DR: 70.1%; FPR: 5.4%; triploidy DR: 100%; FPR: 6.3%. Second trimester triple screening had the lowest DRs and highest FPRs for all conditions (trisomy 13 DR: 43.9%; FPR: 8.1%; trisomy 18 DR: 70.5%; FPR: 3.3%; 45,X DR: 77.2%; FPR: 9.3%. Prenatal screening tests differ in their ability to accurately detect chromosomal anomalies. Patients should be counseled about the ability of prenatal screening to detect anomalies other than trisomy 21 prior to undergoing screening.

  14. Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age.

    Science.gov (United States)

    Jones, Keith T

    2008-01-01

    Mammalian oocytes begin meiosis in the fetal ovary, but only complete it when fertilized in the adult reproductive tract. This review examines the cell biology of this protracted process: from entry of primordial germ cells into meiosis to conception. The defining feature of meiosis is two consecutive cell divisions (meiosis I and II) and two cell cycle arrests: at the germinal vesicle (GV), dictyate stage of prophase I and at metaphase II. These arrests are spanned by three key events, the focus of this review: (i) passage from mitosis to GV arrest during fetal life, regulated by retinoic acid; (ii) passage through meiosis I and (iii) completion of meiosis II following fertilization, both meiotic divisions being regulated by cyclin-dependent kinase (CDK1) activity. Meiosis I in human oocytes is associated with an age-related high rate of chromosomal mis-segregation, such as trisomy 21 (Down's syndrome), resulting in aneuploid conceptuses. Although aneuploidy is likely to be multifactorial, oocytes from older women may be predisposed to be becoming aneuploid as a consequence of an age-long decline in the cohesive ties holding chromosomes together. Such loss goes undetected by the oocyte during meiosis I either because its ability to respond and block division also deteriorates with age, or as a consequence of being inherently unable to respond to the types of segregation defects induced by cohesion loss.

  15. Cancer quasispecies and stem-like adaptive aneuploidy [v1; ref status: indexed, http://f1000r.es/29s

    Directory of Open Access Journals (Sweden)

    Domenico Napoletani

    2013-12-01

    Full Text Available In this paper we develop a theoretical frame to understand self-regulation of aneuploidy rate in cancer and stem cells. This is accomplished building upon quasispecies theory, by leaving its formal mathematical structure intact, but by drastically changing the meaning of its objects. In particular, we propose a novel definition of chromosomal master sequence, as a sequence of physically distinct whole or fragmented chromosomes, whose length is taken to be the sum of the copy numbers of each whole or fragmented chromosome. This fundamental change in the functional objects of quasispecies theory allows us to show that previously measured aneuploidy rates in cancer populations are already close to a formally derived aneuploid error threshold, and that any value of aneuploidy rate larger than the aneuploid error threshold would lead to a loss of fitness of a tumor population. Finally, we make a phenomenological analysis of existing experimental evidence to argue that single clone cancer cells, derived from an aneuploid cancer subpopulation, are capable of self-regulating their aneuploidy rate and of adapting it to distinct environments, namely primary and metastatic microenvironments. We also discuss the potential origin of this self-regulatory ability in the wider context of developmental and comparative biology and we hypothesize the existence of a diversification factor, i.e. a cellular mechanism that regulates adaptation of aneuploidy rates, active in all embryo, adult and cancer stem cells.

  16. Multiple recurrence of trisomy 21 in two Bedouin families: Parental gonadal mosaicism or {open_quotes}aneuploidy{close_quotes} gene effect?

    Energy Technology Data Exchange (ETDEWEB)

    Farag, T.I.; Murthy, D.S.K. [Kuwait Medical Genetics Centre, Sulibikhat (Kuwait)

    1994-09-01

    Two unrelated multiplex Down syndrome families is reported in Kuwait among the highly inbred population with Bedouin ancestors. Each family showed recurrent aneuploidies in three sibs with regular trisomy 21. Recurrent regular trisomy 21 in two or more siblings of healthy, normal parents (parental age <35 years) occurs rarely. Several possible etiological factors for recurrent aneuploidy have been suggested. The recurrence risks for regular trisomy 21 based on livebirth and prenatal diagnosis data were estimated at 1% - 2% for young women. However, there are no estimates for multiple recurrence of regular trisomy 21 in the young parents (<35 years). Clustering of trisomy 21 and trisomy 18 have been observed in Bedouin tribal population. The possibility of parental gonadal mosaicism and/or a possibility of an {open_quotes}aneuploidy gene{close_quotes} effect should be considered in practical genetic counselling of families with multiple recurrence of trisomy 21.

  17. Prevention and correction mechanisms behind anaphase synchrony: implications for the genesis of aneuploidy.

    Science.gov (United States)

    Matos, I; Maiato, H

    2011-01-01

    The perpetuation of the species' genomic identity strongly depends on the accurate maintenance of chromosome number through countless cell generations. The synchronous entry and progression of all chromosomes through anaphase is fundamental for the quality of mitosis and is guaranteed by error prevention and correction mechanisms that ultimately certify the bipolar attachment of chromosomes to the mitotic spindle, the uniform distribution of forces amongst different chromosomes, and the simultaneity of sister-chromatid separation. The existence of a kinetochore-attachment checkpoint (KAC; also known as spindle-assembly checkpoint) ensures a delay in anaphase onset if any kinetochore remains unattached or devoid of a proper complement of microtubules. The stochastic nature of microtubule-kinetochore interactions predisposes the mitotic process to mistakes, but different molecular players cooperate by detecting and releasing incorrect attachments and thus delaying checkpoint satisfaction. Conversely, correct microtubule-kinetochore interactions become selectively stabilized. Once anaphase onset is triggered, the segregation velocities achieved by each chromosome should be similar, so that none of the chromosomes is lagged behind. This reflects the uniformity of forces acting on the different chromosomes and relies on a conspicuous mitotic spindle property known as microtubule poleward flux. Importantly, not all incorrect attachments are detected and resolved prior to anaphase leading to asynchronous chromosome segregation, but several mechanisms are in place to prevent aneuploidy. One of these mechanisms relies on anaphase spindle forces and another, known as the NoCut checkpoint, delays cell cleavage during cytokinesis until chromosomes can free the spindle mid-region. In this review we discuss how these different mechanisms act in concert to ensure the fidelity of the mitotic process.

  18. Quantitative fluorescent-PCR detection of sex chromosome aneuploidies and AZF deletions/duplications.

    Science.gov (United States)

    Plaseski, Toso; Noveski, Predrag; Trivodalieva, Svetlana; Efremov, Georgi D; Plaseska-Karanfilska, Dijana

    2008-12-01

    The most common genetic causes of spermatogenic failure are sex chromosomal abnormalities (most frequently Klinefelter's syndrome) and deletions of the azoospermia factor (AZF) regions (AZFa, AZFb, and AZFc) of the Y chromosome. Several studies have proposed that partial AZFc deletions/duplications may be a risk factor for spermatogenic impairment. We describe a multiplex quantitative fluorescent-polymerase chain reaction (QF-PCR) method that allows simultaneous detection of these genetic causes and risk factors of male infertility. The 11-plex QF-PCR permitted the amplification of the amelogenin gene, four polymorphic X-specific short tandem repeat (STR) markers (XHPRT, DXS6803, DXS981, and exon 1 of the androgen receptor gene), nonpolymorphic Y-specific marker (SRY gene), polymorphic Y-specific STR marker (DYS448), and coamplification of DAZ/DAZL, MYPT2Y/MYPT2, and two CDY2/CDY1 fragments that allow for determination of the DAZ, MYPT2Y, and CDY gene copy number. A total of 357 DNA samples from infertile/subfertile men (n = 205) and fertile controls (n = 152) was studied. We detected 14 infertile males with sex chromosome aneuploidy (10 with Klinefelter's syndrome, 2 XX, and 2 XYY males). All previously detected AZF deletions, that is, AZFc (n8), AZFb (n1), AZFb + c (n1), gr/gr (n11), gr/gr with b2/b4 duplication (n3), and b2/b3 (n5), gave a specific pattern with the 11-plex QF-PCR. In addition, 32 DNA samples showed a pattern consistent with presence of gr/gr or b2/b4 and 4 with b2/b3 duplication. We conclude that multiplex QF-PCR is a rapid, simple, reliable, and inexpensive method that can be used as a first-step genetic analysis in infertile/subfertile patients.

  19. "How should I tell my child?" Disclosing the diagnosis of sex chromosome aneuploidies.

    Science.gov (United States)

    Dennis, Anna; Howell, Susan; Cordeiro, Lisa; Tartaglia, Nicole

    2015-02-01

    To date, the disclosure of a sex chromosome aneuploidy (SCA) diagnosis to an affected individual has not been explored. This study aimed to assess the timing and content revealed to an affected child by his or her parent(s), resources accessed in preparation, parental feelings of preparedness, common parental concerns, and recommendations for disclosure approaches. Two online surveys were created: 1) for parents of a child with a diagnosis and 2) for individuals with a diagnosis. One-hundred thirty-nine parent surveys (XXY n = 68, XXX n = 21, XYY n = 9, other SCAs n = 41) and 67 individual surveys (XXY n = 58, XXX n = 9) were analyzed. Parents most frequently discussed the topics of learning disabilities (47 %) and genetics (45 %) with their child during the initial disclosure. A significantly greater proportion of parent respondents reported feeling prepared vs. unprepared for disclosure, regardless of their child's diagnosis (z-test of proportions, all p's < 0.001). Both prepared and unprepared parents most frequently accessed resources such as websites, support groups, and discussion with the child's physician prior to disclosure, with unprepared parents accessing fewer resources (M = 2.0 ± 1.41) than prepared parents [M = 2. ± 1.56; t(101) =-2.02, p < 0.05]. Common parental concerns included making the conversation age-appropriate, discussing infertility, and possible impact on the child's self-esteem. Both parent and individual respondents endorsed being honest with the child, disclosing the diagnosis early and before puberty, and discussing the diagnosis gradually over time. These results provide recommendations for parents, and suggest benefits from additional resources and supports to alleviate concerns when approaching diagnosis disclosure.

  20. Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies.

    Science.gov (United States)

    Raznahan, Armin; Lue, YanHe; Probst, Frank; Greenstein, Deanna; Giedd, Jay; Wang, Christina; Lerch, Jason; Swerdloff, Ronald

    2015-11-01

    Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study--XO, XX, XY and XXY--to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males ("forebrain cholinergic" and "cerebelo-pontine-thalamo-cortical"), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA.

  1. Prenatal detection of aneuploidies using fluorescence in situ hybridization: A preliminary experience in an Indian set up

    Indian Academy of Sciences (India)

    Vaidehi Jobanputra; Kalol Kumar Roy; Kiran Kucheria

    2002-03-01

    Fluorescence in situ hybridization (FISH) is a powerful molecular cytogenetic technique which allows rapid detection of aneuploidies on interphase cells and metaphase spreads. The aim of the present study was to evaluate FISH as a tool in prenatal diagnosis of aneuploidies in high risk pregnancies in an Indian set up. Prenatal diagnosis was carried out in 88 high-risk pregnancies using FISH and cytogenetic analysis. Multicolour commercially available FISH probes specific for chromosomes 13, 18, 21, X and Y were used. Interphase FISH was done on uncultured cells from chorionic villus and amniotic fluid samples. FISH on metaphase spreads was done from cord blood samples. The results of FISH were in conformity with the results of cytogenetic analysis in all the normal and aneuploid cases except in one case of structural chromosomal abnormality. The hybridization efficiency of the 5 probes used for the detection of aneuploidies was 100%. Using these probes FISH assay yielded discrete differences in the signal profiles between cytogenetically normal and abnormal samples. The overall mean interphase disomic signal patterns of chromosomes 13, 18, 21, X and Y were 94.45%; for interphase trisomic signal pattern of chromosome 21 was 97.3%. Interphase FISH is very useful in urgent high risk cases. The use of FISH overcomes the difficulties of conventional banding on metaphase spreads and reduces the time of reporting. However, with the limited number of probes used, the conventional cytogenetic analysis serves as a gold standard at present. It should be employed as an adjunctive tool to conventional cytogenetics.

  2. Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy.

    Science.gov (United States)

    Ottesen, Anne Marie; Aksglaede, Lise; Garn, Inger; Tartaglia, Nicole; Tassone, Flora; Gravholt, Claus H; Bojesen, Anders; Sørensen, Kaspar; Jørgensen, Niels; Rajpert-De Meyts, Ewa; Gerdes, Tommy; Lind, Anne-Marie; Kjaergaard, Susanne; Juul, Anders

    2010-05-01

    Tall stature and eunuchoid body proportions characterize patients with 47,XXY Klinefelter syndrome, whereas patients with 45,X Turner syndrome are characterized by impaired growth. Growth is relatively well characterized in these two syndromes, while few studies describe the growth of patients with higher grade sex chromosome aneuploidies. It has been proposed that tall stature in sex chromosome aneuploidy is related to an overexpression of SHOX, although the copy number of SHOX has not been evaluated in previous studies. Our aims were therefore: (1) to assess stature in 305 patients with sex chromosome aneuploidy and (2) to determine the number of SHOX copies in a subgroup of these patients (n = 255) these patients and 74 healthy controls. Median height standard deviation scores in 46,XX males (n = 6) were -1.2 (-2.8 to 0.3), +0.9 (-2.2 to +4.6) in 47,XXY (n = 129), +1.3 (-1.8 to +4.9) in 47,XYY (n = 44), +1.1 (-1.9 to +3.4) in 48,XXYY (n = 45), +1.8 (-2.0 to +3.2) in 48,XXXY (n = 9), and -1.8 (-4.2 to -0.1) in 49,XXXXY (n = 10). Median height standard deviation scores in patients with 45,X (n = 6) were -2.6 (-4.1 to -1.6), +0.7 (-0.9 to +3.2) in 47,XXX (n = 40), -0.6 (-1.9 to +2.1) in 48,XXXX (n = 13), and -1.0 (-3.5 to -0.8) in 49,XXXXX (n = 3). Height increased with an increasing number of extra X or Y chromosomes, except in males with five, and in females with four or five sex chromosomes, consistent with a nonlinear effect on height.

  3. RNAi mediated acute depletion of Retinoblastoma protein (pRb promotes aneuploidy in human primary cells via micronuclei formation

    Directory of Open Access Journals (Sweden)

    Iovino Flora

    2009-11-01

    Full Text Available Abstract Background Changes in chromosome number or structure as well as supernumerary centrosomes and multipolar mitoses are commonly observed in human tumors. Thus, centrosome amplification and mitotic checkpoint dysfunctions are believed possible causes of chromosomal instability. The Retinoblastoma tumor suppressor (RB participates in the regulation of synchrony between DNA synthesis and centrosome duplication and it is involved in transcription regulation of some mitotic genes. Primary human fibroblasts were transfected transiently with short interfering RNA (siRNA specific for human pRb to investigate the effects of pRb acute loss on chromosomal stability. Results Acutely pRb-depleted fibroblasts showed altered expression of genes necessary for cell cycle progression, centrosome homeostasis, kinetochore and mitotic checkpoint proteins. Despite altered expression of genes involved in the Spindle Assembly Checkpoint (SAC the checkpoint seemed to function properly in pRb-depleted fibroblasts. In particular AURORA-A and PLK1 overexpression suggested that these two genes might have a role in the observed genomic instability. However, when they were post-transcriptionally silenced in pRb-depleted fibroblasts we did not observe reduction in the number of aneuploid cells. This finding suggests that overexpression of these two genes did not contribute to genomic instability triggered by RB acute loss although it affected cell proliferation. Acutely pRb-depleted human fibroblasts showed the presence of micronuclei containing whole chromosomes besides the presence of supernumerary centrosomes and aneuploidy. Conclusion Here we show for the first time that RB acute loss triggers centrosome amplification and aneuploidy in human primary fibroblasts. Altogether, our results suggest that pRb-depleted primary human fibroblasts possess an intact spindle checkpoint and that micronuclei, likely caused by mis-attached kinetochores that in turn trigger

  4. FAST-SeqS: a simple and efficient method for the detection of aneuploidy by massively parallel sequencing.

    Directory of Open Access Journals (Sweden)

    Isaac Kinde

    Full Text Available Massively parallel sequencing of cell-free, maternal plasma DNA was recently demonstrated to be a safe and effective screening method for fetal chromosomal aneuploidies. Here, we report an improved sequencing method achieving significantly increased throughput and decreased cost by replacing laborious sequencing library preparation steps with PCR employing a single primer pair designed to amplify a discrete subset of repeated regions. Using this approach, samples containing as little as 4% trisomy 21 DNA could be readily distinguished from euploid samples.

  5. Occurrence of aneuploidy for the X chromosome in over 1,300 unrelated specimens screened for the fragile X chromosome

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1994-07-15

    An apparent association between the occurrence of the fragile X syndrome and Klinefelter and Down syndromes has been reported over the past few years. We reported 3 cells with extra X chromosomes [XXY (one cell), XXXY (2 cells)] in a fragile X male who exhibited 37 fragile X chromosomes in 200 cells studied. After making this observation, we decided to determine the number of X chromosomes in all fragile X chromosome analyses to see if there was any increased mitotic nondisjunction for the X chromosome. We conclude that there was no association between the fragile X syndrome and X chromosome mitotic nondisjunction/aneuploidy in this group of individuals. 9 refs., 1 tab.

  6. Aneuploidy screening by array comparative genomic hybridization improves success rates of in vitro fertilization: A multicenter Indian study

    Directory of Open Access Journals (Sweden)

    Aditi Kotdawala

    2016-01-01

    Full Text Available Objective: To evaluate the usefulness of preimplantation genetic screening (PGS using array comparative genomic hybridization (aCGH in the Indian population. Materials and Methods: This is a retrospective, multicenter study including 235 PGS cycles following intracytoplasmic sperm injection performed at six different infertility centers from September 2013 to June 2015. Patients were divided as per maternal age in several groups (40 years and as per indication for undergoing PGS. Indications for performing PGS were recurrent miscarriage, repetitive implantation failure, severe male factor, previous trisomic pregnancy, and advanced maternal age (≥35. Day 3 embryo biopsy was performed and analyzed by aCGH followed by day 5 embryo transfer in the same cycle or the following cycle. Outcomes such as pregnancy rates (PRs/transfer, implantation rates, miscarriage rates, percentage of abnormal embryos, and number of embryos with more than one aneuploidy and chaotic patterns were recorded for all the treated subjects based on different age and indication groups. Results: aCGH helped in identifying aneuploid embryos, thus leading to consistent implantation (range: 33.3%-42.9% and PRs per transfer (range: 31.8%-54.9% that were obtained for all the indications in all the age groups, after performing PGS. Conclusion: Aneuploidy is one of the major factors which affect embryo implantation. aCGH can be successfully employed for screening of aneuploid embryos. When euploid embryos are transferred, an increase in PRs can be achieved irrespective of the age or the indication.

  7. Differential effect of aneuploidy on the X chromosome and genes with sex-biased expression in Drosophila.

    Science.gov (United States)

    Sun, Lin; Johnson, Adam F; Li, Jilong; Lambdin, Aaron S; Cheng, Jianlin; Birchler, James A

    2013-10-01

    Global analysis of gene expression via RNA sequencing was conducted for trisomics for the left arm of chromosome 2 (2L) and compared with the normal genotype. The predominant response of genes on 2L was dosage compensation in that similar expression occurred in the trisomic compared with the diploid control. However, the male and female trisomic/normal expression ratio distributions for 2L genes differed in that females also showed a strong peak of genes with increased expression and males showed a peak of reduced expression relative to the opposite sex. For genes in other autosomal regions, the predominant response to trisomy was reduced expression to the inverse of the altered chromosomal dosage (2/3), but a minor peak of increased expression in females and further reduced expression in males were also found, illustrating a sexual dimorphism for the response to aneuploidy. Moreover, genes with sex-biased expression as revealed by comparing amounts in normal males and females showed responses of greater magnitude to trisomy 2L, suggesting that the genes involved in dosage-sensitive aneuploid effects also influence sex-biased expression. Each autosomal chromosome arm responded to 2L trisomy similarly, but the ratio distributions for X-linked genes were distinct in both sexes, illustrating an X chromosome-specific response to aneuploidy.

  8. Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects.

    Science.gov (United States)

    Osoegawa, Kazutoyo; Iovannisci, David M; Lin, Bin; Parodi, Christina; Schultz, Kathleen; Shaw, Gary M; Lammer, Edward J

    2014-02-01

    Congenital heart defects (CHDs) are common malformations, affecting four to eight per 1,000 total births. Conotruncal defects are an important pathogenetic subset of CHDs, comprising nearly 20% of the total. Although both environmental and genetic factors are known to contribute to the occurrence of conotruncal defects, the causes remain unknown for most. To identify novel candidate genes/loci, we used array comparative genomic hybridization to detect chromosomal microdeletions/duplications. From a population base of 974,579 total births born during 1999-2004, we screened 389 California infants born with tetralogy of Fallot or d-transposition of the great arteries. We found that 1.7% (5/288) of males with a conotruncal defect had sex chromosome aneuploidy, a sevenfold increased frequency (relative risk = 7.0; 95% confidence interval 2.9-16.9). We identified eight chromosomal microdeletions/duplications for conotruncal defects. From these duplications and deletions, we found five high priority candidate genes (GATA4, CRKL, BMPR1A, SNAI2, and ZFHX4). This is the initial report that sex chromosome aneuploidy is associated with conotruncal defects among boys. These chromosomal microduplications/deletions provide evidence that GATA4, SNAI2, and CRKL are highly dosage sensitive genes involved in outflow tract development. Genome wide screening for copy number variation can be productive for identifying novel genes/loci contributing to non-syndromic common malformations.

  9. An Optimized Method for Accurate Fetal Sex Prediction and Sex Chromosome Aneuploidy Detection in Non-Invasive Prenatal Testing.

    Science.gov (United States)

    Wang, Ting; He, Quanze; Li, Haibo; Ding, Jie; Wen, Ping; Zhang, Qin; Xiang, Jingjing; Li, Qiong; Xuan, Liming; Kong, Lingyin; Mao, Yan; Zhu, Yijun; Shen, Jingjing; Liang, Bo; Li, Hong

    2016-01-01

    Massively parallel sequencing (MPS) combined with bioinformatic analysis has been widely applied to detect fetal chromosomal aneuploidies such as trisomy 21, 18, 13 and sex chromosome aneuploidies (SCAs) by sequencing cell-free fetal DNA (cffDNA) from maternal plasma, so-called non-invasive prenatal testing (NIPT). However, many technical challenges, such as dependency on correct fetal sex prediction, large variations of chromosome Y measurement and high sensitivity to random reads mapping, may result in higher false negative rate (FNR) and false positive rate (FPR) in fetal sex prediction as well as in SCAs detection. Here, we developed an optimized method to improve the accuracy of the current method by filtering out randomly mapped reads in six specific regions of the Y chromosome. The method reduces the FNR and FPR of fetal sex prediction from nearly 1% to 0.01% and 0.06%, respectively and works robustly under conditions of low fetal DNA concentration (1%) in testing and simulation of 92 samples. The optimized method was further confirmed by large scale testing (1590 samples), suggesting that it is reliable and robust enough for clinical testing.

  10. Aneuploidy analysis of non-pronuclear embryos from IVF with use of array CGH: a case report.

    Science.gov (United States)

    Lixin, Deng; Zhifeng, Xiang; Cong, He; Jinzhou, Zhang; Hongbin, Xie

    2014-06-01

    By using array comparative genomic hybridization (array CGH), to analyze the aneuploidy of the single blastomeres from non-pronuclear embryos on cleavage-stage in IVF cycle. Four non-pronuclear embryos were got from an IVF cycle, and the each single cell was biopsied from the four cleavage-stage embryos on the third day after the insemination which was investigated by using array CGH. After the biopsy, all the embryos continued to cleave, and lately entered the morula stage on the fifth day, just one embryo 3 was developed to early blastocyst stage on the sixth day. The four blastomere 24 chromosomes showed one X monomer and three normal XY diploids; the autosome chromosomes of blastomeres were abnormally gained or lost at different chromosome from four embryos, such as Embryo 1 : 49,X (-1, -5, -11, -19, -20, -21, -Y, +3, +6, +7, +8, +10, +13, +14, +16, +17, +18); Embryo 2 : 44,XY (-12, -15); Embryo 3: 47,XY (-3, -8, -9, -21, +7, +17, +18, +19, +20); Embryo 4 : 54,XY (+4, +7, +10, +12, +13, +16, +17, +22). With the use of the array CGH, the aneuploidy analysis could review the abnormal chromosomes of single blastomere from the non-pronuclear embryos, which can harbor the risk of abnormal sex chromosome and autosome chromosomes.

  11. An Optimized Method for Accurate Fetal Sex Prediction and Sex Chromosome Aneuploidy Detection in Non-Invasive Prenatal Testing.

    Directory of Open Access Journals (Sweden)

    Ting Wang

    Full Text Available Massively parallel sequencing (MPS combined with bioinformatic analysis has been widely applied to detect fetal chromosomal aneuploidies such as trisomy 21, 18, 13 and sex chromosome aneuploidies (SCAs by sequencing cell-free fetal DNA (cffDNA from maternal plasma, so-called non-invasive prenatal testing (NIPT. However, many technical challenges, such as dependency on correct fetal sex prediction, large variations of chromosome Y measurement and high sensitivity to random reads mapping, may result in higher false negative rate (FNR and false positive rate (FPR in fetal sex prediction as well as in SCAs detection. Here, we developed an optimized method to improve the accuracy of the current method by filtering out randomly mapped reads in six specific regions of the Y chromosome. The method reduces the FNR and FPR of fetal sex prediction from nearly 1% to 0.01% and 0.06%, respectively and works robustly under conditions of low fetal DNA concentration (1% in testing and simulation of 92 samples. The optimized method was further confirmed by large scale testing (1590 samples, suggesting that it is reliable and robust enough for clinical testing.

  12. An Optimized Method for Accurate Fetal Sex Prediction and Sex Chromosome Aneuploidy Detection in Non-Invasive Prenatal Testing

    Science.gov (United States)

    Li, Haibo; Ding, Jie; Wen, Ping; Zhang, Qin; Xiang, Jingjing; Li, Qiong; Xuan, Liming; Kong, Lingyin; Mao, Yan; Zhu, Yijun; Shen, Jingjing; Liang, Bo; Li, Hong

    2016-01-01

    Massively parallel sequencing (MPS) combined with bioinformatic analysis has been widely applied to detect fetal chromosomal aneuploidies such as trisomy 21, 18, 13 and sex chromosome aneuploidies (SCAs) by sequencing cell-free fetal DNA (cffDNA) from maternal plasma, so-called non-invasive prenatal testing (NIPT). However, many technical challenges, such as dependency on correct fetal sex prediction, large variations of chromosome Y measurement and high sensitivity to random reads mapping, may result in higher false negative rate (FNR) and false positive rate (FPR) in fetal sex prediction as well as in SCAs detection. Here, we developed an optimized method to improve the accuracy of the current method by filtering out randomly mapped reads in six specific regions of the Y chromosome. The method reduces the FNR and FPR of fetal sex prediction from nearly 1% to 0.01% and 0.06%, respectively and works robustly under conditions of low fetal DNA concentration (1%) in testing and simulation of 92 samples. The optimized method was further confirmed by large scale testing (1590 samples), suggesting that it is reliable and robust enough for clinical testing. PMID:27441628

  13. Detection of aneuploidy in sperm of an ataxia telangiectasia patient using three-chromosome fluorescence in situ hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Lowe, X.R.; Baulch, J.E. [Lawrence Livermore National Lab., CA (United States); Arnheim, N. [USC, Los Angeles, CA (United States)] [and others

    1994-09-01

    Ataxia telangiectasia (A-T) is an inherited, recessive, cancer-prone disorder. Fluorescence in situ hybridization (FISH) with DNA probes specific for three chromosomes was applied to sperm of an A-T patient to determine if there may be an increased germinal risk for aneuploidy. Air-dried sperm smears were treated with proteinase K and were decondensed with DTT and LIS. The slides were then hybridized with fluorescently labeled repetitive DNA probes specific for chromosomes X, Y and 8, and a total of 11,825 sperm cells were scored. The ratio of sperm bearing X-8 and Y-8 was 1:1, as predicted. The frequencies of hyperhaploidy were 3.9, 1.0, 17.6 and 7.8 per 10,000 cells for categories X-X-8, Y-Y-8, X-Y-8 and 8-8-(X or Y), respectively, In addition, the frequency of diploidy (X-Y-8-8) was 18.6 and auto-diploidies (X-X-8-8 and Y-Y-8-8) were 1.0 and 2.0, respectively. These frequencies were not significantly different when compared with levels in healthy men (p > 0.1). Our finding suggests that chromosome X, Y and 8 aneuploidies are not elevated in the sperm of A-T patients, but studies with additional patients and chromosomes are needed.

  14. Aneuploidy does not explain the difference in outcomes observed between Asian and Caucasian patients undergoingin vitro fertilization

    Institute of Scientific and Technical Information of China (English)

    Jonathan Kort; David Smotrich; Michelle Gaona; XiaWang; BarryBehr

    2015-01-01

    Objective:To understand whether reduced pregnancy and live birth rates for Asian patients undergoing in vitro fertilization (IVF) could be explained by discrepant rates of aneuploid embryos.Methods:A retrospective cohort study of all autologous and donor IVF cycles utilizing pre-implantation genetic screening (PGS) at a single infertility clinic from January 2012 to December 2013.Results:After controlling for maternal age, there was no difference in aneuploidy rates of Caucasian patients compared to Asian patients’. A trend was discerned that embryos of Caucasians form blastocysts more frequently than those of Asian patients, reaching significance for patients aged 25 to 30 and 40 to 45, but there was no difference in the likelihood of having at least one euploid blastocyst to transfer in any age group. Conclusion:While there may be a slight difference in blastocyst formation rates, there is no difference in aneuploidy or euploid blastocyst transfer rates between Asian and Caucasian patients that would explain the discrepancy in IVF outcomes observed between these patient populations. Possible ethnicity specific differences in non-ploidy related embryo viability and endometrial receptivity should be investigated as potential etiologies for this observation.

  15. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies.

    Science.gov (United States)

    Selesniemi, Kaisa; Lee, Ho-Joon; Muhlhauser, Ailene; Tilly, Jonathan L

    2011-07-26

    Increased meiotic spindle abnormalities and aneuploidy in oocytes of women of advanced maternal ages lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Despite the significance of the problem, strategies to sustain oocyte quality with age have remained elusive. Here we report that adult female mice maintained under 40% caloric restriction (CR) did not exhibit aging-related increases in oocyte aneuploidy, chromosomal misalignment on the metaphase plate, meiotic spindle abnormalities, or mitochondrial dysfunction (aggregation, impaired ATP production), all of which occurred in oocytes of age-matched ad libitum-fed controls. The effects of CR on oocyte quality in aging females were reproduced by deletion of the metabolic regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Thus, CR during adulthood or loss of PGC-1α function maintains female germline chromosomal stability and its proper segregation during meiosis, such that ovulated oocytes of aged female mice previously maintained on CR or lacking PGC-1α are comparable to those of young females during prime reproductive life.

  16. Elevated intracellular pH appears in aged oocytes and causes oocyte aneuploidy associated with the loss of cohesion in mice.

    Science.gov (United States)

    Cheng, Jin-Mei; Li, Jian; Tang, Ji-Xin; Chen, Su-Ren; Deng, Shou-Long; Jin, Cheng; Zhang, Yan; Wang, Xiu-Xia; Zhou, Chen-Xi; Liu, Yi-Xun

    2016-09-16

    Increases in the aneuploidy rate caused by the deterioration of cohesion with increasing maternal age have been well documented. However, the molecular mechanism for the loss of cohesion in aged oocytes remains unknown. In this study, we found that intracellular pH (pHi) was elevated in aged oocytes, which might disturb the structure of the cohesin ring to induce aneuploidy. We observed for the first time that full-grown germinal vesicle (GV) oocytes displayed an increase in pHi with advancing age in CD1 mice. Furthermore, during the in vitro oocyte maturation process, the pHi was maintained at a high level, up to ∼7.6, in 12-month-old mice. Normal pHi is necessary to maintain protein localization and function. Thus, we put forward a hypothesis that the elevated oocyte pHi might be related to the loss of cohesion and the increased aneuploidy in aged mice. Through the in vitro alkalinization treatment of young oocytes, we observed that the increased pHi caused an increase in the aneuploidy rate and the sister inter-kinetochore (iKT) distance associated with the strength of cohesion and caused a decline in the cohesin subunit SMC3 protein level. Young oocytes with elevated pHi exhibited substantially the increase in chromosome misalignment.

  17. Elevated level of spindle checkprotein MAD2 correlates with cellular mitotic arrest, but not with aneuploidy and clinicopathological characteristics in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Chew-Wun Wu; Chin-Wen Chi; Tze-Sing Huang

    2004-01-01

    AIM: To study the relevance of spindle assembly checkprotein MAD2 to cellular mitotic status, aneuploidy and other clinicopathological characteristics in gastric cancer.METHODS: Western blot analyses were performed to analyze the protein levels of MAD2 and cyclin B1 in the tumorous and adjacent nontumorous tissues of 34 gastric cancer patients. Cell cycle distribution and DNA ploidy of cancer tissues were also determined by flow cytometry.Conventional statistical methods were adopted to determine the relevance of abnormal MAD2 level to mitotic status,aneuploidy and clinicopathological parameters.RESULTS: Out of 34 gastric cancer patients 25 (74%)exhibited elevated MAD2 levels in their tumorous tissues compared with the corresponding nontumorous tissues.Elevation of MAD2 levels significantly correlated with the increased levels of cydin B1 expression and G2/M-phase distribution (P = 0.038 and P = 0.033, respectively), but was not relevant to aneuploidy. The gastric cancer patients with elevated MAD2 levels showed a tendency toward better disease-free and overall survival (P>0.05). However, no association was found between elevated MAD2 levels and patients' clinicopathological characteristics.CONCLUSION: Elevation of MAD2 level is present in 74%of gastric cancer patients, and correlates with increased mitotic checkpoint activity. However, elevation of MAD2level is not associated with patients' aneuploidy and any of the clinicopathological characteristics.

  18. Pigmentary mosaicism following the lines of Blaschko in a girl with a double aneuploidy mosaicism : (47,XX,+7/45,X)

    NARCIS (Netherlands)

    Niessen, RC; Jonkman, MF; Muis, N; Hordijk, R; van Essen, AJ

    2005-01-01

    We report on a 6-year-old girl with linear streaks of apparent hypopigmentation and hyperpigmentation following the Blaschko lines, growth retardation, bupthalmos of the left eye, and mild mental retardation. She had a 45,X karyotype in lymphocytes. In cultured fibroblasts a double aneuploidy mosaic

  19. Detection of DNA Aneuploidy in Exfoliated Airway Epithelia Cells of Sputum Specimens by the Automated Image Cytometry and Its Clinical Value in the Identification of Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    杨健; 周宜开

    2004-01-01

    To evaluate the value of detecton of DNA aneuploidy in exfoliated airway epithelia cells of sputum specimens by the automated image cytometry for the identification of lung cancer, 100patients were divided into patient group (50 patients with lung cancer)and control group (30 patients with tuberculosis and 20 healthy people). Sputum was obtained for the quantitative analysis of DNA content of exfoliated airway epithelial cells with the automated image cytometry, together with the examinations of brush cytology and conventional sputum cytology. Our results showed that DNA aneuploidy (DI>2.5 or 5c) was found in 20 out of 50 sputum samples of lung cancer, 1 out of 30 sputum samples from tuberculosis patients, and none of 20 sputum samples from healthy people. The positive rates of conventional sputum cytology and brush cytology were 16 % and 32 %,which was lower than that of DNA aneuploidy detection by the automated image cytometry (P<0.01 ,P>0.05). Our study showed that automated image cytometry, which uses DNA aneuploidy as a marker for tumor, can detect the malignant cells in sputum samples of lung cancer and it is a sensitive and specific method serving as a complement for the diagnosis of lung cancer.

  20. The high frequency of sperm aneuploidy in klinefelter patients and in nonobstructive azoospermia is due to meiotic errors in euploid spermatocytes.

    Science.gov (United States)

    Vialard, François; Bailly, Marc; Bouazzi, Habib; Albert, Martine; Pont, Jean Christophe; Mendes, Vanda; Bergere, Marianne; Gomes, Denise Molina; de Mazancourt, Philippe; Selva, Jacqueline

    2012-01-01

    For nonobstructive azoospermic (NOA) patients with a normal karyotype or for Klinefelter syndrome (47,XXY) patients, intracytoplasmic sperm injection is associated with an increased aneuploidy risk in offspring. We examined testicular cells from patients with different azoospermia etiologies to determine the origin of the aneuploid spermatozoa. The incidence of chromosome abnormalities was investigated in all types of azoospermia. Four study subgroups were constituted: Klinefelter patients (group 1), NOA patients with spermatogenesis failure but a normal karyotype (group 2), obstructive azoospermic patients with normal spermatogenesis (group 3), and control patients with normal sperm (group 4). The pachytene stage (in the three azoospermic groups) and postmeiotic cells (in all groups) were analyzed with fluorescence in situ hybridization. No aneuploid pachytene spermatocytes were observed. Postmeiotic aneuploidy rates were higher in the two groups with spermatogenesis failure (5.3% and 4.0% for groups 1 and 2, respectively) than in patients with normal spermatogenesis (0.6% for group 3 and group 4). Whatever the etiology of the azoospermia, the spermatozoa originated from euploid pachytene spermatocytes. These results strengthen the hypothesis whereby sperm aneuploidy in both Klinefelter patients and NOA patients with a normal karyotype results from meiotic abnormalities and not from aneuploid spermatocytes. The fact that sperm aneuploidy was more frequent when spermatogenesis was altered suggests a deleterious testicular environment. The study results also provide arguments for offering preimplantation genetic diagnosis or prenatal diagnosis when a pregnancy occurs for fathers with NOA (whatever the karyotype).

  1. Malignant chondroblastoma presenting as a recurrent pelvic tumor with DNA aneuploidy and p53 mutation as supportive evidence of malignancy

    Energy Technology Data Exchange (ETDEWEB)

    Ostrowski, M.L. [Department of Pathology and Laboratory Medicine, Baylor College of Medicine, The Methodist Hospital and Texas Children' s Hospital, Houston, Texas (United States); Department of Pathology and Laboratory Medicine, Houston, TX (United States). Methodist Hospital; Johnson, M.E. [Department of Orthopedic Surgery, Baylor College of Medicine, The Methodist Hospital and Texas Children' s Hospital, Houston, Texas (United States); Truong, L.D.; Hicks, M.J.; Spjut, H.J. [Department of Pathology and Laboratory Medicine, Baylor College of Medicine, The Methodist Hospital and Texas Children' s Hospital, Houston, Texas (United States); Smith, F.E. [Department of Oncology, Baylor College of Medicine, The Methodist Hospital and Texas Children' s Hospital, Houston, Texas (United States)

    1999-11-01

    We report a rare case of malignant chondroblastoma, which presented in a 47-year-old man as a recurrent tumor, 18 years following wide excision of a typical pelvic chondroblastoma. Radiologic studies of the recurrent tumor showed a large, lytic, destructive lesion of the right pelvic bones and femur, with a pathologic fracture of the latter, a large pelvic soft tissue mass, and multiple pulmonary metastases. Biopsy tissue showed typical features of chondroblastoma, but also increased nuclear atypia, hyperchromasia, and pleomorphism, compared to the original tumor, and, most significantly, abnormal mitotic figures. Immunohistochemical studies of the recurrent tumor revealed p53 mutation and extensive proliferative activity, and flow cytometric studies showed DNA aneuploidy, none of which was present in the original tumor. The patient received chemotherapy and radiation, but died of disease eight months after presentation. We also review chondroblastoma in general, to assign this unusual lesion to a tumor subtype. (orig.)

  2. Rapid detection of chromosome 18 aneuploidies in amniocytes by using primed in situ labeling (PRINS) technique

    Institute of Scientific and Technical Information of China (English)

    杨建滨; 郑树

    2002-01-01

    This paper presents a feasible method for rapid detection of the interphase nuclei of uncultured amniocytes for chromosomes 18 by using our modified in situ labeling (PRINS) technique.A total of 262 independent,uncultured amniotic fluid samples were analysed in a blind fashion before the karyotype was available.In addition,62 samples were examined by fluorescence in situ hybridization (FISH) for comparison.In more than 95% of the samples PRINS reactions with primer 18cen were successfully induced.Two samples were properly identified and correctly scored as trisomic 18.PRINS reaction could be performed automatically in less than one hour with a propgrammable thernocycler.Our studies showed that the PRINS technique is simple.rapid and cost-effective.It is as sensitive and specific as FISH;can enhance the eccuracy of standard cytogenetic analysis;and allows identification of chromosomes 18 aneuploidies in uncultrued amniocytes in significantly less time.

  3. 18,X,Y aneuploidies and transmission electron microscopy studies in spermatozoa from five carriers of different reciprocal translocations

    Institute of Scientific and Technical Information of China (English)

    Elena Moretti; Nicola Antonio Pascarelli; Valentina Giannerini; Michela Geminiani; Cecilia Anichini; Oiulia Collodel

    2009-01-01

    We analysed ejaculated spermatozoa from five infertile men with different balanced reciprocal translocations to contribute to the study of meiotic segregation of chromosomes 18, X and Y and also to evaluate sperm morphology by transmission electron microscopy (TEM) analysis. Conventional lymphocyte karyotype analyses highlighted dif-ferent reciprocal balanced translocations: t(12; 13), t(4;9), t(X;8), t(8; 10) and t(3; 16). Semen analysis was performed by light and TEM. Fluorescence in situ hybridization was performed directly on sperm nuclei using centromeric probes for chromosomes 18, X and Y. The carriers of the balanced reciprocal translocations considered in the pres-ent study showed a very similar pattern of sperm pathologies: diffused presence of apoptosis and immaturity. All patients showed meiotic segregation derangements, highlighted by the presence of sperm diploidies and sex chro-mosome disomies particularly related to the failure of the first meiotic division. However, an increased incidence of chromosome 18 aneuploidy was detected in spermatozoa from t(X;8) and t(8;10) carriers. We have also reported values from sex chromosomes such as t(X;8), although the X chromosome was involved in translocation. Since pa-tients with reciprocal translocations and spermatogenetic impairment are candidates for intracytoplasmic sperm in-jection cycles, the study of sperm parameters, and particularly of the level of aneuploidy rates, would provide better information for couples at risk and would contribute to the data in the literature for a better understanding of the ef-fects of chromosomal rearrangement on the whole meiotic process and, in particular, on chromosomes not involved in translocation.

  4. High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects.

    Directory of Open Access Journals (Sweden)

    Kerri M Luzzo

    Full Text Available BACKGROUND: Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment. METHODOLOGY/PRINCIPAL FINDINGS: We examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage. CONCLUSIONS/SIGNIFICANCE: Our results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes.

  5. Absence of aneuploidy and gastrointestinal tumours in a man with a chromosomal 2q13 deletion and BUB1 monoallelic deficiency.

    Science.gov (United States)

    Hoang, Don; Sue, Gloria R; Xu, Fang; Li, Peining; Narayan, Deepak

    2013-02-25

    Chromosomal instability is a potentially critical step in the development of colorectal cancer. The budding uninhibited by benzimidazole 1 (BUB1) gene is a highly conserved protein that plays a critical role at the spindle assembly checkpoint during cell division. BUB1 mutations function in a dominant-negative fashion and have been implicated in causing dysfunctional kinetochore attachments, premature chromatid separation, accelerated mis-segregation of whole chromosomes and aneuploidy. BUB1 mutations have been observed in patients with colorectal cancers. We report a remarkable case of BUB1 haploinsufficiency owing to a 1.7 Mb deletion of chromosome 2q13 in a 54-year-old man with no prior history of carcinoma. These mutant alleles were observed in both tissue from the hand and peripheral blood. Aneuploidy was not observed on cytogenetic analysis. These findings highlight the insufficiency of BUB1 haploinsufficiency to directly stimulate tumourigenesis, and suggest that other factors may be more critical to this process.

  6. Correlation of HER2 overexpression with gene amplification and its relation to chromosome 17 aneuploidy: a 5-year experience with invasive ductal and lobular carcinomas.

    Science.gov (United States)

    Nassar, Aziza; Khoor, Andras; Radhakrishnan, Reshmitha; Radhakrishnan, Anu; Cohen, Cynthia

    2014-01-01

    The HER2 oncogene shows expression or amplification, or both, in approximately 15% to 20% of breast cancers and has been associated with poor prognosis and a response to trastuzumab therapy. HER2 gene status determines the eligibility of breast cancer patients for trastuzumab therapy and a large fraction (41-56%) of these patients respond to targeted therapy. Several studies have related the increased expression of HER2 to an increased copy number of chromosome 17, rather than amplification of the HER2 gene. We compared the results of immunohistochemistry and fluorescence in situ hybridization in both invasive ductal and invasive lobular carcinomas, to determine the frequency of chromosome 17 aneuploidy associated with discordant results. In total, 390 invasive ductal carcinomas and 180 invasive lobular carcinomas diagnosed from January 2000 to December 2005 were included in the study only if results were available for immunohistochemistry (HercepTest; DAKO, Carpinteria, California) and fluorescence in situ hybridization (PathVysion HER2 DNA Probe Kit; Abbott Laboratories, Des Plaines, Illinois). Tumors classified as invasive ductal carcinomas were graded according to the Bloom-Richardson grading system. Correlation between the results of immunohistochemistry and fluorescence in situ hybridization was performed for all categories. Among invasive ductal carcinomas, 29% (115/390) showed chromosome 17 aneuploidy, mostly associated with grade 3/HER2 2+ (45%) or grade 2/HER2 3+ (55%) that were not amplified. Also, 34% (12/35) of invasive lobular carcinomas showed chromosome 17 aneuploidy; approximately one-third of these cases were HER2 2+ (33%) and HER2 3+ (37%) that were not amplified. Discordance between the results of immunohistochemistry and fluorescence in situ hybridization in both ductal and lobular carcinomas is largely associated with chromosome 17 aneuploidy.

  7. Parental exposure to environmental concentrations of diuron leads to aneuploidy in embryos of the Pacific oyster, as evidenced by fluorescent in situ hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Barranger, Audrey, E-mail: audrey.barranger@ifremer.fr [Ifremer, SG2M, Laboratory of Genetics and Pathology of Marine Molluscs, Avenue de Mus du Loup, 17390 La Tremblade (France); Ifremer, Department of Biogeochemistry and Ecotoxicology, Laboratory of Ecotoxicology, Rue de l’Ile d’Yeu, BP 21105, 44311 Nantes Cedex 03 (France); Benabdelmouna, Abdellah, E-mail: abdellah.benabdelmouna@ifremer.fr [Ifremer, SG2M, Laboratory of Genetics and Pathology of Marine Molluscs, Avenue de Mus du Loup, 17390 La Tremblade (France); Dégremont, Lionel [Ifremer, SG2M, Laboratory of Genetics and Pathology of Marine Molluscs, Avenue de Mus du Loup, 17390 La Tremblade (France); Burgeot, Thierry; Akcha, Farida [Ifremer, Department of Biogeochemistry and Ecotoxicology, Laboratory of Ecotoxicology, Rue de l’Ile d’Yeu, BP 21105, 44311 Nantes Cedex 03 (France)

    2015-02-15

    Highlights: • FISH was realized on oyster embryos from diuron-exposed genitors. • rDNA genes were used as probes on the interphase nuclei of embryo preparations. • Higher aneuploidy level was observed in embryos from diuron-exposed genitors. • Hypo- and hyperdiploid (triploid) nuclei were detected. - Abstract: Changes in normal chromosome numbers (i.e. aneuploidy) due to abnormal chromosome segregation may arise either spontaneously or as a result of chemical/radiation exposure, particularly during cell division. Coastal ecosystems are continuously subjected to various contaminants originating from urban, industrial and agricultural activities. Genotoxicity is common to several families of major environmental pollutants, including pesticides, which therefore represent a potential important environmental hazard for marine organisms. A previous study demonstrated the vertical transmission of DNA damage by subjecting oyster genitors to short-term exposure to the herbicide diuron at environmental concentrations during gametogenesis. In this paper, Fluorescent in situ hybridization (FISH) was used to further characterize diuron-induced DNA damage at the chromosomal level. rDNA genes (5S and 18-5.8-28S), previously mapped onto Crassostrea gigas chromosomes 4, 5 and 10, were used as probes on the interphase nuclei of embryo preparations. Our results conclusively show higher aneuploidy (hypo- or hyperdiploidy) level in embryos from diuron-exposed genitors, with damage to the three studied chromosomal regions. This study suggests that sexually developing oysters are vulnerable to diuron exposure, incurring a negative impact on reproductive success and oyster recruitment.

  8. The eXtraordinarY Kids Clinic: an interdisciplinary model of care for children and adolescents with sex chromosome aneuploidy

    Science.gov (United States)

    Tartaglia, Nicole; Howell, Susan; Wilson, Rebecca; Janusz, Jennifer; Boada, Richard; Martin, Sydney; Frazier, Jacqueline B; Pfeiffer, Michelle; Regan, Karen; McSwegin, Sarah; Zeitler, Philip

    2015-01-01

    Purpose Individuals with sex chromosome aneuploidies (SCAs) are born with an atypical number of X and/or Y chromosomes, and present with a range of medical, developmental, educational, behavioral, and psychological concerns. Rates of SCA diagnoses in infants and children are increasing, and there is a need for specialized interdisciplinary care to address associated risks. The eXtraordinarY Kids Clinic was established to provide comprehensive and experienced care for children and adolescents with SCA, with an interdisciplinary team composed of developmental–behavioral pediatrics, endocrinology, genetic counseling, child psychology, pediatric neuropsychology, speech–language pathology, occupational therapy, nursing, and social work. The clinic model includes an interdisciplinary approach to care, where assessment results by each discipline are integrated to develop unified diagnostic impressions and treatment plans individualized for each patient. Additional objectives of the eXtraordinarY Kids Clinic program include prenatal genetic counseling, research, education, family support, and advocacy. Methods Satisfaction surveys were distributed to 496 patients, and responses were received from 168 unique patients. Results Satisfaction with the overall clinic visit was ranked as “very satisfied” in 85%, and as “satisfied” in another 9.8%. Results further demonstrate specific benefits from the clinic experience, the importance of a knowledgeable clinic coordinator, and support the need for similar clinics across the country. Three case examples of the interdisciplinary approach to assessment and treatment are included. PMID:26229481

  9. A rare Robertsonian translocation rob(14;22) carrier with azoospermia, meiotic defects, and testicular sperm aneuploidy.

    Science.gov (United States)

    Sobotka, Vladimir; Vozdova, Miluse; Heracek, Jiri; Rubes, Jiri

    2015-01-01

    Male infertility is a serious problem in an increasing number of couples. We report an infertile man with non-obstructive azoospermia and karyotype 45,XY,rob(14;22). The immunofluorescence analysis of his testicular tissue using antibodies to SYCP1, SYCP3, HORMAD2, MLH1, and centromeres showed delayed synapsis of the chromosomes involved in the translocation, a varying extent of trivalent asynapsis and its association with sex chromosomes. The mean frequency of meiotic recombination per cell was within the range of normal values. Fluorescence in situ hybridization (FISH) with probes for chromosomes 14 and 22 revealed 5.83% of chromosomally abnormal testicular spermatozoa. FISH with probes for chromosomes X, Y, and 21 showed frequencies of disomic and diploid testicular spermatozoa increased when compared to ejaculated sperm of healthy donors, but comparable with published results for azoospermic patients. PGD by FISH for the translocation and aneuploidy of chromosomes X, Y, 13, 18, and 21 showed a normal chromosomal complement in one out of three analyzed embryos. A healthy carrier girl was born after the embryo transfer. This study shows the benefits of preimplantation genetic diagnosis in a case of a rare Robertsonian translocation carrier with azoospermia and a relatively low frequency of chromosomally unbalanced testicular spermatozoa.

  10. Detection of skewed X-chromosome inactivation in Fragile X syndrome and X chromosome aneuploidy using quantitative melt analysis.

    Science.gov (United States)

    Godler, David E; Inaba, Yoshimi; Schwartz, Charles E; Bui, Quang M; Shi, Elva Z; Li, Xin; Herlihy, Amy S; Skinner, Cindy; Hagerman, Randi J; Francis, David; Amor, David J; Metcalfe, Sylvia A; Hopper, John L; Slater, Howard R

    2015-07-01

    Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed X-chromosome inactivation (XCI) in fragile X syndrome full mutation (FM: CGG > 200) females. XCI skewing has been also linked to abnormal X-linked gene expression with the broader clinical impact for sex chromosome aneuploidies (SCAs). In this study, 10 FREE2 CpG sites were targeted using methylation specific quantitative melt analysis (MS-QMA), including 3 sites that could not be analysed with previously used EpiTYPER system. The method was applied for detection of skewed XCI in FM females and in different types of SCA. We tested venous blood and saliva DNA collected from 107 controls (CGG chromosome test; (ii) locus-specific XCI skewing towards the hypomethylated state in FM females; and (iii) skewed XCI towards the hypermethylated state in SCA with 3 or more X chromosomes, and in 5% of the 47,XXY individuals. MS-QMA output also showed significant correlation with the EpiTYPER reference method in FM males and females (P < 0.0001) and SCAs (P < 0.05). In conclusion, we demonstrate use of MS-QMA to quantify skewed XCI in two applications with diagnostic utility.

  11. Interrelationship between chromosome 8 aneuploidy, C-MYC amplification and increased expression in individuals from northern Brazil with gastric adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Danielle Queiroz Calcagno; Márcia Valéria Pitombeira Ferreira; Marília de Arruda Cardoso Smith; Rommel Rodríguez Burbano; Mariana Ferreira Leal; Aline Damaceno Seabra; André Salim Khayat; Elizabeth Suchi Chen; Samia Demachki; Paulo Pimentel Assump(c)(a)o; Mario Henrique Gir(a)o Faria; Silvia Helena Barem Rabenhorst

    2006-01-01

    AIM: To investigate chromosome 8 numerical aberrations, C-MYC oncogene alterations and its expression in gastric cancer and to correlate these findings with histopathological characteristics of gastric tumors.METHODS: Specimens were collected surgically from seven patients with gastric adenocarcinomas. Immunostaining for C-MYC and dual-color fluorescence in situ hybridization (FISH) for C-MYC gene and chromosome 8centromere were performed.RESULTS: All the cases showed chromosome 8 aneuploidy and C-MYC amplification, in both the diffuse and intestinal histopathological types of Lauren. No significant difference (P < 0.05) was observed between the level of chromosome 8 ploidy and the site, stage or histological type of the adenocarcinomas. C-MYC high amplification,like homogeneously stained regions (HSRs) and double minutes (DMs), was observed only in the intestinal-type.Structural rearrangement of C-MYC, like translocation,was observed only in the diffuse type. Regarding C-MYC gene, a significant difference (P < 0.05) was observed between the two histological types. The C-MYC protein was expressed in all the studied cases. In the intestinaltype the C-MYC immunoreactivity was localized only in the nucleus and in the diffuse type in the nucleus and cytoplasm.CONCLUSION: Distinct patterns of alterations between intestinal and diffuse types of gastric tumors support the hypothesis that these types follow different genetic pathways.

  12. DNA aneuploidy as a topographic malignant transformation pattern in a pleomorphic adenoma of long-term evolution: a case report

    Directory of Open Access Journals (Sweden)

    Gallego Lorena

    2011-11-01

    Full Text Available Abstract Introduction We present a case of long-term evolution of a submandibular pleomorphic adenoma. There is little information about topographic malignant transformation patterns of pleomorphic adenomas. Case presentation We extensively analyze a giant submandibular mixed tumor of 25-year evolution in a 57-year-old Caucasian woman. Deoxyribonucleic acid ploidy was evaluated in different superficial and deep areas using flow cytometry analysis and correlated with pathological and immunohistochemical characteristics. Superficial areas exhibited a typical histological pleomorphic adenoma pattern and were deoxyribonucleic acid diploid. Deep samples showed deoxyribonucleic acid aneuploidy, atypical histological benign features and expression of markers involved at an early-stage of malignant transformation, such as tumor protein 53 and antigen Ki67. Conclusion These findings revealed that deep tumor compartments may be involved in the initial stages of malignant transformation. Deoxyribonucleic acid ploidy analysis may provide an additional diagnosis tool and indicate 'uncertain' areas that require careful study to avoid diagnostic errors. Larger studies are needed to confirm our results and to evaluate the usefulness of the technique.

  13. Loss of maternal ATRX results in centromere instability and aneuploidy in the mammalian oocyte and pre-implantation embryo.

    Science.gov (United States)

    Baumann, Claudia; Viveiros, Maria M; De La Fuente, Rabindranath

    2010-09-23

    The α-thalassemia/mental retardation X-linked protein (ATRX) is a chromatin-remodeling factor known to regulate DNA methylation at repetitive sequences of the human genome. We have previously demonstrated that ATRX binds to pericentric heterochromatin domains in mouse oocytes at the metaphase II stage where it is involved in mediating chromosome alignment at the meiotic spindle. However, the role of ATRX in the functional differentiation of chromatin structure during meiosis is not known. To test ATRX function in the germ line, we developed an oocyte-specific transgenic RNAi knockdown mouse model. Our results demonstrate that ATRX is required for heterochromatin formation and maintenance of chromosome stability during meiosis. During prophase I arrest, ATRX is necessary to recruit the transcriptional regulator DAXX (death domain associated protein) to pericentric heterochromatin. At the metaphase II stage, transgenic ATRX-RNAi oocytes exhibit abnormal chromosome morphology associated with reduced phosphorylation of histone 3 at serine 10 as well as chromosome segregation defects leading to aneuploidy and severely reduced fertility. Notably, a large proportion of ATRX-depleted oocytes and 1-cell stage embryos exhibit chromosome fragments and centromeric DNA-containing micronuclei. Our results provide novel evidence indicating that ATRX is required for centromere stability and the epigenetic control of heterochromatin function during meiosis and the transition to the first mitosis.

  14. Loss of maternal ATRX results in centromere instability and aneuploidy in the mammalian oocyte and pre-implantation embryo.

    Directory of Open Access Journals (Sweden)

    Claudia Baumann

    2010-09-01

    Full Text Available The α-thalassemia/mental retardation X-linked protein (ATRX is a chromatin-remodeling factor known to regulate DNA methylation at repetitive sequences of the human genome. We have previously demonstrated that ATRX binds to pericentric heterochromatin domains in mouse oocytes at the metaphase II stage where it is involved in mediating chromosome alignment at the meiotic spindle. However, the role of ATRX in the functional differentiation of chromatin structure during meiosis is not known. To test ATRX function in the germ line, we developed an oocyte-specific transgenic RNAi knockdown mouse model. Our results demonstrate that ATRX is required for heterochromatin formation and maintenance of chromosome stability during meiosis. During prophase I arrest, ATRX is necessary to recruit the transcriptional regulator DAXX (death domain associated protein to pericentric heterochromatin. At the metaphase II stage, transgenic ATRX-RNAi oocytes exhibit abnormal chromosome morphology associated with reduced phosphorylation of histone 3 at serine 10 as well as chromosome segregation defects leading to aneuploidy and severely reduced fertility. Notably, a large proportion of ATRX-depleted oocytes and 1-cell stage embryos exhibit chromosome fragments and centromeric DNA-containing micronuclei. Our results provide novel evidence indicating that ATRX is required for centromere stability and the epigenetic control of heterochromatin function during meiosis and the transition to the first mitosis.

  15. A dominant negative mutant of TLK1 causes chromosome missegregation and aneuploidy in normal breast epithelial cells

    Directory of Open Access Journals (Sweden)

    Williams Briana

    2003-10-01

    Full Text Available Abstract Background In Arabidopsis thaliana, the gene Tousled encodes a protein kinase of unknown function, but mutations in the gene lead to flowering and leaf morphology defects. We have recently cloned a mammalian Tousled-Like Kinase (TLK1B and found that it phosphorylates specifically histone H3, in vitro and in vivo. We now report the effects that overexpression of a kinase-dead mutant of TLK1B mediates in a normal diploid cell line. Results Expression of a kinase-dead mutant resulted in reduction of phosphorylated histone H3, which could have consequences in mitotic segregation of chromosomes. When analyzed by FACS and microscopy, these cells displayed high chromosome number instability and aneuploidy. This phenomenon was accompanied by less condensed chromosomes at mitosis; failure of a number of chromosomes to align properly on the metaphase plate; failure of some chromosomes to attach to microtubules; and the occasional presentation of two bipolar spindles. We also used a different method (siRNA to reduce the level of endogenous TLK1, but in this case, the main result was a strong block of cell cycle progression suggesting that TLK1 may also play a role in progression from G1. This block in S phase progression could also offer a different explanation of some of the later mitotic defects. Conclusions TLK1 has a function important for proper chromosome segregation and maintenance of diploid cells at mitosis in mammalian cells that could be mediated by reduced phosphorylation of histone H3 and condensation of chromosomes, although other explanations to the phenotype are possible.

  16. “How should I tell my child?” Disclosing the Diagnosis of Sex Chromosome Aneuploidies

    Science.gov (United States)

    Dennis, Anna; Howell, Susan; Cordeiro, Lisa; Tartaglia, Nicole

    2017-01-01

    To date, the disclosure of a sex chromosome aneuploidy (SCA) diagnosis to an affected individual has not been explored. This study aimed to assess the timing and content revealed to an affected child by his or her parent(s), resources accessed in preparation, parental feelings of preparedness, common parental concerns, and recommendations for disclosure approaches. Two online surveys were created: 1) for parents of a child with a diagnosis and 2) for individuals with a diagnosis. One-hundred thirty-nine parent surveys (XXY n=68, XXX n=21, XYY n=9, other SCAs n=41) and 67 individual surveys (XXY n=58, XXX n=9) were analyzed. Parents most frequently discussed the topics of learning disabilities (47%) and genetics (45%) with their child during the initial disclosure. A significantly greater proportion of parent respondents reported feeling prepared vs. unprepared for disclosure, regardless of their child’s diagnosis (z-test of proportions, all p’s<.001). Both prepared and unprepared parents most frequently accessed resources such as websites, support groups, and discussion with the child’s physician prior to disclosure, with unprepared parents accessing fewer resources (M = 2.0 ± 1.41) than prepared parents [M= 2. ± 1.56; t(101) = −2.02, p<.05]. Common parental concerns included making the conversation age-appropriate, discussing infertility, and possible impact on the child’s self-esteem. Both parent and individual respondents endorsed being honest with the child, disclosing the diagnosis early and before puberty, and discussing the diagnosis gradually over time. These results provide recommendations for parents, and suggest benefits from additional resources and supports to alleviate concerns when approaching diagnosis disclosure. PMID:25179748

  17. The eXtraordinarY Kids Clinic: an interdisciplinary model of care for children and adolescents with sex chromosome aneuploidy

    Directory of Open Access Journals (Sweden)

    Tartaglia N

    2015-07-01

    Full Text Available Nicole Tartaglia,1,2 Susan Howell,1,2 Rebecca Wilson,2 Jennifer Janusz,1,2 Richard Boada,1,2 Sydney Martin,2 Jacqueline B Frazier,2 Michelle Pfeiffer,2 Karen Regan,2 Sarah McSwegin,2 Philip Zeitler1,2 1Department of Pediatrics, University of Colorado School of Medicine, 2Child Development Unit, Children's Hospital Colorado, Aurora, CO, USA Purpose: Individuals with sex chromosome aneuploidies (SCAs are born with an atypical number of X and/or Y chromosomes, and present with a range of medical, developmental, educational, behavioral, and psychological concerns. Rates of SCA diagnoses in infants and children are increasing, and there is a need for specialized interdisciplinary care to address associated risks. The eXtraordinarY Kids Clinic was established to provide comprehensive and experienced care for children and adolescents with SCA, with an interdisciplinary team composed of developmental–behavioral pediatrics, endocrinology, genetic counseling, child psychology, pediatric neuropsychology, speech–language pathology, occupational therapy, nursing, and social work. The clinic model includes an interdisciplinary approach to care, where assessment results by each discipline are integrated to develop unified diagnostic impressions and treatment plans individualized for each patient. Additional objectives of the eXtraordinarY Kids Clinic program include prenatal genetic counseling, research, education, family support, and advocacy. Methods: Satisfaction surveys were distributed to 496 patients, and responses were received from 168 unique patients. Results: Satisfaction with the overall clinic visit was ranked as “very satisfied” in 85%, and as “satisfied” in another 9.8%. Results further demonstrate specific benefits from the clinic experience, the importance of a knowledgeable clinic coordinator, and support the need for similar clinics across the country. Three case examples of the interdisciplinary approach to assessment and

  18. Failure to thrive as primary feature in two patients with subtle chromosomal aneuploidy: Interstitial deletion 2q33

    Energy Technology Data Exchange (ETDEWEB)

    Grace, K.; Mulla, W.; Stump, T. [Children`s Hospital of Philadelpha, PA (United States)] [and others

    1994-09-01

    It is well known that patients with chromosomal aneuploidy present with multiple congenital anomalies and dysmorphia, and that they may have associated failure to thrive. However, rarely is failure to thrive the predominant presenting feature. We report two such patients. Patient 1 had a marked history of failure to thrive, (weight 50% for 5 1/2 months at 20 months, length 50% for 15 months at 20 months). Patient 2 was noted to be growth retarded at 2 months upon presenting to the hospital with respiratory symptoms (weight 50% for a newborn, length 50% for 36 weeks gestation). There was relative head sparing in both patients. Chromosome analysis in patient 1, prompted by a negative work-up for the failure to thrive, and emerging evidence of developmental delay, revealed a 46,XY,del(2)(q32.2q33) karyotype. Chromosome analysis in patient 2, done as part of a complete workup for the failure to thrive, revealed a 46,XX,del(2)(q33.2q33.2 or q33.2q33.3) karyotype. On careful examination, subtle dysmorphic features were seen. In both patients these included a long flat philtrum, thin upper lip and high arched palate. Patient 1 also had a small posterior cleft of the palate. These patients have the smallest interstitial deletions of chromosome 2 so far reported. Their deletions overlap within 2q33 although they are not identical. Review of the literature reveals 15 patients with interstitial deletions which include 2q33. Marked growth retardation is reported in 14 of these cases. Cleft palate/abnormal uvula were frequently associated. These cases illustrate the need to include high resolution chromosomal studies as part of a complete work-up for unexplained failure to thrive.

  19. Induction of aneuploidy in male mouse germ cells detected by the sperm-FISH assay: a review of the present data base.

    Science.gov (United States)

    Adler, I-D; Schmid, T E; Baumgartner, A

    2002-07-25

    Multicolour fluorescence in situ hybridization (FISH) with chromosome-specific DNA-probes can be used to assess aneuploidy (disomy) and diploidy in sperm of any species provided the DNA-probes are available. In the present EU research project, DNA-probes for mouse chromosomes 8, X and Y were employed each labelled with different colours. Male mice were treated with the test chemicals and sperm were sampled from the Caudae epididymes 22-24 days later to allow spermatocytes exposed during meiosis to develop into mature sperm. At present, the data base comprises 10 chemicals: acrylamide (AA), carbendazim (CB), colchicine (COL), diazepam (DZ), griseofulvin (GF), omeprazole (OM), taxol (TX), thiobendazole (TB), trichlorfon (TF) and vinblastine (VBL). Of these, COL and TF induced disomic sperm only. DZ and GF induced disomic and diploid sperm, while CB and TB induced diploid sperm only. VBL gave contradictory results in repeated experiments in an inter-laboratory comparison. AA, OM and TX did not induce an increase in disomic or diploid sperm at the doses used. The induction of aneuploidy by DZ was also tested in humans. Sperm samples from patients after attempted suicide and from patients with chronic Valium((R)) abuse were evaluated using human DNA-probes specific for chromosomes 1,16, 21, X and Y. A quantitative comparison between mouse and man indicates that male meiosis in humans is 10-100 times more sensitive than in mice to aneuploidy induction by DZ. The positive response of mice to TF supports the hypothesis by Czeizel et al. [Lancet 341 (1993) 539] that TF may be causally related to the occurrence of congenital abnormality clusters in a Hungarian village.

  20. The usage and current approaches of cell free fetal DNA (cffDNA as a prenatal diagnostic method in fetal aneuploidy screening

    Directory of Open Access Journals (Sweden)

    Hülya Erbaba

    2015-12-01

    Full Text Available Prenatal diagnosis of invasive and noninvasive tests can be done in a way (NIPT, but because of the invasive methods have risks of infection and abortion, diagnosing non-invasive procedure increasing day by day. One of the widespread cell free fetal DNA in maternal blood test (cffDNA that is increasing in clinical use has been drawing attention. The incidence of aneuploidy chromosomal anomaly of the kind in which all live births; Trisomy 21 (Down Syndrome 1/800, trisomy 13 (Patau syndrome 1 /10,000, trisomy 18 (Edwards syndrome is a form of 1/6000. Because of the high mortality and morbidity, it is vital that congenital anomalies should be diagnosed in prenatal period. Aneuploidy testing for high-risk pregnant women after the 10th week of pregnancy in terms of the blood sample is taken and free fetal DNA in maternal plasma is based on the measurement of the relative amount. Knowledge of the current criteria for use by healthcare professionals in the field test will allow the exclusion of maternal and fetal risks. In this study, it is aimed to demonstrate current international approaches related to the positive and negative sides of non-invasive that is one of the prenatal diagnostic methods of cffDNA test. J Clin Exp Invest 2015; 6 (4: 414-417

  1. Chromosomal and cytoplasmic context determines predisposition to maternal age-related aneuploidy: brief overview and update on MCAK in mammalian oocytes.

    Science.gov (United States)

    Eichenlaub-Ritter, Ursula; Staubach, Nora; Trapphoff, Tom

    2010-12-01

    It has been known for more than half a century that the risk of conceiving a child with trisomy increases with advanced maternal age. However, the origin of the high susceptibility to nondisjunction of whole chromosomes and precocious separation of sister chromatids, leading to aneuploidy in aged oocytes and embryos derived from them, cannot be traced back to a single disturbance and mechanism. Instead, analysis of recombination patterns of meiotic chromosomes of spread oocytes from embryonal ovary, and of origins and exchange patterns of extra chromosomes in trisomies, as well as morphological and molecular studies of oocytes and somatic cells from young and aged females, show chromosome-specific risk patterns and cellular aberrations related to the chronological age of the female. In addition, analysis of the function of meiotic- and cell-cycle-regulating genes in oogenesis, and the study of the spindle and chromosomal status of maturing oocytes, suggest that several events contribute synergistically to errors in chromosome segregation in aged oocytes in a chromosome-specific fashion. For instance, loss of cohesion may differentially predispose chromosomes with distal or pericentromeric chiasmata to nondisjunction. Studies on expression in young and aged oocytes from human or model organisms, like the mouse, indicate that the presence and functionality/activity of gene products involved in cell-cycle regulation, spindle formation and organelle integrity may be altered in aged oocytes, thus contributing to a high risk of error in chromosome segregation in meiosis I and II. Genes that are often altered in aged mouse oocytes include MCAK (mitotic-centromere-associated protein), a microtubule depolymerase, and AURKB (Aurora kinase B), a protein of the chromosomal passenger complex that has many targets and can also phosphorylate and regulate MCAK localization and activity. Therefore we explored the role of MCAK in maturing mouse oocytes by immunofluorescence

  2. Aneuploidy in stem cells

    NARCIS (Netherlands)

    Garcia-Martinez, Jorge; Bakker, Bjorn; Schukken, Klaske M; Simon, Judith E; Foijer, Floris

    2016-01-01

    Stem cells hold enormous promise for regenerative medicine as well as for engineering of model systems to study diseases and develop new drugs. The discovery of protocols that allow for generating induced pluripotent stem cells (IPSCs) from somatic cells has brought this promise steps closer to real

  3. Prolonged interval between fusion and activation impairs embryonic development by inducing chromosome scattering and nuclear aneuploidy in pig somatic cell nuclear transfer.

    Science.gov (United States)

    You, Jinyoung; Song, Kilyoung; Lee, Eunsong

    2010-01-01

    The aim of the present study was to examine the effect of various intervals between electrofusion and activation (FA interval) on the nuclear remodelling and development of somatic cell nuclear transfer (SCNT) embryos in pigs. Reconstructed oocytes were activated at 0 (simultaneous fusion and activation; SFA), 1, 2 and 3 h (delayed activation) after electrofusion; these groups were designated as DA1, DA2 and DA3, respectively. When oocyte nuclear status was examined at 0.5, 1, 2 and 3 h after electrofusion, the incidence of chromosome scattering was increased (P or=3) pseudopronuclei (PPN) (0.0% of SFA; 5.3% of DA1; 21.7% of DA2; and 33.5% of DA3). The development of SCNT embryos to the blastocyst stage was decreased (P nuclear aneuploidy.

  4. Induction of p21CIP1 protein and cell cycle arrest after inhibition of Aurora B kinase is attributed to aneuploidy and reactive oxygen species.

    Science.gov (United States)

    Kumari, Geeta; Ulrich, Tanja; Krause, Michael; Finkernagel, Florian; Gaubatz, Stefan

    2014-06-01

    Cell cycle progression requires a series of highly coordinated events that ultimately lead to faithful segregation of chromosomes. Aurora B is an essential mitotic kinase, which is involved in regulation of microtubule-kinetochore attachments and cytokinesis. Inhibition of Aurora B results in stabilization of p53 and induction of p53-target genes such as p21 to inhibit proliferation. We have previously demonstrated that induction of p21 by p53 after inhibition of Aurora B is dependent on the p38 MAPK, which promotes transcriptional elongation of p21 by RNA Pol II. In this study, we show that a subset of p53-target genes are induced in a p38-dependent manner upon inhibition of Aurora B. We also demonstrate that inhibition of Aurora B results in down-regulation of E2F-mediated transcription and that the cell cycle arrest after Aurora B inhibition depends on p53 and pRB tumor suppressor pathways. In addition, we report that activation of p21 after inhibition of Aurora B is correlated with increased chromosome missegregation and aneuploidy but not with binucleation or tetraploidy. We provide evidence that p21 is activated in aneuploid cells by reactive oxygen species (ROS) and p38 MAPK. Finally, we demonstrate that certain drugs that act on aneuploid cells synergize with inhibitors of Aurora B to inhibit colony formation and oncogenic transformation. These findings provide an important link between aneuploidy and the stress pathways activated by Aurora B inhibition and also support the use of Aurora B inhibitors in combination therapy for treatment of cancer.

  5. A Method to Quantify Cell-Free Fetal DNA Fraction in Maternal Plasma Using Next Generation Sequencing: Its Application in Non-Invasive Prenatal Chromosomal Aneuploidy Detection.

    Directory of Open Access Journals (Sweden)

    Xu-Ping Xu

    Full Text Available The fraction of circulating cell-free fetal (cff DNA in maternal plasma is a critical parameter for aneuploidy screening with non-invasive prenatal testing, especially for those samples located in equivocal zones. We developed an approach to quantify cff DNA fractions directly with sequencing data, and increased cff DNAs by optimizing library construction procedure.Artificial DNA mixture samples (360, with known cff DNA fractions, were used to develop a method to determine cff DNA fraction through calculating the proportion of Y chromosomal unique reads, with sequencing data generated by Ion Proton. To validate our method, we investigated cff DNA fractions of 2,063 pregnant women with fetuses who were diagnosed as high risk of fetal defects. The z-score was calculated to determine aneuploidies for chromosomes 21, 18 and 13. The relationships between z-score and parameters of pregnancies were also analyzed. To improve cff DNA fractions in our samples, two groups were established as follows: in group A, the large-size DNA fragments were removed, and in group B these were retained, during library construction.A method to determine cff DNA fractions was successfully developed using 360 artificial mixture samples in which cff DNA fractions were known. A strong positive correlation was found between z-score and fetal DNA fraction in the artificial mixture samples of trisomy 21, 18 and 13, as well as in clinical maternal plasma samples. There was a positive correlation between gestational age and the cff DNA fraction in the clinical samples, but no correlation for maternal age. Moreover, increased fetal DNA fractions were found in group A compared to group B.A relatively accurate method was developed to determine the cff DNA fraction in maternal plasma. By optimizing, we can improve cff DNA fractions in sequencing samples, which may contribute to improvements in detection rate and reliability.

  6. Relationship between spindle checkpoint and embryo aneuploidy%纺锤体检测点与胚胎非整倍体的关系

    Institute of Scientific and Technical Information of China (English)

    刘琨; 任育宏; 张学红; 薛石龙

    2013-01-01

    纺锤体检测点对有丝分裂和减数分裂中期与后期转换过程中纺锤体的形成起着非常重要的作用,其组成成分最初是在发芽的酵母中通过基因检测证实,此后发展到人,大量细胞中均发现某些检测蛋白.研究表明,纺锤体检测系统参与雌性哺乳动物减数分裂的调控,防止胚胎非整倍体的发生.本文阐述在有丝分裂和减数分裂中关于纺锤体检测点的研究进展,了解检测信号传导通路及其在减数分裂中防止染色体异常的作用,进一步探讨胚胎非整倍体发生的原因.%Spindle checkpoint plays a very important role on the mitotic and meiotic metaphase and anaphase transition process in which spindle is developed.Its composition is confirmed initially in budding yeast by genetic testing,and then some detecting proteins were found in human cells.It is found that spindle detection system is involved in the regulation of mammalian female meiosis and prevents the occurrence of embryo aneuploidy.Therefore,this paper elaborated the research progress of spindle checkpoint development in mitosis and meiosis,learning more about the detection signal transduction pathway and its role in prevention of abnormal chromosome in meiosis,to further explore the causes of embryo aneuploidy.

  7. Women's Experiences and Preferences for Service Delivery of Non-Invasive Prenatal Testing for Aneuploidy in a Public Health Setting: A Mixed Methods Study.

    Science.gov (United States)

    Lewis, Celine; Hill, Melissa; Chitty, Lyn S

    2016-01-01

    Non-invasive prenatal testing (NIPT) for aneuploidy is currently only available in the UK through the private sector outside of the research arena. As part of an implementation study in the UK National Health Service we conducted a mixed methods study to assess women's experience of being offered NIPT using validated measures of decisional conflict, decisional regret and anxiety. Clinical service preferences were also explored. Women with a Down syndrome screening risk >1:1000 were invited to take part in the study and offered NIPT, NIPT and invasive testing (for women with a risk above 1:150) or no further testing. A cross-sectional survey and semi-structured interviews were conducted at two time points; at the time of testing and one month following receipt of results (or equivalent for NIPT decliners). In total, 845 questionnaires and 81 interviews were analysed. The main motivation to accept NIPT was for reassurance (30.8%). Decisional conflict occurred in a minimal number of cases (3.8%), however, none of the participants experienced decisional regret. Around a third (29.9%) of women had elevated anxiety at the time of testing, including intermediate risk women who traditionally would not be offered further testing (54.4% high risk; 20.1% medium risk), a finding supported through the qualitative interviews where prolonged or additional anxiety was found to occur in some medium risk cases. Women were overwhelmingly positive about the opportunity to have a test that was procedurally safe, accurate, reduced the need for invasive testing and identified cases of Down syndrome that might otherwise have been missed. Reassurance was identified as the main motivator for accepting NIPT, particularly amongst medium risk women, with high risk women inclined to accept NIPT to inform decisions around invasive testing. The current turnaround time for test result was identified as a key limitation. All the women interviewed thought NIPT should be adopted as part of NHS

  8. Women's Experiences and Preferences for Service Delivery of Non-Invasive Prenatal Testing for Aneuploidy in a Public Health Setting: A Mixed Methods Study.

    Directory of Open Access Journals (Sweden)

    Celine Lewis

    Full Text Available Non-invasive prenatal testing (NIPT for aneuploidy is currently only available in the UK through the private sector outside of the research arena. As part of an implementation study in the UK National Health Service we conducted a mixed methods study to assess women's experience of being offered NIPT using validated measures of decisional conflict, decisional regret and anxiety. Clinical service preferences were also explored. Women with a Down syndrome screening risk >1:1000 were invited to take part in the study and offered NIPT, NIPT and invasive testing (for women with a risk above 1:150 or no further testing. A cross-sectional survey and semi-structured interviews were conducted at two time points; at the time of testing and one month following receipt of results (or equivalent for NIPT decliners. In total, 845 questionnaires and 81 interviews were analysed. The main motivation to accept NIPT was for reassurance (30.8%. Decisional conflict occurred in a minimal number of cases (3.8%, however, none of the participants experienced decisional regret. Around a third (29.9% of women had elevated anxiety at the time of testing, including intermediate risk women who traditionally would not be offered further testing (54.4% high risk; 20.1% medium risk, a finding supported through the qualitative interviews where prolonged or additional anxiety was found to occur in some medium risk cases. Women were overwhelmingly positive about the opportunity to have a test that was procedurally safe, accurate, reduced the need for invasive testing and identified cases of Down syndrome that might otherwise have been missed. Reassurance was identified as the main motivator for accepting NIPT, particularly amongst medium risk women, with high risk women inclined to accept NIPT to inform decisions around invasive testing. The current turnaround time for test result was identified as a key limitation. All the women interviewed thought NIPT should be adopted as part

  9. Prevalence of X-aneuploidies, X-structural abnormalities and 46,XY sex reversal in Turkish women with primary amenorrhea or premature ovarian insufficiency.

    Science.gov (United States)

    Geckinli, B B; Toksoy, G; Sayar, C; Soylemez, M A; Yesil, G; Aydın, H; Karaman, A; Devranoglu, B

    2014-11-01

    Our objective was to identify the distribution of cytogenetic abnormalities of 175 Turkish women with primary amenorrhea (PA) or premature ovarian insufficiency (POI). A retrospective study was performed using medical records of 94 patients with PA and 81 patients with POI at the Genetics Department, Zeynep Kamil Women's and Children's Research and Training Hospital, Istanbul, Turkey. G-banded metaphase karyotype analysis were prepared and analyzed. Chromosomal abnormalities were present in 44 of 175 cases (25%). 15 were full blown or mosaic numerical X chromosome abnormalities (8.5%), 10 were full blown or mosaic X-chromosome structural anomalies (5.7%), one was X-autosome translocation (0.5%), 3 were autosomal anomalies (1.7%), 12 were XY karyotype (6.8%), one was 45,X/46,XY mosaic and 2 were full blown or mosaic structural anomalies of Y chromosome (1.7%). The prevalence of chromosomal abnormalities was 25% in this large series of Turkish women with primary amenorrhea or premature ovarian insufficiency, most cases involving X-aneuploidy or X-structural abnormalities or 46,XY karyotype. High prevalence of chromosomal abnormalities is associated with POI starting at an early age (average age: 26 years).

  10. A study of aneuploidy and DNA fragmentation in spermatozoa of three men with sex chromosome mosaicism including a 45,X cell line.

    Science.gov (United States)

    Nguyen, Minh Huong; Morel, Frederic; Bujan, Louis; May-Panloup, Pascale; De Braekeleer, Marc; Perrin, Aurore

    2015-06-01

    Meiotic segregation of mosaic males with a 45,X cell line has been little examined. In this study, we evaluated the risk of aneuploid gametes using fluorescence in situ hybridization (FISH) and DNA fragmentation in ejaculated spermatozoa of three men with sex chromosome mosaicism including a 45,X cell line. Triple- and dual-color FISH were performed. Sperm DNA fragmentation was detected using the TUNEL assay. A significantly increased frequency of XY disomic spermatozoa was observed for patients (P)1 and P2. A significant increase in diploidy and autosomal aneuploidy was found in P2 and P3, respectively. The rate of DNA fragmentation was not different from that observed in a control group. Data from the literature are scarce (only 3 cases reported), making comparison of the present data difficult, especially as the frequencies of the cell lines comprising the mosaicism differed between patients. Furthermore, the proportion of the different cell lines can differ from one tissue to another in the same patient. Whether the relative levels of the several cell lines present in the mosaicism can influence the rate of aneuploid spermatozoa remains unknown.

  11. 产前超声检查在诊断染色体非整倍体异常胎儿中的价值%Application of prenatal ultrasound in the diagnosis of chromosomal aneuploidy abnormalities

    Institute of Scientific and Technical Information of China (English)

    钟惟娜; 邓学东

    2012-01-01

    目的 探讨产前超声检查在非整倍体异常胎儿诊断中的价值.方法 对2009年9月至2011年12月在我院经羊水细胞染色体核型分析诊断为非整倍体异常的24例胎儿产前超声异常声像图特征进行总结分析.结果 24例羊水细胞染色体核型分析确诊为非整倍体异常的胎儿中超声显示异常20例(83.3%,20/24),包括21-三体9例(9/13)、18-三体3例(3/3)、13-三体3例(3/3)、45,X 5例(5/5).其中单发畸形4例(20%,4/20),多发畸形13例(65%,13/20),仅表现为超声软标志异常3例(15%,3/20).18-三体、13-三体及45,X胎儿均有超声可检出的明显结构畸形或异常,21-三体胎儿3例,仅表现为超声软标志异常.24例非整倍体异常胎儿中以心脏畸形检出例数居多(41.7%,10/24),而颈部淋巴水囊瘤是45,X胎儿一个极其重要的超声标志.结论 非整倍体异常胎儿常伴有异常的超声声像图表现,部分还有相应的典型超声畸形谱,超声作为非侵入性检查技术对于非整倍体异常胎儿的诊断有重要临床意义.%Objective To investigate the clinical application of prenatal ultrasound in the diagnosis of chromosomal aneuploidy abnormalities . Methods Ultrasound imaging features in 24 aneuploidy abnormal fetuses which were diagnosed by amniocentesis in our hospital from September 2009 to December 2011 were analyzed retrospectively. Results Twenty -four cases of aneuploidy abnormalities dectected by amniocentesis were examined by prenatal ultrasound. Of these cases, twenty were found abnormalities , including 9 with trisomy 21,3 with trisomy 18,3 with trisomy 13 and 5 with 45 ,X monomer. Prenatal ultrasound showed single malformation in 4 cases, multi-malformation in 13 cases and separate ultrasonographic soft markers in 3 cases. Fetuses with trisomy 18,trisomy 13 and 45,X monomer were all had obvious structural abnormalities detected by ultrasound , otherwise, 3 cases of trisomy 21 had only ultrasonographic soft markers. In

  12. Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells.

    Directory of Open Access Journals (Sweden)

    Avigail Dreazen Wittenberg

    Full Text Available Constitutive expression of active Akt (Akttg drives hyperplasia and hypertrophy of pancreatic β-cells, concomitantly with increased insulin secretion and improved glucose tolerance, and at a later stage the development of insulinoma. To determine which functions of Akt are mediated by ribosomal protein S6 (rpS6, an Akt effector, we generated mice that express constitutive Akt in β-cells in the background of unphosphorylatable ribosomal protein S6 (rpS6P-/-. rpS6 phosphorylation deficiency failed to block Akttg-induced hypertrophy and aneuploidy in β-cells, as well as the improved glucose homeostasis, indicating that Akt carries out these functions independently of rpS6 phosphorylation. In contrast, rpS6 phosphorylation deficiency efficiently restrained the reduction in nuclear localization of the cell cycle inhibitor p27, as well as the development of Akttg-driven hyperplasia and tumor formation in β-cells. In vitro experiments with Akttg and rpS6P-/-;Akttg fibroblasts demonstrated that rpS6 phosphorylation deficiency leads to reduced translation fidelity, which might underlie its anti-tumorigenic effect in the pancreas. However, the role of translation infidelity in tumor suppression cannot simply be inferred from this heterologous experimental model, as rpS6 phosphorylation deficiency unexpectedly elevated the resistance of Akttg fibroblasts to proteotoxic, genotoxic as well as autophagic stresses. In contrast, rpS6P-/- fibroblasts exhibited a higher sensitivity to these stresses upon constitutive expression of oncogenic Kras. The latter result provides a possible mechanistic explanation for the ability of rpS6 phosphorylation deficiency to enhance DNA damage and protect mice from Kras-induced neoplastic transformation in the exocrine pancreas. We propose that Akt1 and Kras exert their oncogenic properties through distinct mechanisms, even though both show addiction to rpS6 phosphorylation.

  13. Phosphorylated Ribosomal Protein S6 Is Required for Akt-Driven Hyperplasia and Malignant Transformation, but Not for Hypertrophy, Aneuploidy and Hyperfunction of Pancreatic β-Cells.

    Science.gov (United States)

    Wittenberg, Avigail Dreazen; Azar, Shahar; Klochendler, Agnes; Stolovich-Rain, Miri; Avraham, Shlomit; Birnbaum, Lea; Binder Gallimidi, Adi; Katz, Maximiliano; Dor, Yuval; Meyuhas, Oded

    2016-01-01

    Constitutive expression of active Akt (Akttg) drives hyperplasia and hypertrophy of pancreatic β-cells, concomitantly with increased insulin secretion and improved glucose tolerance, and at a later stage the development of insulinoma. To determine which functions of Akt are mediated by ribosomal protein S6 (rpS6), an Akt effector, we generated mice that express constitutive Akt in β-cells in the background of unphosphorylatable ribosomal protein S6 (rpS6P-/-). rpS6 phosphorylation deficiency failed to block Akttg-induced hypertrophy and aneuploidy in β-cells, as well as the improved glucose homeostasis, indicating that Akt carries out these functions independently of rpS6 phosphorylation. In contrast, rpS6 phosphorylation deficiency efficiently restrained the reduction in nuclear localization of the cell cycle inhibitor p27, as well as the development of Akttg-driven hyperplasia and tumor formation in β-cells. In vitro experiments with Akttg and rpS6P-/-;Akttg fibroblasts demonstrated that rpS6 phosphorylation deficiency leads to reduced translation fidelity, which might underlie its anti-tumorigenic effect in the pancreas. However, the role of translation infidelity in tumor suppression cannot simply be inferred from this heterologous experimental model, as rpS6 phosphorylation deficiency unexpectedly elevated the resistance of Akttg fibroblasts to proteotoxic, genotoxic as well as autophagic stresses. In contrast, rpS6P-/- fibroblasts exhibited a higher sensitivity to these stresses upon constitutive expression of oncogenic Kras. The latter result provides a possible mechanistic explanation for the ability of rpS6 phosphorylation deficiency to enhance DNA damage and protect mice from Kras-induced neoplastic transformation in the exocrine pancreas. We propose that Akt1 and Kras exert their oncogenic properties through distinct mechanisms, even though both show addiction to rpS6 phosphorylation.

  14. Detection of chromosome aneuploidy in breast lesions with fluorescence in situ hybridization: Comparison of whole nuclei to thin tissue sections and correlation with flow cytometric DNA analysis

    Energy Technology Data Exchange (ETDEWEB)

    Visscher, D.W.; Wallis, T.; Ritchie, C.A. [Wayne State Univ., Detroit, MI (United States)

    1995-09-01

    We compared flow-cytometric DNA histogram pattern to counts of 4 fluorescent-labelled centromeric probes (chromosomes 1, 7, 8, and 17) in whole nuclei (WN) and in nuclei from formalin-fixed deparaffinized thin tissue section (TS) in 25 breast lesions. In benign lesions, signal gains (i.e., trisomic nuclei) were never observed in greater than 10% of nuclei from either WN or TS preparations. Loss of signal in benign breast lesions, however, varied considerably (0-43%) between individual case and between chromosome probes. The mean incidence of signal loss in WN of benign lesions ranged from 8.9% (chromosome 7) to 14.4 % (chromosome 1) of nuclei. These signal loss frequencies exceeded those of benign lymphoid control cells. In three benign lesions, signal loss in WN (with one probe) was observed in at least 25% of nuclei. Signal losses in benign TS, on average, were 50-150% greater than in matched WN preparations (chromosome 1: 21.7%, chromosome 7: 21.5%). Malignant lesions generally, but not always, displayed fewer monosomic nuclei and more trisomic nuclei in compared to TS, compatible with a slicing (i.e., nuclear truncation) artifact. Signal counts in carcinomas correlated well with flow cytometric DNA index; however, they were also characterized by evidence of genetic instability, manifest as signal gains in a subset of nuclei (10-25%) with individual probes in diploid range cases, as well as intratumoral heterogeneity, reflected as discrepancies in probe counts between WN and TS samples. We conclude that signal losses with centromeric probes are largely, but not entirely, explained by nuclear slicing. The minimum signal loss threshold for establishment of monosomy using interphase cytogenetics is thus unclear, even in WN. Signal gains indicative of trisomy, in contrast, are reliably associated with malignancy and may reflect gross DNA aneuploidy as well as genetic instability. 10 refs., 1 fig., 3 tabs.

  15. Motivations for undertaking DNA sequencing-based non-invasive prenatal testing for fetal aneuploidy: a qualitative study with early adopter patients in Hong Kong.

    Directory of Open Access Journals (Sweden)

    Huso Yi

    Full Text Available BACKGROUND: A newly introduced cell-free fetal DNA sequencing based non-invasive prenatal testing (DNA-NIPT detects Down syndrome with sensitivity of 99% at early gestational stage without risk of miscarriage. Attention has been given to its public health implications; little is known from consumer perspectives. This qualitative study aimed to explore women's motivations for using, and perceptions of, DNA-NIPT in Hong Kong. METHODS AND FINDINGS: In-depth interviews were conducted with 45 women who had undertaken DNA-NIPT recruited by purposive sampling based on socio-demographic and clinical characteristics. The sample included 31 women identified as high-risk from serum and ultrasound based Down syndrome screening (SU-DSS. Thematic narrative analysis examined informed-decision making of the test and identified the benefits and needs. Women outlined a number of reasons for accessing DNA-NIPT: reducing the uncertainty associated with risk probability-based results from SU-DSS, undertaking DNA-NIPT as a comprehensive measure to counteract risk from childbearing especially at advanced age, perceived predictive accuracy and absence of risk of harm to fetus. Accounts of women deemed high-risk or not high-risk are distinctive in a number of respects. High-risk women accessed DNA-NIPT to get a clearer idea of their risk. This group perceived SU-DSS as an unnecessary and confusing procedure because of its varying, protocol-dependent detection rates. Those women not deemed high-risk, in contrast, undertook DNA-NIPT for psychological assurance and to reduce anxiety even after receiving the negative result from SU-DSS. CONCLUSIONS: DNA-NIPT was regarded positively by women who chose this method of screening over the routine, less expensive testing options. Given its perceived utility, health providers need to consider whether DNA-NIPT should be offered as part of universal routine care to women at high-risk for fetal aneuploidy. If this is the case, then

  16. 荧光原位杂交技术检测自然流产组织染色体非整倍体%Detection of chromosomal aneuploidies in spontaneous abortion samples by fluorescence in situ hybridization

    Institute of Scientific and Technical Information of China (English)

    魏萍; 李运星; 陈春; 曾兰; 秦胜芳; 汪雪雁; 席娜

    2015-01-01

    目的 探讨荧光原位杂交(fluorescence in situ hybridization,FISH)技术在自然流产组织染色体非整倍体检测中的价值和自然流产患者中染色体非整倍体比例.方法 对81份自然流产组织标本进行13、21和16、22及18、X、Y三组染色体探针的FISH检测.结果 81份自然流产组织中成功标记80份,检测成功率98.77%,其中异常标本35例,异常检出率43.75%,分别为常染色体三体19例,性染色体单体6例,三倍体9例,四倍体1例.结论 FISH技术用于自然流产组织染色体非整倍体分析具有快速、简便等优点,FISH分析可满足染色体非整倍体分析的需要;早期的自然流产病例中染色体非整倍体占较大的比例.%Objective To analyze 81 spontaneous abortion samples with fluorescence in situ hybridization (FISH).Methods Chromosome 13,21,16,22,18,X and Y probes were used to detect the samples.Results FISH was successful in 80 cases (98.77%).Among these,35 (43.75%) had an abnormal karyotype,which included 19 autosomal aneuploidies,6 sex chromosome aneuploidies,9 triploidies and 1 tetraploidy.Conclusion FISH is a rapid and easy method for detecting chromosomal aneuploidies in spontaneous abortion samples,and has a higher detection rate in early spontaneous abortion samples.

  17. 多重连接依赖探针扩增技术检测胎儿非整倍体染色体异常%Fetal aneuploidy detected by multiplex ligation-dependent probe amplification (MLPA)

    Institute of Scientific and Technical Information of China (English)

    吴琦嫦; 王文博; 江雨; 孔辉; 钟晓玲; 于威威; 孙丽; 周裕林

    2010-01-01

    Objective To investigate the role of muhiplex ligation-dependent probe amplification(MLPA) in identifying fetal aneuploidy of chromosomes 13,18,21,X,and Y. Methods From June 2007 to December 2008,263 samples(prenatal diagnosis group),including amniotic or umbilical cord blood from pregnant women who required prenatal diagnosis,were processed in parallel by MLPA and conventional karyotype to detect fetal aneuploidy.Another 26 samples(fetal death group).ineluding retained abortion and fetal death,were also processed bv MLPA. Results Five cases of 21-trisomy,4 eases of 18-trisomy,1 case of 13-trisomy and 3 cases of 45,X were identified among the prenatal diagnosis group by MLPA,and the results were consistent with karyotype.Two cases of 45,X and 1 case of 18-trisomy were identified among the retained abortion and fetal death group. Conclusions MLPA is a rapid,efficient,simple,reliable and economical technique in detecting most common chromosomal aneuploidies and have important clinical value.%目的 探讨多重连接依赖探针扩增技术(multiplex ligation-dependent probe amplifiea-tion,MLPA)在检测胎儿非整倍体染色体异常中的作用. 方法 2007年6月至2008年12月对263例需进行产前诊断的孕妇(产前诊断组)取羊水或脐血进行MLPA检测,同时进行传统的染色体核型分析.对26例发生稽留流产或死胎的孕妇取胎儿组织提取DNA进行MLPA检测. 结果 产前诊断组检出5例21-三体,4例18-三体,1例13-三体和3例45,X,与细胞核型分析结果一致.稽留流产或死胎组检出2例45,x和1例18-三体. 结论 MLPA可用于检测胎儿最常见的13、18、21、X、Y染色体非整倍体异常,用于产前诊断,快速简单,准确经济,有一定的临床推广价值.

  18. DNA aneuploidy in colorectal adenomas: Role in the adenoma-carcinoma sequence Aneuploidía del ADN en adenomas colónicos: Papel en la secuencia adenoma-carcinoma

    Directory of Open Access Journals (Sweden)

    M. Alcántara Torres

    2005-01-01

    Full Text Available Introduction: aneuploidy has been observed in 6-27% of lesions known to be precursors of colorectal cancer, such as adenomas or ulcerative colitis. It has been suggested that aneuploidy may predispose to malignancy in these cases. However, its role in the adenoma-carcinoma sequence has not been definitely established. The objective of this study was to assess the incidence of aneuploidy in colon adenomas, as well as to study its possible role in the adenoma-carcinoma sequence. Material and methods: the study was performed on a series of 57 large bowel adenomas measuring 10 mm or more, collected from 54 consecutive patients. All specimens were obtained either by endoscopic or by surgical resection. There were 49 adenomas with low-grade dysplasia, two with high-grade dysplasia, two intramucous carcinomas, and four microinvasive carcinomas. A flow cytometric DNA analysis was performed in fresh specimens following Vindelov´s method. Results: aneuploid DNA was detected in five out of 49 low-grade dysplasia adenomas (10%, in all four high-grade dysplasia adenomas or intramucous carcinomas (100%, and in three out of four microinvasive carcinomas (75%. The association between aneuploidy and high-grade dysplasia adenomas, intramucous, or microinvasive carcinoma was statistically significant (p Introducción: en patología benigna de intestino grueso precursora del cáncer colorrectal, como adenomas o colitis ulcerosa, se ha observado aneuploidía en el 6-27% de los casos y se ha sugerido que su presencia predispone al desarrollo de malignidad. Sin embargo, su papel en la secuencia adenoma-carcinoma no se ha demostrado de forma concluyente. El objetivo de nuestro trabajo fue valorar la incidencia de aneuploidía en adenomas colónicos, con y sin signos de malignidad, y estudiar su posible papel en la secuencia adenoma-carcinoma. Material y métodos: el estudio se realizó en una serie de 57 adenomas de intestino grueso, de 10 o más mil

  19. Application of quantitative fluorescence PCR for the prenatal diagnosis of common fetal chromosomal aneuploidies%定量荧光PCR在胎儿常见染色体非整倍体产前诊断中的应用

    Institute of Scientific and Technical Information of China (English)

    刘晓亮; 张媛媛; 崔婉婷; 何蓉; 赵彦艳

    2015-01-01

    目的 评估定量荧光PCR(quantitative fluorescent PCR,QF-PCR)技术在胎儿常见染色体非整倍体产前诊断中的应用.方法 收集孕18~22周羊水标本2436份,针对21、18、13、性染色体上共32个多态性短串联重复序列(short tandem repeat,STR)位点进行多重QF-PCR扩增及毛细管电泳,所有标本同时进行染色体核型分析.结果 QF-PCR检出胎儿染色体非整倍体76例(3.12%).其中21-三体51例,18-三体12例,13-三体2例,三倍体1例,上述结果与核型分析完全一致;QF-PCR提示性染色体数目异常10例,其中9例与核型分析结果一致,1例经核型分析证实为X染色体结构异常.此外,核型分析检出染色体结构异常24例(0.99%),仅1例QF-PCR显示部分STR位点异常,提示可能存在染色体结构异常;核型分析另检出染色体数目异常嵌合体2例(0.08%),仅1例QF-PCR显示临界值,提示可能为嵌合体.结论 QF-PCR可以准确的诊断21、18、13及性染色体的非整倍体改变,可以用于胎儿常见染色体非整倍体的产前快速筛查.%Objective To assess the value of quantitative fluorescence PCR (QF-PCR) for the prenatal diagnosis of common fetal chromosomal aneuploidies.Methods A total of 2436 amniotic fluid samples were collected at 18 to 22 gestational weeks.Multiplex QF-PCR was performed with fluorescencelabeled primers specific for 32 polymorphic short tandem repeat (STR) sites on chromosomes 21, 18, 13, X and Y.The PCR products were assayed by capillary electrophoresis.All samples were also assayed by karyotyping.Results Seventy-six (3.12%) samples were diagnosed as chromosomal aneuploidies by QF-PCR, among which 51 were trisomy 21, 12 were trisomy 18, 2 were trisomy 13, and 1 was triploidy.The results were all consistent with those of karyotyping.Ten samples were suspected as sex chromosomal aneuploidies, among which 9 were confirmed, except for 1 case with X structural abnormality.In addition,karyotyping has diagnosed 24 (0

  20. 应用定量荧光PCR检测自然流产绒毛染色体非整倍体%Detection of chromosome aneuploidies in spontaneous abortion villus samples by quantitative fluorescence PCR

    Institute of Scientific and Technical Information of China (English)

    武真真; 刘宁; 赵勇江; 赵振华; 孔祥东

    2016-01-01

    Objective To assess the value of quantitative fluorescence polymerase chain reaction(QF-PCR) for the detection of chromosomal aneuploidies in chorionic villus samples from early abortion.Methods One hundred seventy seven specimens were collected.Genomic DNA was extracted,and aneuploidies of 8 chromosomes(13,15,16,18,21,22,X and Y) were detected by QF-PCR analysis.Results The QF-PCR was successful in 176(99.4%) of the cases.All detection was completed in 48 hours.Sixty three (35.8%) cases have shown abnormal signals,which included 3 cases of trisomy 13,3 cases of trisomy 15,14 cases of trisomy 16,2 cases of trisomy 18,7 cases of trisomy 22,3 cases of trisomy 21,13 cases of 45,X,1 case of 47,XXX,2 cases of 47,XXY,2 cases of haploidy,11 cases of triploidy,1 case of trisomy 16 and trisomy 22,1 case of trisomy 21 and trisomy 22.Trisomy 16 was the most common chromosome aneuploidy (22.22%),which was followed by 45,X (20.63%),triploidy (17.46%) and trisomy 22 (11.11%).Conclusion QF-PCR is a quick and easy method for detecting chromosomal aneuploidies in chorionic villi tissue.The results can provide important information for genetic counseling for spontaneous abortions.%目的 探讨定量荧光聚合酶链反应技术(quantitative fluorescent polymerase chain reaction,QF-PCR)对于早期自然流产绒毛染色体非整倍体检测的价值.方法 因自然流产而清宫的绒毛组织标本177份,应用基因组DNA提取试剂盒提取绒毛标本中DNA,针对13、15、16、18、21、22号和X、Y染色体行QF-PCR分析.结果 在177份标本中,成功检测176份(99.4%),QF-PCR检测均在48 h得出结果.其中检测结果正常114份(64.2%),检测出异常信号63例(35.8%),其中3例13-三体、3例15-三体、14例16-三体、2例18-三体、7例22-三体、3例21-三体、13例45,X、1例47,XXX、2例47,XXY、2例单倍体、11例三倍体、1例16-和22-三体、1例21-和22-三体.早期胚胎流产物最常见的非整倍体异常依次为16

  1. 高龄孕妇胎儿染色体非整倍体异常的早孕期检测%Detection of fetal chromosomal aneuploidy in pregnant women at advanced maternal age during the first trimester

    Institute of Scientific and Technical Information of China (English)

    汪淑娟; 高志英; 卢彦平; 李亚里; 姜淑芳; 汪龙霞; 张立文

    2014-01-01

    Objective To investigate the value of maternal plasma cell-free fetal DNA (cff-DNA) examination in detection of fetal chromosomal aneuploidy in pregnant women at advanced maternal ages during the first trimester of pregnancy. Methods A total of 136 pregnant women (11 to 13+6 gestational weeks) with advanced maternal ages were screened for fetal chromosomal aneuploidy with ultrasound and maternal plasma cff-DNA examination during March 1, 2011 to August 31, 2013, and the results were then confirmed by karyotype analysis and fluorescence in situ hybridization (FISH). Results Of the 136 women examined, cff-DNA screening detected chromosomal aneuploidy in 5 cases, including trisome-21 in 3 cases, trisome-18 in 1 case, and 45,X in 1 case as confirmed subsequently by karyotype analysis. Ultrasound screening reported a normal finding in one case of trisomy-21, thickening of the NT in the case of trisomy-18, and fetal anasarca in the case of 45,X. Karyotype analysis and follow-up of the women did not find chromosomal abnormality in the 131 negative cases screened by cff-DNA detection. Conclusion Screening of materal plasma cff-DNA allows accurate and early detection of fetal chromosomal aneuploidy in women of advanced maternal ages to avoid unnecessary invasive antenatal examinations.%目的:评价孕妇血浆胎儿游离DNA检测对高龄孕妇胎儿染色体非整倍体异常的早孕期检测价值。方法自2011年3月1日~2013年8月31日,采用早孕期超声筛查和孕妇血浆胎儿游离DNA检测技术,对136例孕11-13+6周的高龄孕妇进行检测,并通过染色体核型分析、荧光染色体原位杂交进行结果验证。结果cff-DNA检测,检出3例21-三体,1例18-三体(同时存在NT增厚),1例45,X(超声提示胎儿全身水肿),与荧光染色体杂交的结果一致,分别为47,XN,+21、47,XN,+18、45,X;筛查阴性者,未发现染色体异常。结论在早孕期开展cff-DNA检测,能更早期、

  2. Noninvasive DNA testing technology in the application of the fetal chromosomal aneuploidy disease%无创DNA检测技术对胎儿染色体非整倍体疾病的筛查效果

    Institute of Scientific and Technical Information of China (English)

    马婷婷; 刘华平; 侯朝晖; 任东平

    2015-01-01

    目的 探讨无创DNA产前检测技术在胎儿染色体非整倍体疾病中的临床应用.方法 将2011年12月—2014年12月在空军总医院产前门诊,经知情同意自愿接受无创DNA产前检测的2 078例单胎自然妊娠孕妇作为研究对象.检测方法从孕妇外周血中提取胎儿游离DNA并进行PCR扩增后利用最新的高通量测序技术,推算出胎儿患染色体非整倍体疾病(如21-三体、18-三体、13-三体综合征等)的风险率.对检测高风险者行产前咨询,建议行羊水穿刺等确诊手段,随访其妊娠结局.结果 无创DNA产前检测异常者23例.10例提示21-三体高风险,2例提示18-三体高风险,1例提示18-三体临界高风险,3例提示13-三体高风险,3例提示性染色体异常(2例提示45,X0;1例提示47,X X Y),4例提示其他染色体异常(2例7号染色体偏多,1例16号染色体偏多,1例17号染色体偏多).经羊水穿刺检查确诊为胎儿非整倍体疾病者11例.确诊病例分别为21-三体6例;18-三体2例;13-三体2例;47,XXY 1例.另外,2例DNA检测提示异常,羊水穿刺检查结果阴性,随访妊娠结局未见异常.应用无创DNA产前检测技术筛查胎儿染色体非整倍体异常的灵敏度为100%,特异度为99.81%,假阳性率为0.19%,假阴性率为0%.结论 无创DNA产前检测技术能够对胎儿染色体非整倍体疾病进行准确筛查,值得推广.%Objective To evaluate the role of noninvasive prenatal detection of DNA technology in the clinical application of fetal chromosomal aneuploidy disease.Methods A total of 2 078 pregnant women of natural singletons pregnancy who approved of accepting noninvasive prenatal detection of DNA in antenatal clinics, Air Force General Hospital antenatal clinics were recruited for this study from December 2011 to December 2014. The method collected peripheral blood of pregnant women, extracted cell-free fetal DNA, and used PCR amplification, then applied a new generation of high

  3. Study of the Sperm Chromosomal Aneuploidies of Teratozoospermic Men%畸形精子症患者精子染色体非整倍体的研究

    Institute of Scientific and Technical Information of China (English)

    朱元; 伍琼芳; 辛才林; 赵琰; 林戈; 谭跃球; 程德华; 卢光琇

    2013-01-01

    Objective: To explore the sperm chromosomal aneuploidies with teratozoospermic men. Methods: Sperm obtained from isolated teratozoospermic men (n=18) and control men with normal fertility (n=5) were analyzed using fluorescent in situ hybridization (FISH) to detect aneuplody of chromosomes 18, X and Y. Results: Totally 58 178 spermatozoa were counted from the teratozoospermia group and 16 369 spermatozoa were counted from the control, with the hybridization rates of 97.5% and 98.3%, respectively. The major types of chromosomal aneuploidies were disomy (YY18, XX18, XY18, Y1818 and X1818) and diploidy (1818XX, 1818YY, 1818XY). In the teratozoospermic group and the control, the disomy rates of 18 chromosome were 0.29 ± 0.16% and 0.03 ± 0.02%, the disomy rates of sex chromosome were 0.65 ± 0.24% and 0.05 ± 0.02%, the diploidy rates were 0.14 ± 0.12% and 0.04 ± 0.03%, respectively. All the differences between the 2 groups were significant (P<0.05). Conclusion: Sperm of isolated teratozoospermic men have higher rates of 18, X and Y chromosomal aneuploidies than those of the fertile controls.%目的:研究畸形精子症患者精子染色体的非整倍体率.方法:应用18号、X和Y染色体着丝粒探针,采用荧光原位杂交(FISH)技术比较畸形精子症患者(畸精组,n=18)和生育力正常且精子正常形态率、浓度、活力等均正常男性(对照组,n=5)精子中18号、X和Y染色体的非整倍体率.结果:畸精组共计数精子58178条,对照组共计数精子16369条.畸精组和对照组杂交效率分别为97.5%和98.3%;染色体非整倍体类型主要有二体(XX 18、YY18、XY18、Y1818和X1818)和二倍体(1818XX、1818YY、1818XY).畸精组和对照组的18号染色体二体率分别为0.29±0.16%和0.03±0.02%,性染色体二体率分别为0.65±0.24%和0.05±0.02%,二倍体率分别为0.14±0.12%和0.04±0.03%.18号、X和Y染色体非整倍体率组间均有统计学差异(P<0.05).结论:与生育力和

  4. 血清学结合超声检查在非整倍体产前筛查中的应用%Application of serologic examination combined with ultrasonography in prenatal screening of aneuploidy

    Institute of Scientific and Technical Information of China (English)

    吴清明; 周瑾; 刘伟; 王瑞; 杨柳

    2011-01-01

    Objective: To explore the application values of serologic examination combined with ultrasonography in prenatal screening of fetal aneuploidy. Methods: Maternal serologic triple examination ( AFP, Free β - hCG and uE3 ) during the second trimester of pregnancy combined with fetal systematical ultrasonography was used for prenatal screening of fetal chromosomal aneuploidy among 1 831 pregnant women of 16 ~ 25 gestational weeks, the pregnant women with high risk of prenatal screening received chromosomal karyotype analysis of amniotic cells. Results: Among 1 831 pregnant women, 107 high risk cases were screened out, including 98 high risk cases of serologic screening, 9 cases with abnormal fetuses detected by ultrasonography, 2 cases diagnosed as Down's syndrome and 2 cases diagnosed as trisomy 18 definitely by chromosomal analysis of amniotic cells. Conclusion: The prenatal screening programme of serologic triple examination during the second trimester of pregnancy combined with fetal systematical ultrasonography can expand the coverage extent of screening objects, reduce misdiagnosis and missed diagnosis, increase the detection rate of fetal chromosomal aneuploidy effectively, which is a simple, minimally invasive and effective prenatal screening protocol.%目的:探讨血清学结合超声在胎儿非整倍体产前筛查中的应用价值.方法:采用孕中期孕母血清学三联(AFP、Freeβ-hCG、uE3)检测结介胎儿系统超声检查,对1 831例孕16~25周孕妇进行胎儿非整倍体染色体病产前筛查,对筛查高风险孕妇,进行羊水细胞染色体核型分析.结果:1 831例孕妇中筛查出高危孕妇107例,其中血清学筛查高危孕妇98例,超声检查胎儿异常9例,经羊水细胞染色体分析产前诊断确诊唐氏综合征2例、18-三体综合征2例.结论:孕中期血清三联筛查结合胎儿系统超声检查的产前筛查方案,可扩大筛查目标的涵盖范围,减少漏诊及误诊;有效提高胎儿非整

  5. 中孕期染色体非整倍体异常胎儿的超声表现分析%Analysis on the ultrasonic manifestations of fetuses with chromosomal aneuploidy abnormality in second trimester of pregnancy

    Institute of Scientific and Technical Information of China (English)

    田晓先; 梁洁梅; 黎新艳; 林莲恩; 李雪芹

    2011-01-01

    目的:分析胎儿染色体异常中孕期超声表现,为胎儿染色体的异常诊断提供线索.方法:回顾性分析49例胎儿染色体异常的中孕期超声表现.结果:49例胎儿非整倍体患者中42例有异常超声表现,30例为超声形态结构异常,18例发现超声软指标,其中6例合并结构异常,7例超声未见明显异常.结论:大部分非整倍体胎儿中孕期可有异常的超声表现.包括形态学和软指标上的异常.提示当胎儿中孕期有异常的超声表现时,应考虑染色体异常的可能性,并提供相应的遗传学咨询.%Objective: To analyze the ultrasonic manifestations of fetuses with chromosomal abnormality in second trimester of pregnancy, provide some clues for the diagnosis of fetal chromosomal abnormality.Methods: The ultrasonic manifestations of 49 fetuses with chromosomal abnormality in second trimester-of pregnancy were analyzed retrospectively.Results: Among 49 fetuses with chromosomal aneuploidy abnormality, 72 fetuses were found with abnormal ultrasonic manifestations, 30 fetuses were found with abnormal morphology and structure, 18 fetuses were found with ultrasonic soft indexes, 6 fetuses were combined with abnormal structure, 7 fetuses were not found with apparent abnormality.Conclusion: Most of the fetuses with chromosomal aneuploidy abnormality in second trimester of pregnancy have abnormal ultrasonic manifestations, including morphological abnormality and abnormal soft indexes, the phenomenon indicates that the possibility of chromosomal abnormality should be considered and corresponding genetic consultation should be provided when the fetuses are found with abnormal ultrasonic manifestations.

  6. Optimized procedure for fluorescence in situ hybridization in rapid prenatal diagnosis of common aneuploidy%改进荧光原位杂交技术快速产前诊断常见染色体异常

    Institute of Scientific and Technical Information of China (English)

    吴菁; 钟梅; 卢建; 潘小英; 郭莉; 王挺

    2011-01-01

    目的 探讨改进荧光原位杂交(fluorescence in situ hybridization,FISH)技术,快速产前诊断羊水间期细胞常见染色体异常的临床应用可行性.方法 改进FISH杂交过程的处理方法和探针杂交液用量,对300例羊水间期细胞进行FISH检测,以羊水细胞培养、核型分析作为结果验证.结果 300例羊水样本,FISH检出17例异常:7例21三体、4例18三体、2例X、l例XXY、1例XXX、1例XYY、1例三倍体,与羊水细胞核型分析结果完全符合.结论 改进FISH技术后检测的准确性、特异性没有受到影响,且检测成本明显降低,可以在临床推广应用于快速产前诊断常见染色体异常.%Objective To optimize the procedure of fluorescence in situ hybridization (FISH),and evaluate it in rapid prenatal diagnosis of common aneuploidy.Methods Amniotic fluid samples from 300pregnant women were tested by both interphase FISH and conventional cell culture for karyotyping from September 2009 and September 2010.Results Seven cases of trisomy 21,4 of trisomy 18,2 of monosomy X,1 of XXY,1 of XXX,and 1 of triploidy were detected by FISH in the 300 amniotic fluid samples.It was concordant with the results from conventional karyotype analysis. The concordance rate was 100%.Conclusion Through a technical modification of FISH procedure,the detection accuracy and specificity was not affected but testing cost reduced greatly. It can be used in rapid prenatal diagnosis of common aneuploidy.

  7. Application of fluorescence in situ hybridization in rapid prenatal diagnosis of chromosome aneuploidy in uncultured amniotic fluid samples%FISH技术在产前诊断胎儿染色体数异常中的应用

    Institute of Scientific and Technical Information of China (English)

    张利平; 剡红民; 秦翠云; 娄超; 马晓萍; 郑军; 强荣

    2011-01-01

    目的 探讨荧光原位杂交(FISH)技术在快速产前诊断胎儿染色体非整倍体异常中的价值.方法 使用荧光原位杂交技术,选用荧光素标记的双色13/21染色体位点特异性探针和三色18/X/Y染色体着丝粒探针,检测760例胎儿羊水细胞.结果 采用双色13/21号和三色18/X/Y染色体荧光探针检测间期未培养羊水细胞,发现8例21三体综合征,1例13三体综合征,1例45,XO,1例47,XXX,3例性染色体嵌合体.荧光原位杂交检测结果 和常规细胞遗传学检测结果 相比,两者符合率为99%.结论 荧光原位杂交技术在产前快速诊断胎儿染色体非整倍体异常有很高的临床价值.%Objective To investgate clinical value of fluorescence in situ hybridization (FISH) in rapid prenatal diagnosis of chromosome aneuploidy of the fetus. Methods Fluorescein-labeled bicolor 13th/21th chromosomal loci specificity probe and triad colour 18th/X/Y kinomere probe were used to detect cells in uncultured amniotic fluid samples of 760 pregnact women. Results 8 fetuses with trisomy 21 syndrome, I fetus with trisomy 13 syndrome, I fetus with with 45 ,XO, 1 fetus with 47,XXX and 5 fetuses with sex chromosome mosaic syndrome were identified. The coincidence rate of diagnosis between FISH and conventional cytogenetics was 99%. Conclusion FISH technique has a high clinic value in rapid diagnosis of chromosome aneuploidy.

  8. Illumina测序技术在母血检测胎儿非整倍体中应用%Detecting fetal chromosomal aneuploidy by Illumina-solexa sequencing DNA in maternal plasma

    Institute of Scientific and Technical Information of China (English)

    冯穗华; 张红云; 陈建勇; 王威; 黄泳华; 陈芳; 蒋馥蔓; 李卫凯; 麦巧娇; 瞿京辉; 张燕玲

    2012-01-01

    目的 研究Illumina测序技术在母血中检测胎儿非整倍体的可行性,及其在无创性产前诊断中的应用前景.方法 68例孕12-39周具有产前诊断指征的单胎妊娠孕妇抽取外周血进行离心、提取血浆中游离DNA,运用Illumina Hiseq2000测序技术进行DNA测序及统计分析.结果 68例孕妇通过Illumina测序技术检测出3例21三体,2例18三体、1例13三体及1例47,XYY.因为濒死胎儿羊水脱落细胞活力极低而致羊水培养失败,传统型染色体核型分析未检测出1例21三体.结论 Illumina测序作为一种无创性产前诊断技术,可准确地筛查21、18、13、X、Y等染色体非整倍体异常,具有安全、准确率高及假阳性率低的优点,值得临床推广.%Objective To study the feasibility of detecting fetal chromosomal aneuploidy and the perspective of non invasive prenatal diagnosis by Illumina sequencing DNA in maternal plasma. Methods 68 singleton pregnant women with gestation weeks of 12 — 39 were recruited. Maternal plasma DNA was extracted and sequenced on Illumina/ Hiseq2000 platform for subsequent statistics analysis. Results Three cases of trisomy 21,two cases of trisomy 18,one cases of trisomy 13,one cases of 47,XYY were successfully indentified by Illumina sequencing. One case of trisomy 21 wasn't detected in traditional karyotyping analysis because the cell of amniotic fluid had exceeding low vitality in the dying fetus. Conclusion As a kind technique of noninvasive prenatal diagnosis,Illumina sequencing Of maternal plasma DNA was effective in identifying fetal chromosomal aneuploidy such as 21,18,13,X,Y. Considering its accuracy and se curity,it Would be worth spreading in clinic.

  9. Ti års erfaring med førstetrimester screening for føtal aneuploidi ved hjælp af biokemi fra gestationsuge 6+0 til 13+6

    DEFF Research Database (Denmark)

    Tørring, Niels; Petersen, Olav Bjørn; Uldbjerg, Niels

    2014-01-01

    i gestationsugerne 8-10. Formål At validere resultaterne af det danske screeningsprogram af første trimester screening for føtal trisomi 21, trisomi 13, trisomi 18 samt triploidi i perioden 2003 til 2013 Datasæt Region Midtjyllands database (RM) (oktober 2003 til oktober 2013); n = 147...... blodprøve i gestationsuge 9 sammenlignet med øvrige uger skyldes at PAPP-A´s diskriminationsevne er maksimal omkring gestationsuge 9. Detektion af Trisomi 18, 13 og triploidi: Tallene i parentes angiver detektionsraten efter inklusion af misdannelsesscanning i gestationsuge 18-19. Singleton (alle prøver......) for føtal trisomi 18: 79,5 % (93,2 %) Singleton (alle prøver) for føtal trisomi 13: 85,7 % (94,3 %) Singleton (alle prøver) for føtal triploidi: 85,2 % (96,3 %) Konklusion Resultaterne viser, at første trimester screening i Danmark for føtal aneuploidi er en robust undersøgelse med høj sensitivitet...

  10. Influence of Chinese Medicine on the Rate of Sperm Aneuploidy and Assisted Reproductive Technology Result%中药治疗对精子非整倍体率及辅助生殖结局的影响

    Institute of Scientific and Technical Information of China (English)

    韩临晓; 孙晓岩; 陈博; 郑志涛; 钟秋生; 潘瑞华

    2016-01-01

    Abstract Objective To study the influence of Chinese medicine on the rate of sperm aneuploidy and assisted reproductive technology(ART ) result .Methods 58 infertile men with oligoasthenoterazoospermia w ho received ART treatment were divided into experimental group (26 cases )and control group (32 cases ) .The experimental group received ART treatment after 3 course of Chinese medicine .The control group received ART treatment di‐rectly .Fluorescence in situ hybridization(FISH )was used to analyze spermatozoa chromosomes .The rate of fertili‐zation ,the rate of cleavage ,the rate of high embryo ,he rate of useful embryo ,the rate of pregnancy ,the rate of a‐bortion and the rate of implantation were observed and compared between two groups .Results Before treatment , the rate of sperm aneuploidy for experimental group and control group was 2.3% and 2.1% respectively ,with no significant difference .After treatment ,the rate of sperm aneuploidy for experimental group was 1.7% w hich was significant lower than before ( P < 0.05) .For experimental group and control group ,the rate of fertilization was 82.55% ,80. 80% ,the rate of cleavage was 99.25% ,98.77% ,the rate of high embryo was 24.91% ,24.07% ,the rate of useful embryo was 76.23% ,70.68% ,the rate of pregnancy was 57.69% ,31.25% ,the rate of abortion was 7.70% ,12.50% ,the rate of implantation was 38.98% ,22.20% .There was significant difference for the rate of pregnancy and implantation between two groups (both P< 0.05) .Conclusion Chinese medicine can reduce the rate of sperm aneuploidy and improve ART result .%目的研究中药治疗对少弱畸形精子症患者的精子染色体非整倍体率及辅助生殖技术(as‐sisted reproductive technology ,ART )结局的影响。方法将58例要求接受 ART 的少弱畸形精子症患者随机分为试验组和对照组。试验组26例,采用生精汤治疗3个月后进行精子染色体分析,再接受辅助生殖治疗;对照组32例,

  11. Detection of fetal sex chromosomal aneuploidies by massively parallel sequencing of cell-free DNA in maternal plasma%孕妇血浆游离DNA高通量测序用于胎儿性染色体非整倍体检测的初步探讨

    Institute of Scientific and Technical Information of China (English)

    林颖; 蒋馥蔓; 秦岭; 马定远; 刘立夫; 陈芳; 张红云; 王威; 季修庆

    2013-01-01

    Objective To explore the clinical efficacy and practical feasibility of massively parallel sequencing (MPS) of cell-free DNA from maternal plasma for detection of sex chromosomal aneuploidies in prenatal diagnosis.Methods A total of 5540 maternal plasma samples from singleton pregnancy in the first or second trimester of pregnancy were collected from August 2011 to December 2012,and detected by using MPS.The sequencing data were compared with the human reference gene-database and statistically analyzed by informatics.The positive cases of sex chromosomal aneuploidies were advised to accept prenatal fetal chromosomal karyotype analysis of amniotic fluid cells using G-banding technique.Results In 10 of 5540 pregnant women MPS revealed sex chromosomal aneuploidies.Using the results of fetal chromosomal karyotyping as golden standard,6 of 10 cases were validated by prenatal karyotyping,including 3 cases of 45,X,1 cases of 47,XXY and 2 case of 47,XYY,while the other 4 cases were confirmed to be euploid karyotype.Conclusion MPS based on maternal plasma DNA to detect fetal sex chromosomal aneuploidies should be feasible,but there can be false positive results.The MPS technology should still be improved for detecting sex chromosomal aneuploidies.%目的 初步探讨孕妇血浆游离DNA高通量测序用于产前胎儿性染色体非整倍体检测的效果及临床可行性.方法 2011年至2012年收集早、中孕期单胎孕妇5540例,在知情同意的原则下采集外周血血浆进行游离DNA的高通量测序检测,通过生物信息学分析,获得测序结果;对测序检出的性染色体非整倍体患者行羊水穿刺,进行染色体G显带分析.结果 5540例样本中测序方法共检出10例性染色体非整倍体,其中6例与G带核型分析结果一致,包括3例45,X,1例47,XXY,2例47,XYY,其余4例G带核型正常.结论 孕母血浆游离DNA高通量测序可对性染色体非整倍体胎儿进行无创性产前检测,但存在假阳性,还需

  12. Detecting aneuploidies of fetus by multiplex ligation-dependent probe amplification%多重连接探针扩增技术检测胎儿非整倍体异常

    Institute of Scientific and Technical Information of China (English)

    王凤羽; 马林先; 李聪敏; 张华; 丰慧根

    2012-01-01

    目的:探讨多重连接探针扩增技术(MLPA)在常见染色体非整倍体异常及其在产前诊断中的应用价值.方法:选择200份羊水标本,提取标本DNA,采用MLPA技术对样本染色体进行分析,并与传统染色体核型分析结果进行比较.结果:在200例样本中,除1例因羊水污染应用传统染色体核型分析失败外,其余检测结果与传统染色体核型分析方法的结果一致(21三体4例,18三体3例,13三体1例,X单体1例,X三体1例,其余190例正常).结论:MLPA技术分析胎儿染色体非整倍体异常是一种简单、快速且有效的方法.%Aim: To investigate the application value of the multiplex ligation-dependent probe amplification technique ( MLPA ) in common aneuploidies and prenatal diagnosis. Methods: A total of 200 amniotic fluid samples were collected. The DNA extracted from amniotic fluid was detected by MLPA. The results of chromosomal G-banding and MLPA of amniotic fluid were compared. Results:Out of 200 samples, the results of 199 by MLPA were consistent with traditional karyotype analysis, including4 trisomy 21,3 trisomy 18 ,1 trisomy 13 ,1 monosomy X,l female with extra X and 190 normal karyotype. Only one case with contamination was failed to reach conclusion by karyotype analysis. Conclusion: MLPA is a simple, rapid and efficacy method for analyzing aneuploids in amniotic fluid.

  13. 多重探针连接依赖式扩增快速检测染色体非整倍体异常%Rapid detection of chromosomal aneuploidies by multiplex ligation-dependent probe amplification

    Institute of Scientific and Technical Information of China (English)

    范新萍; 王立荣; 肖白; 刘敬忠; 高淑英; 张璘; 张颖; 顾莹

    2008-01-01

    Objective To test whether multiplex ligation-dependent probe amplification(MLPA)could be used for the prenatal detection of the most common aneuploidies of chromosomes 13,18,21,X,and Y.Methods 34 cases including 22 blood samples(12 with trisomy 21,1 with monosomy X,one male witll extra Y and 8 healthy persons),4 cord blood samples with Down syndrome and 8 amniotic fluid samples ( 1 with trisomy 21 and 7 normal fetuses)were recruited into this study.All samples were confirmed by karvotype analysis. DNA was extracted from blood and amniotic lysate was incubated with proteinase K.MLPA was used to determine the relative copy numbers.Results The resuhs were available within 48 h and were concordant with karyotype analysis in all but one case of amniotic fluid that was suggested to be triploid sample 69,XXY by MLPA or contaminated by maternal blood.This sample actually was found containing a number of red blood cells after centfifugation in test. In total,the concordance rate with clinical characteristics was 97.1%.The Ratio values of 13,18,21,X in normal samples were approaching 1.0 except chromosome Y having slightly higher variation in relative copy number.The difference of ratio means between the normal and trisomy 21 samples was statistically significant by one-way ANOVA(F=298.906.P=0.000).Conclusion Computer assisted MLPA with high sensitivity is a rapid,simple,automatic and reliable method for detection of common chromosomal aneuploidies.%目的 评价多重探针连接依赖式扩增(muhiplex ligation-dependent probe amplification,MLPA)在常见染色体非整倍体异常及其在产前诊断中的应用价值.方法 收集经染色体核型分析证实的12例21三体、1例(45,X)、1例(47,XYY)患者,8名正常健康人外周血标本和4例21三体胎儿脐带血标本及1例21三体胎儿羊水、7例核型正常胎儿羊水,共计34份样本.提取外周血或脐带血基因组DNA,羊水标本蛋白酶K消化获得细胞裂解液,采用MLPA技术检测34

  14. Chromosomal Aneuploidies and Early Embryonic Developmental Arrest

    Directory of Open Access Journals (Sweden)

    Maria Maurer

    2015-07-01

    Full Text Available Background: Selecting the best embryo for transfer, with the highest chance of achieving a vital pregnancy, is a major goal in current in vitro fertilization (IVF technology. The high rate of embryonic developmental arrest during IVF treatment is one of the limitations in achieving this goal. Chromosomal abnormalities are possibly linked with chromosomal arrest and selection against abnormal fertilization products. The objective of this study was to evaluate the frequency and type of chromosomal abnormalities in preimplantation embryos with developmental arrest. Materials and Methods: This cohort study included blastomeres of embryos with early developmental arrest that were biopsied and analyzed by fluorescence in-situ hybridization (FISH with probes for chromosomes 13, 16, 18, 21 and 22. Forty-five couples undergoing IVF treatment were included, and 119 arrested embryos were biopsied. All probes were obtained from the Kinderwunsch Zentrum, Linz, Austria, between August 2009 and August 2011. Results: Of these embryos, 31.6% were normal for all chromosomes tested, and 68.4% were abnormal. Eleven embryos were uniformly aneuploid, 20 were polyploid, 3 were haploid, 11 displayed mosaicism and 22 embryos exhibited chaotic chromosomal complement. Conclusion: Nearly 70% of arrested embryos exhibit chromosomal errors, making chromosomal abnormalities a major cause of embryonic arrest and may be a further explanation for the high developmental failure rates during culture of the embryos in the IVF setting.

  15. 应用多重连接依赖探针扩增技术快速检测胎儿染色体非整倍体异常%Application of multiplex ligation-dependent probe amplification for rapid detection of aneuploidies in prenatal diagnosis

    Institute of Scientific and Technical Information of China (English)

    马定远; 许争峰; 胡平; 张菁菁; 易龙; 季修庆; 杨驰; 成建; 李璃; 林颖

    2011-01-01

    Objective To determine the applicability of multiplex ligation-dependent probe amplification (MLPA) for rapid detection of aneuploidies in prenatal diagnosis.Methods A total of 561 prenatal samples were analyzed in parallel by MLPA and traditional karyotyping. Another 20 clinical samples with known common chromosome abnormalities were also determined by MLPA to evaluate the accuracy and reliability of MLPA. The results obtained from MLPA were compared with that from traditional karyotyping.Results The results were available within 48 h.A total of 38 aneuploidies were identified by MLPA,including 20 cases of trisomy 21,10 cases of trisomy 18,1 case of trisomy 13,4 cases of Turner syndrome,1 case of Klinefelter syndrome,1 case of 47,XYY trisomy and 1 case of 48,XYY,+18.MLPA was able to detect all the expected aneuploidies with 100% accuracy.The results obtained from MLPA agreed with traditional karyotyping.Among 561 prenatal samples,the results of 550 samples were concordant with those of karyotyping,and the coincidence rate of MLPA was 98.04%.Conclusion MLPA is a rapid,simple and reliable method for detection of the most common chromosome aneuploidies in prenatal diagnosis.MLPA is a valuable tool in prenatal clinical practice.%目的 探讨多重连接依赖探针扩增(multiplex ligation-dependent probe amplification,MLPA)技术在常见染色体非整倍体异常检测及其在产前诊断中的应用价值.方法 应用MLPA技术检测561份产前诊断样本和20例已知染色体异倍体标本,所有样本均进行常规染色体核型分析,比较MLPA结果和染色体核型分析结果,评价MLPA技术的临床符合率.结果 MLPA技术能够在48 h内出具检测结果,共检测出38例染色体异倍体,包括20例21-三体,10例18-三体,1例13-三体,4例Turner综合征,1例Klinefelter综合征,1例超雄综合征,1例48,XYY,+18双三体综合征.MLPA结果与染色体核型结果一致,检测结果100%准确.在561份产前诊断样本中,有550

  16. 多重定量荧光PCR在胎儿常见染色体非整倍体快速诊断中的应用%Application of multiple quantitative fluorescence polymerase chain reaction approach for rapid prenatal diagnosis of common chromosome aneuploidies

    Institute of Scientific and Technical Information of China (English)

    胡婷; 刘洪倩; 朱红梅; 王婧; 张海霞; 祝茜; 赖怡; 秦利; 王和

    2014-01-01

    目的 探讨多重定量荧光PCR(quantitative fluorescence polymerase chain reaction,QFPCR)技术在胎儿常见染色体非整倍体异常快速诊断中的应用.方法 用QF-PCR技术对我院4649名行羊膜腔穿刺术孕妇的4760份羊水样本21、18、13、X和Y染色体数目进行分析,并与染色体核型分析结果进行比较.结果 QF-PCR检测成功率为98.4%.QF-PCR检测出21、18、13、X及Y染色体非整倍体48例(2例核型为46,XY,rob(13∶21),+21;4例为双胎之一21三体),均与核型分析结果一致,5种常见染色体非整倍体异常分析敏感性和特异性均为100%;检出1例21三体嵌合体及4例性染色体异常的嵌合体(1例核型分析漏诊);QF-PCR漏诊4例性染色体嵌合体;染色体核型分析失败的64例样本,QF-PCR检测均得到结果.QF-PCR检测结果与核型分析符合率为98.3%.结论 QF-PCR技术可快速、准确的诊断21、18、13、X及Y染色体非整倍体,并能检出部分嵌合体,作为染色体核型分析的有效补充,在快速产前诊断中具有重要临床实用价值.%Objective To assess the value of multiple quantitative fluorescence polymerase chain reaction (QF-PCR) approach for rapid prenatal diagnosis of common chromosomal aneuploidies.Methods A total of 4760 amniotic samples from 4649 pregnant women were analyzed with QF-PCR for 21,18,13,X and Y aneuploidies,and the results were compared with those of karyotype analysis.Results The overall success rate for QF-PCR was 98.4%.All the 48 cases of 21,18,13,X and Y aneuploidies (including 2 case of 46,XY,rob(13 ∶ 21),+ 21; 4 trisomy 21 in 4 twins) were detected by QF-PCR,with the overall sensibility and specificity both reaching 100%.One mosaicism of trisomy 21 and 4 mosaicisms of sex chromosome (1 misdiagnosed by karyotype analysis) were also detected by QF-PCR.Four mosaicisms of sex chromosome were verified as missed diagnosis.All the 64 cases failed by karyotype analysis were successfully analyzed by the

  17. The effect of folate and riboflavin on chromosomes 8 and 17 aneuploidy in lymphocytes of breast cancer patients and normal controls%叶酸和核黄素对乳腺癌患者淋巴细胞8和17号染色体非整倍体的影响

    Institute of Scientific and Technical Information of China (English)

    倪娟; 邹天宁; 汪旭

    2013-01-01

    OBJECTIVE: The research was to test the effect of folate (FA) and riboflavin (RF) on chromosome 8 and 17 aneuploidy in lymphocytes of breast cancer patients and normal controls. METHODS: Lymphocytes were cultured in each of the four media: high (200 nmol/L,HF) and low (20 nmol/L LF) FA, high (500 nmol/L,HR) and low (1 nmol/L,LR) RF media (LFLR,LFHR,HFLR, HFHR). Chromosomes 8 and 17 aneuploidy was measured in mononucleated (MONO) and cytokinesis-blocked binucleated (BN) cells using dual-color fluorescence in situ hybridization (FISH). RESULTS: In lymphocytes of breast cancer subjects and controls, LF media (LFLR or LFHR) induced significant and similar increases in frequencies of aneuploidy of chromosomes 8 and 17 relative to culture in HF media (HFLR or HFHR) (P0.05). CONCLUSION: FA deficiency is a possible cause of chromosome 8 and 17 aneuploidy. FA is the dominant factor that affects chromosome segregation in our experimental system.%目的:探讨叶酸和核黄素对乳腺癌患者外周血淋巴细胞8和17号染色体非整倍体的影响.方法:采用多色荧光原位杂交(FISH)比较乳腺癌患者与对照组淋巴细胞在叶酸高(200 nmol/L,HF)、低(20 nmol/L,LF)浓度和核黄素高(500 nmol/L,HR)、低(1nmol/L,LR)浓度不同组合(LFLR,LFHR,HFLR,HFHR)下,8和17号染色体在单核细胞及胞质阻断双核细胞中非整倍体的发生频率及其差异.结果:乳腺癌及对照组在高叶酸组合(HFLR+HFHR)培养条件下8和17号染色体单、双核细胞异常信号数总和均显著低于低叶酸组合(LFLR+LFLR) (P<0.01).在各组合浓度下,两条染色体的异常信号频率总和在单核和双核细胞中,乳腺癌患者均较对照组显著增高(P<0.01).叶酸和乳腺癌因素对两条染色体的异常分离均有显著影响(P<0.01),但叶酸缺乏的影响强于乳腺癌因素;核黄素缺乏与乳腺癌因素对两条染色体分离的变异贡献率差异无统计学意义(P>0.05).结论:叶酸缺乏可能导致8

  18. Clinical value of eatly-mid trimester ultrasound scan in the diagnosis of ehromosomal aneuploidy abnormalities%早中孕产前超声检查在染色体非整倍体异常胎儿中的诊断价值

    Institute of Scientific and Technical Information of China (English)

    陈秋妍; 张茜; 郭红梅; 曾秀梅

    2016-01-01

    目的:探讨早中孕期产前超声检查在染色体非整倍体异常胎儿中的诊断价值。方法对2014年3月~2015年10月在我院经羊水细胞、脐血细胞及绒毛细胞染色体核型分析诊断为非整倍体异常的38例胎儿早中孕期(11~28周)产前超声异常声像图进行总结分析。结果38例羊水细胞染色体核型分析确诊为非整倍体异常的胎儿中超声显示异常32例(84.2%,32/38),包括21-三体17例(17/23)、18-三体11例(11/11)、13-三体2例(2/2),45,X 2例(2/2)。其中单发畸形10例(31.2%,10/32),多发畸形12例(37.6%,12/32),仅表现为超声软指标10例(31.2%,10/32)。18-三体、13-三体、45,X胎儿均有超声结构异常,18-三体胎儿中8例表现为超声结构异常合并软指标异常。21-三体胎儿中10例,仅表现为超声软指标异常,7例表现为超声结构异常合并软指标异常。38例非整倍体异常胎儿中以心脏畸形检出例数居多(31.5%,12/38),而颈部淋巴水囊瘤是45,X胎儿的典型超声表现。结论非整倍体异常胎儿常伴有异常的超声声像图表现,部分还有相应的典型超声畸形谱和超声软指标,早中孕期产前超声检查作为非侵入性检查技术对于非整倍体异常胎儿的诊断有重要价值。%Objective To investigate the clinical application of eatly-mid trimester ultrasound scan in the diagnosis of ehromo-somal aneuploidy abnormalities .Methods Early-mid trimester ultrasound imaging features in 38 aneuploidy abnormal fetuses which were diagnosed by CVS , amniocentesis and umbilical vein puncture in our hospital from April 2014 to Octocber 2015 were analyzed retrospectively .Results 38 cases of aneuploidy abnormalities dectected by CVS , amniocentesis and umbilical vein puncture were examined by prenatal ultrasound .Of these cases, 32 were found abnormalities , including 17 with

  19. FISH快速检测自然流产绒毛染色体非整倍体异常的临床价值%Rapid Detection of Chromosomal Aneuploidy in Chorionic Villus of Spontaneous Abortion by Fluorescence in Situ Hybridization

    Institute of Scientific and Technical Information of China (English)

    吴庆华; 史惠蓉; 解艳华; 江淼; 赵振华; 鲁宁; 孔祥东

    2012-01-01

    目的:探讨应用荧光原位杂交技术( FISH)对早期自然流产绒毛染色体非整倍体检测的临床价值.方法:对30例因自然流产行清宫术的绒毛组织行FISH分析,使用7种探针对13、16、18、21、22号和X、Y染色体进行了检测,并对这30例流产夫妇行外周血淋巴细胞染色体常规核型分析.结果:FISH分析的30例自然流产的绒毛组织中,有17例检测出了异常信号,检出率为57%,其中8例16-三体、2例22-三体、2例13-三体和5例三倍体.30例自然流产夫妇外周血淋巴细胞染色体核型未见异常.结论:FISH技术可以快速、简便地检测出流产物绒毛组织染色体非整倍体的异常,FISH技术的应用可以为自然流产夫妇遗传咨询提供重要的信息.%Objective;To evaluate the application of fluorescence in situ hybridization (FISH) for the detection of chromosomal aneuploidy in chorionic villus of spontaneous abortion. Methods:Thirty cases of chori-onic villus were analyzed by FISH, and seven probes were used to detect chromosomes 13, 16, 18, 21, 22, X, Y respectively. Results:In the thirty cases, seventeen cases were shown abnormal signals by FISH with detection rate of 57%, including eight cases of 16-trisomy, two cases of 22-trisomy, two cases of 13-trisomy and five cases of triploidy. Conclusions:FISH analysis is a rapid and easy method in the detection of chromosomal aneuploidy in chorionic villus. The application of FISH can provide important information of genetic counseling for the patients with spontaneous abortion.

  20. 孕妇血浆胎儿游离DNA检测对胎儿染色体拷贝数异常的诊断意义%Significance of detecting free DNA from maternal plasma for the diagnosis of fetal chromosomal aneuploidies

    Institute of Scientific and Technical Information of China (English)

    刘红彦; 吴东; 李慧; 郭社珂; 张朝阳; 廖世秀; 王应太

    2012-01-01

    目的 探讨应用孕妇血浆胎儿游离DNA高通量基因测序技术检测胎儿染色体拷贝数的准确性和实际临床可行性.方法 选择需做产前诊断的153名孕妇,采用高通量基因测序技术检测母体血浆胎儿游离DNA,分析胎儿染色体拷贝数;同时行羊膜腔穿刺进行胎儿染色体核型分析.结果 153名孕妇中,母体血浆游离DNA平行测序技术共检测出6例染色体异常高风险胎儿.羊水分析证实6例均为染色体异常,其中非整倍体5例,分别为47,XYY; 45,X;47,XY,+18;47,XY,+21以及47,XY,+13;染色体结构异常1例,核型为46,XY,der (13; 21)(q10; q10),+21.另检出染色体多态性3例(1例46,XY,21p+;2例46,XY,Yqh-).两种方法检测胎儿染色体拷贝数异常结果一致.结论 母体血浆游离DNA高通量测序分析可以用于胎儿染色体拷贝数异常的检测,具有无创、灵敏度高、特异性强等优点,在胎儿染色体拷贝数异常疾病的产前检测中具有广泛的应用前景.%Objective To determine the feasibility and accuracy of detecting numerical chromosomal abnormalities by high-flux sequencing analysis of free fetal DNA from maternal plasma.Methods High-flux sequencing was applied to analyze fetal chromosome sequence copy numbers in 153 pregnant women.Fetal karyotyping was also carried out on amniocentesis samples.Results Six cases were detected with fetal chromosomal abnormalities by high-flux sequencing analysis, among which five were confirmed by karyotyping to be chromosomal aneuploidies ( 47,XYY; 45,X; 47,XY; + 18,47 ; XY,+ 21 and 47,XY,+13),1 case was confirmed to be structural rearrangement,i.e.,46,XY,der ( 13 ; 21 ) ( q10 ; q10),+ 21.Furthermore,3 chromosomal polymorphisms (one 46,XY,2 lp+ and two 46,XY,Yqh- ) were identified.The two methods yielded similar results on fetal chromosome copy number detection.Conclusion High-flux sequencing analysis of free DNA derived from maternal plasma is efficient for detecting fetal chromosomal

  1. 应用多重连接依赖探针扩增技术快速检测胎儿染色体非整倍体与结构异常%Application of multiplex ligation-dependent probe amplification for rapid detection of aneuploidies and structural chromosomal abnormalities in prenatal diagnosis

    Institute of Scientific and Technical Information of China (English)

    张菁菁; 胡平; 罗春玉; 季修庆; 周静; 刘安; 马定远; 许争峰

    2014-01-01

    目的 探讨多重连接依赖探针扩增(multiplex ligation-dependent probe amplification,MLPA)技术在羊水细胞染色体非整倍体及染色体结构异常检测中的应用.方法 应用MLPA技术对286份羊水样本进行检测,并与常规染色体核型分析进行对比,对于检测到的染色体结构异常应用微阵列比较基因组杂交技术(array comparative genomic hybridization,aCGH)进行验证.结果 在286份羊水中,共检测到10例21-三体,2例18三体,1例13三体,1例嵌合21-三体,1例X单体,1例X染色体短臂大片段缺失,1例18号染色体短臂部分三体,1例18号染色体长臂和短臂大片段缺失.所有MLPA结果与染色体核型分析均一致.对于检测到的染色体结构异常均应用aCGH技术验证,检测结果符合率100%.结论 MLPA可快速检出常见染色体非整倍体以及染色体结构异常包括大片段缺失与重复,为临床产前诊断提供有价值的信息.%Objective To explore the value of multiplex ligation-dependent probe amplification (MLPA) for rapid detection of aneuploidies and structural chromosomal abnormalities during prenatal diagnosis.Methods Two hundred and eight six amniotic fluid samples were analyzed with both MLPA and conventional karyotyping.Structural abnormalities were verified with array comparative genomic hybridization.Results Ten cases of trisomy 21,2 cases of trisomy 18,1 case of trisomy 13,1 case of mosaic trisomy 21,1 case of 45,X,1 case of large deletion of Xp,1 case of trisomy 18p and 1 case of large deletion of 18p and 18q were identified.The same results were derived by both MLPA and conventional karyotyping.Structural abnormalities were verified by array comparative genomic hybridization (aCGH)with 100% accuracy.Conclusion In addition to aneuploidies,MLPA can rapidly identify large deletions and duplications of chromosomes 21,18,13,X and Y.MLPA is supplementary to conventional karyotyping for identification of such chromosomal abnormalities

  2. Application of next-generation DNA sequencing for prenatal testing of fetal chromosomal aneuploidies%新一代测序技术用于胎儿染色体非整倍体无创产前检测的研究

    Institute of Scientific and Technical Information of China (English)

    刘静; 王华; 席惠; 贾政军; 周玉春; 邬玲仟

    2015-01-01

    Objective To explore the value of next-generation sequencing for the non-invasive prenatal testing of fetal chromosomal aneuploidies.Methods Plasma from 4004 women with singleton pregnancy at a gestational age between 12~35+5 weeks was collected prior to amniocentesis between April 19th 2011 and December 31st 2013.The samples were divided into three groups:(1) High risk for Down syndrome by biochemical screening;(2) Advanced maternal age;(3) Abnormalities by ultrasound or other methods.Plasma DNA extracted from above samples was sequenced at low coverage.Positive results were verified against the karyotypes of the fetuses.For those with negative results,the fetuses were followed up by telephone call for at least six months after birth.Results Among 4003 samples subjected to non-invasive prenatal diagnosis,66 (1.65%) had a positive result.In group 1,22 cases of trisomy 21 (T21),3 cases of risomy 18 (T18),1 case of 13 trisomy (T13),8 cases of 45,X and 2 cases of other chromosomal abnormality were detected.In group 2,13 cases of T21,2 cases of T18,1 case of T13,5 cases of 45,X,2 cases of 47,XXN and 1 case of other chromosomal abnormality were detected.In group 3,1 case of T21,1 case of T18,1 case of T13,and 3 cases of 47,XXN were detected.For 55 samples underwent prenatal diagnosis,30 cases of T21 and 4 cases of T18 were discovered,which was consistent with the results of noninvasive prenatal diagnosis.For the 13 cases indicated as 45,X,3 were verified by karyotype analysis,2 were verified as mosaicism (45,X/46,XN),8 were 46,XN (false positives).For the 5 cases indicated as 47,XXN,2 were verified by karyotype analysis,the other 3 were 46,XN (false positives).Karyotypes of 3 cases suspected for other chromosomal abnormalities were all verified as 46,XN (false positive).Until May 1st 2014,telephone follow-up for those with negative screening results only identified a boy with facial abnormalities and developmental delay,which was similar to his older sister

  3. Application of fluorescence in situ hybridization to prenatal diagnosis of aneuploidy in 110 uncultured amniotic fluid samples%应用优化荧光原位杂交技术诊断110例羊水间期细胞常见非整倍体

    Institute of Scientific and Technical Information of China (English)

    刘晗; 廖灿; 黄以宁; 潘敏; 易翠兴; 袁思敏; 胡舜妍; 钟惠珠

    2010-01-01

    Objective To optimize the prenatal diagnosis platform by using domestically made fluorescence in situ hybridization(FISH) kit and to explore the clinical application of FISH to rapid prenatal diagnosis of a wide range of chromosomal abnormalities. Methods Amniotic fluid samples from 110 pregnant women were studied with the rapid prenatal diagnosis method of FISH and the conventional cell culture method of karyotyping, the results from both methods were compared. Results Four cases of trisomy 21 ,1 case of trisomy 18,58 cases of 46, XX, and 47 cases of 46, XY were detected by FISH in the 110 amniotic fluid samples. It is concordant with the results from conventional karyotype analysis. The concordance rate is 100%. Conclusion Domestically made FISH kit can be used to rapidly and accurately detect the most common chromosome aneuploidies by using less sample volume while the price is relatively low. FISH can be a reliable and rapid prenatal diagnostic tool as an adjunct to classical cytogenetic study. It can be used for rapid and accurate prenatal diagnosis of women with high risk of maternal serum screening.%目的 优化现有荧光原位杂交(fluorescence in situ hybridization,FISH)技术,探讨FISH快速产前诊断多种染色体异常的临床应用.方法 改良FISH操作过程中的滴片和杂交液用量,对110例孕妇羊水样本同时进行FISH快速产前诊断和常规细胞培养核型分析.结果 110例羊水样本中,FISH检测出了4例21三体、1例18三体、58例46,XX、47例46,XY,与染色体核型分析的结果一致,符合率100%.结论 国产FISH试剂能快速、准确检测常见的5种染色体数日异常,使用样本量少、价廉.FISH技术可作为经典染色体核型分析的辅助方法,能应用于唐氏血清学高风险孕妇的快速产前诊断.

  4. 无创产前基因测序在胎儿染色体非整倍体基因检测中的临床应用%The application of non-invasive prenatal genetic sequencing for fetal chromosomal aneuploidy

    Institute of Scientific and Technical Information of China (English)

    翁慧男; 梁嘉颖; 曾伟宏; 汤惠霞; 孙怡; 马将军

    2015-01-01

    目的:探讨无创产前基因检测技术在胎儿染色体非整倍体疾病诊断中的检出效率及临床应用价值。方法回顾性分析2011年1月到2013年1月在广东省妇幼保健院就诊的孕妇,纳入标准为高龄妊娠,产前筛查高风险、B 超显示胎儿异常等要求无创产前基因检测的孕12周以上的孕妇1865例,通过母体外周血中胎儿游离 DNA,应用无创产前基因检测得出胎儿患染色体非整倍性疾病(21-三体综合征、18-三体综合征、13-三体综合征)的风险率。并对高风险胎儿采取羊水或脐血,再行细胞培养染色体核型分析以确定胎儿染色体核型,对低风险胎儿均随访至出生后。结果实施无创产前基因检测1865例,结果显示为高风险共21例,其中21-三体综合征高风险为14例,18-三体综合征高风险为5例,l3-三体综合征为2例。以羊水或脐血染色体核型分析的结果为金标准进行结果对照,检测出的14例21-三体综合征高风险中,13例确诊为21-三体综合征,另1例拒绝产前诊断,自行引产,无法确诊核型。检测出的5例18-三体综合征高风险经核型分析确诊为18-三体综合征,13-三体综合征无假阳性。所有低风险胎儿出生后的随访中没有发现假阴性。经统计分析胎儿无创产前基因检测21-三体综合征的敏感性为100%,准确性为92.9%。18-三体综合征和13-三体综合征的敏感性及准确性均为100%。结论无创产前胎儿非整倍体基因检测可提高产前诊断效率,其敏感性、准确性与染色体核型分析技术具有高度的一致性,能减少患儿的出生,快捷、安全、较介入性产前诊断易于接受,具有较高的临床实际应用价值。%Objective To explore the efficiency and the clinical application value of non-invasive prenatal genetic testing for fetal chromosomal aneuploidy.Methods A total of 1 865 pregnant women treated in Guangdong Women and Children Hospital from January 201

  5. Evaluation of prenatal screening for fetal chromosomal aneuploidies by non-invasive fetal cell-free DNA test%无创胎儿游离DNA检测技术在产前胎儿非整倍体筛查中的应用评价

    Institute of Scientific and Technical Information of China (English)

    穆煜; 王庆; 孙芾; 王厚芳; 常玲; Afnan Masoud; 唐莹

    2014-01-01

    Objective To evaluate the specificity and sensitivity of non-invasive fetal trisomy test (NIFTY) and study the prospects and feasibility of detected fetal DNA in maternal blood for prenatal screening of fetal chromosomal a-neuploidies. Methods NIFTY utilizes new generation high-throughput massively parallel DNA sequencing technologies to quantitatively analyze fetal cell-free DNA circulating in maternal plasma. According to the altered concentration of DNA to estimate the fetal chromosome numbers. Results From Mar, 2012 to May, 2013, 233 pregnant women in total were de-tected whose gestational ages ranged from 12~24 weeks. All of them had the pregnancies terminated by normal delivery or early terminations due to abnormal fetus. Eleven high risk pregnancies were detected during this period. In these high risk cases, 5 were Trisomy 21, 3 were Trisomy 18, 1 was Trisomy 13 and 2 were sexual chromosome X0. All NIFTY screened high risk cases were confirmed by cytogenetic tests. The specificity of the test was 100%. 222 were low risk for abnormal chromosome and no abnormal baby was found after birth, therefore, the test sensitivity was 100%. Conclusion Maternal peripheral blood fetal cfDNA test is a very good test method to detect fetal chromosomal aneuploidies. Comparing to the first and second trimester maternal serology screen tests, fetal cfDNA tests are reliable, sensitive with high accuracy. As a non-invasive test, it has no damage to pregnant women and no harm to the fetus.%目的:探讨无创胎儿染色体非整倍体检测技术(non-invasive fetal trisomy test, NIFTY)在胎儿染色体非整倍体产前筛查应用中的特异性和灵敏度。方法利用新一代高通量并行测序技术对母体外周血中的胎儿游离DNA(cell-free DNA, cfDNA)进行定量分析,根据相应DNA含量的变化推断胎儿染色体的异常状况。结果2012年3月至2013年5月,检测孕12~24周的孕妇外周血标本,对233份已结束妊娠的孕妇数

  6. 胃癌17号染色体异倍体改变及TP53和拓扑异构酶Ⅱα蛋白过表达与病理诊断的相关性%Correlation between aneuploidy of chromosome 17,over-expression of TP53 and TOP Ⅱα,and the clinicopathoiogical features and diagnosis of gastric adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    鲁海珍; 吴玉鹏; 罗巍; 韩亚玲; 蔡岩; 徐昕; 梁晶; 刘尚梅; 王明荣

    2009-01-01

    Objective The purpose of this study was to investigate the markers which can be used in auxiliary diagnosis of gastric adenocarcinoma (GAC),and their correlation with their clinicopathological features.Methods 122 surgical specimens including 99 gastric adenocarcinoma (GAC),18 adjacent mucosa and 5 distal normal mucosa were collected,and analyzed by in situ hybridization (FISH).The centromere probe cen17,specific for chromosome 17,which was reported to be frequently amplified in GAC,was selected for the FISH analysis.The clinicopathological features of the 99 GAC cases were reviewed,and the level of TP53 and TOP Ⅱα gene expression,located in chromosome 17,was detected using tissue microarray (TMA),compared with that of corresponding adjacent normal mucosa.Data were analyzed with SPSS 11.5 for Windows.Results The statistical results of FISH and TMA showed that 58.6% of cen17 in tumor tissues were aneuploid,and 45.5% of TP53 and 84.7% of TOP Ⅱα were over-expressed in GAC samples,significantly higher than those in non-tumor gastric mucosa (0,12.1% and 14.1%,respectively) (P =0.000).58 GAC tissues were aneuploid of cen 17,including 26 cases TP53-positive and 49 cases TOP Ⅱα-positive.The expression of TP53 in non-tumor gastric mucosa with dysplasia was significantly higher than that in the mucosa without dysplasia (P=0.009).Aneuploidy of cen17 was more frequent in grade 1 or 2 than in grade 3 GAC(P<0.05).Higher frequency of aneuploidy of cen17 was also observed in the gastric cardia than in pylorus (P<0.05),while no correlation was found between aneuploidy of cen17 and age,sex of patients,lymph node metastasis,and clinical stage of tumors.Over-expression of TP53 protein was associated with the size of tumors (P<0.05).In addition,a negative correlation was observed between over-expression of TOP Ⅱα and lymph node metastasis (LNM) as well as TNM classification (P<0.05).Conclusion Detection of aneuploidy of cen17 as well as over-expression of TP53 and

  7. Chromosomal aneuploidy in embryos conceived with unstimulated cycle IVF

    NARCIS (Netherlands)

    Verpoest, W.; Fauser, B. C.; Papanikolaou, E.; Staessen, C.; Van Landuyt, L.; Donoso, P.; Tournaye, H.; Liebaers, I.; Devroey, P.

    2008-01-01

    There is an ever increasing trend in reproductive medicine to reduce the intensity of ovarian stimulation for in vitro fertilization (IVF) and to restrict the number of embryos that are transferred into the uterine cavity. Recent findings suggest that the magnitude of ovarian stimulation affects the

  8. Susceptibility to Aneuploidy in Young Mothers of Down Syndrome Children

    Directory of Open Access Journals (Sweden)

    Lucia Migliore

    2009-01-01

    Full Text Available We recently observed an increased frequency of binucleated micronucleated lymphocytes in women who had a Down syndrome (DS child before 35 years of age and the fluorescence in situ hybridization analysis revealed that micronuclei were mainly originating from chromosomal malsegregation events, including chromosome 21 malsegregation. That study indicated that women who have a DS child at a young age might have a genetic predisposition to chromosome malsegregation in both somatic and germ line cells. Further studies from our group confirmed increased chromosome damage in blood cells of women who had a DS child at a young age and pointed to a possible role for polymorphisms in folate-metabolizing genes in affecting both chromosome damage and DS risk. In the present article, we review the most recent findings on mechanisms and risk factors for chromosome 21 nondisjunction that lead to DS. Multiple risk factors are likely involved in chromosome nondisjunction; they act at different times in the meiotic process and can be of genetic or environmental (epigenetic origin. We also discuss the increased risk of developing Alzheimer's disease (AD later in life that was observed in women who had a DS child at a young age. Studies performed in the last years that have shown that the brain is, in fact, a complex genetic mosaic of aneuploid and euploid cells support the unified hypothesis trying to relate DS, trisomy 21, and AD.

  9. SNP-based Microdeletion and Aneuploidy RegisTry (SMART)

    Science.gov (United States)

    2016-04-19

    22q11 Deletion Syndrome; DiGeorge Syndrome; Trisomy 21; Trisomy 18; Trisomy 13; Monosomy X; Sex Chromosome Abnormalities; Cri-du-Chat Syndrome; Angelman Syndrome; Prader-Willi Syndrome; 1p36 Deletion Syndrome

  10. Imaging clues in the prenatal diagnosis of syndromes and aneuploidy

    Energy Technology Data Exchange (ETDEWEB)

    Estroff, Judy A. [Harvard Medical School, Fetal-Neonatal Radiology, Boston, MA (United States); Children' s Hospital Boston, Advanced Fetal Care Center, Department of Radiology, Boston, MA (United States)

    2012-01-15

    Advances in fetal sonography and MRI have increased both the range and diagnostic accuracy of detectable fetal anomalies, with many anomalies detectable earlier in pregnancy. The presence of structural anomalies greatly raises the risk that the fetus has a syndrome or abnormal karyotype. In addition, new techniques in maternal serum screening have greatly increased the ability to identify pregnant patients at risk for anomalies and syndromes. This paper reviews maternal first- and second-trimester serum screening and imaging and covers many of the most common fetal karyotypic and structural anomalies. (orig.)

  11. Estrogens, Microtubules, and Aneuploidy: Mechanisms of Mammary Gland Tumorigenesis

    Science.gov (United States)

    2002-06-01

    young female ACI and Sprague-Dawley rats on eight occasions. These cells have been cultured in 100 mm dishes coated with rat tail collagen , using DMEM/F12...hep GyPCYP-dependent metabolism of E2 to the catechols. When expression. No effects were detected. This was mirrored by a NA-D, a cofac tor tha cnt

  12. Psychotic disorder and its characteristics in sex chromosome aneuploidies

    Directory of Open Access Journals (Sweden)

    Annapia Verri

    2009-09-01

    Full Text Available Sex chromosome anomalies have been associated with psychoses. We report a patient with XYY chromosome anomaly who developed a paranoid psychosis. The second case deal with a 51-year-old woman affected by Turner Syndrome and Psychotic Disorder, with a prevalent somatic and sexual focus.

  13. Sex ratios in fetuses and liveborn infants with autosomal aneuploidy

    Energy Technology Data Exchange (ETDEWEB)

    Heuther, C.A.; Martin, R.L.M.; Stoppelman, S.M. [Univ. of Cincinnati, OH (United States)] [and others

    1996-06-14

    Ten data sources were used substantially to increase the available data for estimating fetal and livebirth sex ratios for Patau (trisomy 13), Edwards (trisomy 18), and Down (trisomy 21) syndromes and controls. The fetal sex ratio estimate was 0.88 (N = 584) for trisomy 13, 0.90 (N = 1702) for trisomy 18, and 1.16 (N = 3154) for trisomy 21. All were significantly different from prenatal controls (1.07). The estimated ratios in prenatal controls were 1.28 (N = 1409) for CVSs and 1.06 (N = 49427) for amniocenteses, indicating a clear differential selection against males, mostly during the first half of fetal development. By contrast, there were no sex ratio differences for any of the trisomies when comparing gestational ages <16 and >16 weeks. The livebirth sex ratio estimate was 0.90 (N = 293) for trisomy 13, 0.63 (N = 497) for trisomy 18, and 1.15 (N = 6424) for trisomy 21, the latter two being statistically different than controls (1.05) (N = 3660707). These ratios for trisomies 13 and 18 were also statistically different than the ratio for trisomy 21. Only in trisomy 18 did the sex ratios in fetuses and livebirths differ, indicating a prenatal selection against males >16 weeks. No effects of maternal age or race were found on these estimates for any of the fetal or livebirth trisomies. Sex ratios for translocations and mosaics were also estimated for these aneuploids. Compared to previous estimates, these results are less extreme, most likely because of larger sample sizes and less sample bias. They support the hypothesis that these trisomy sex ratios are skewed at conception, or become so during embryonic development through differential intrauterine selection. The estimate for Down syndrome livebirths is also consistent with the hypothesis that its higher sex ratio is associated with paternal nondisjunction. 36 refs., 5 tabs.

  14. Early Biochemical Screening for Fetal Aneuploidy in the First Trimester

    DEFF Research Database (Denmark)

    Tørring, Niels

    2013-01-01

    Background Screening for fetal trisomy 21 in the first trimester includes analysis of the serological markers pregnancy-associated plasma protein A (PAPP-A) and free beta human choriogonadotropin (free βhCG). With the recent launch of the PAPP-A free βhCG and assays on the Roche Cobas and Elecsys...... platforms, we investigated their clinical and analytical performance in samples from gestaional weeks 8+0 to 14+0. Methods. We conducted a multicenter study based on serum samples from 5397 pregnancies including 107 samples from cases of verified fetal trisomy 21 at 8 to 14 weeks of gestation. A technical...... with the standards for biochemical assays for prenatal screening set by the Fetal Medicine Foundation, with low assay imprecision, and a high clinical performance of prenatal screening for fetal trisomy in the first trimester....

  15. O-GlcNAc Misregulation and Aneuploidy in Breast Cancer

    Science.gov (United States)

    2011-05-01

    Molecular Cell . 42:500-510. Celeste, A., S. Petersen, P.J. Romanienko, O. Fernandez-Capetillo, H.T. Chen, O.A. Sedelnikova, B. Reina-San-Martin, V. Coppola...Mendell. 2007. Transactivation of miR-34a by p53 Broadly†Influences Gene Expression and†Promotes†Apoptosis. Molecular Cell . 26:745-752. Dey, B.K...Kohno, S.-i. Kanno, and A. Yasui. 2010. The ACF1 Complex Is Required for DNA Double- Strand Break Repair in Human Cells. Molecular Cell . 40:976-987

  16. A rare sex chromosome aneuploidy: 48,XXYY syndrome.

    Science.gov (United States)

    Atik, Tahir; Çoğulu, Özgür; Özkınay, Ferda

    2016-06-01

    48,XXYY syndrome is a rare sex chromosome abnormality. Although some physical features are similar to Klinefelter syndrome(47,XXY), 48,XXYY is typically associated with different neuropsyhciatric symptoms and phenotypic findings. Approximately 100 cases with 48,XXYY have been reported to date. In this report, a patient who was diagnosed with 48,XXYY syndrome with clincal evaluation and cytogenetic analysis is presented. A 6-year old male patient was hospitalized due to recurrent respiratory tract infections, recurrent abdominal distention and dyspepsia. He was the first and only child of nonconsanguineous parents. He had a history of mild developmental retardation. In his history, it was learned that he received treatment for gastroesophageal reflux and his symptoms improved with treatment. On physical examination, his weight was found to be 31 kg (>97 centile) and his height was found to be 123 cm (90 centile). He had upslanted palpebral fissures, depressed nasal bridge, long philtrum, incomplete cleft lip and micrognathia. Clinodactilia was found in the fifth fingers in both hands and large big toes and adduction in the second and third toes were found in both feet. Karyotype analysis showed a chromosomal composition of 48,XXYY. The patient presented here is the second Turkish case of 48,XXYY syndrome.

  17. 产前健康教育干预降低胎儿非整倍体染色体疾病的临床研究%The Clinical Study of Prenatal health Education Intervention to Reduce Fetal Aneuploidy Induction of Chromosomal Diseases

    Institute of Scientific and Technical Information of China (English)

    王青; 代振英; 肖红; 孙晓芳; 贾颖

    2015-01-01

    目的:探讨产前健康教育干预在提高产前筛查及无创产前检测降低胎儿非整倍体染色体疾病的临床应用价值。方法采用回顾性分析,选择在滨州市妇幼保健院进行检查的孕妇,2012年01月~2012年12月自愿检查712例设定为对照组。2013年1月~2013年12月来院孕妇给予产前健康教干预1020例,设定为观察组。观察两组产前筛查率,高危孕妇的无创产前检测率以及出生缺陷率。结果观察组参加产前筛查率高于对照组(P<0.01),参加产前无创检测高于对照组(P<0.01),差异有统计学意义。在对照组266例未参加筛查的患者中,分娩唐氏儿1例,观察组77例未参加筛查者分娩唐氏儿 0例。结论产前健康教育干预明显提高产前筛查率及无创产前检测率,降低出生缺陷,有良好的临床应用价值。%Objective Prenatal health education intervention in improving the clinical value of prenatal screening and non-Invasive prenatal detection of fetal aneuploidy reduce chromosomal diseases. Methods A retrospective analysis of pregnant women who choose to check the Maternal and Child Health Hospital, Binzhou city,2012 January 2012 to December, voluntary acceptance of 712 patients were examined as control group,2013 January 2013 to December, 1020 pregnant women to prenatal health education intervention as the observation group. Prenatal screening rates ,Non - Invasive prenatal detection rate of high-risk pregnant women and the rate of birth defects were observed in two groups. Results Patients participate in prenatal screening rate than the control group,the differences are statistical y significant(P<0.01),There was 1 cases of Down's children in the control group did not participate in the screening of 266 cases of patients,There was 0 cases of Down's children in the observation group 77 cases did not participate in the screening of patients. Conclusion Prenatal health education intervention

  18. Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints

    DEFF Research Database (Denmark)

    Jahn, Stephan C; Corsino, Patrick E; Davis, Bradley J;

    2013-01-01

    instability. Expression of these complexes in the MCF10A cell line leads to retinoblastoma protein (Rb) hyperphosphorylation, a subsequent increase in proliferation rate, and increased expression of the spindle assembly checkpoint protein Mad2. This results in a strengthening of the spindle assembly...

  19. ANEUPLOIDY AND CHROMOSOME BREAKAGE IN SWIM-UP VERSUS UNPROCESSED SEMEN FROM TWENTY HEALTHY MEN

    Science.gov (United States)

    Toxicologic and epidemiologic studies have investigated a number of factors believed to induce cytogenetic damage in human sperm cells in order to estimate heritable risk to future generations. Most of these studies, however, have not enriched research semen specimens for fertil...

  20. Aneuploidy screening of human IVF embryos: Cytogenetic aspects and clinical implications

    NARCIS (Netherlands)

    E.B. Baart (Esther)

    2007-01-01

    textabstractThe introduction of this thesis provides the reader with the necessary background information to understand the rationale behind the studies conducted. It starts with the observation that human incidence of chromosomal abnormalities in oocytes and embryos. Furthermore, an explanation

  1. Perennial aneuploidy as a potential material for gene introgression between maize and Zea perennis

    Institute of Scientific and Technical Information of China (English)

    FU Jie; TANG Qi-lin; YANG Xiu-yan; CHENG Ming-jun; LÜ Gui-hua; WANG Pei; WU Yuan-qi; ZHENG Ming-min; ZHOU Shu-feng; RONG Ting-zhao

    2015-01-01

    Hybridization, which al ows for gene lfow between crops, is dififcult between maize and Zea perennis. In this study, we aim to initiate and study gene lfow between maize and Z. perennis via a special aneuploid plant (MDT) derived from an interspeciifc hybrid of the two species. The chromosome constitution and morphological characters of MDT as wel as certain backcross progenies were examined. Results from genomic in situ hybridization (GISH) indicate that aneuploid MDT consisted of nine maize chromosomes and 30 Z. perennis chromosomes. The backcross progenies of MDT×maize displayed signiifcant diversity of vegetative and ear morphology;several unusual plants with speciifc chromosome constitution were founded in its progenies. Some special perennial progeny with several maize chromosomes were obtained by backcrossing MDT with Z. perennis, and the ifrst whole chromosome introgression from maize to Z. perennis was detected in this study. With this novel material and method, a number of maize-tetraploid teosinte addition or substitution lines can be generated for further study, which has great signiifcance to maize and Z. perennis genetic research, especial y for promoting introgression and transferring desirable traits.

  2. DNA-aneuploidy in rhabdomyosarcomas as compared with other sarcomas of childhood and adolescence.

    NARCIS (Netherlands)

    Molenaar, W M; Dam-Meiring, A; Kamps, W A; Cornelisse, C J

    1988-01-01

    In the current study DNA-ploidy was determined in a group of 11 desmin-positive rhabdomyosarcomas and found to be aneuploid in all of them. In three cases, synchronous metastases could be studied as well. In two of them a hypotetraploid peak was observed not present in the primary tumor. In two othe

  3. FISH analysis of MALT lymphoma-specific translocations and aneuploidy in primary cutaneous marginal zone lymphoma.

    NARCIS (Netherlands)

    Schreuder, M.I.; Hoefnagel, J.J.; Jansen, P.A.M.; Krieken, J.H.J.M. van; Willemze, R.; Hebeda, K.M.

    2005-01-01

    Primary cutaneous marginal zone lymphomas (PCMZL) share histological and clinical characteristics with mucosa-associated lymphoid tissue (MALT) lymphomas suggesting a common pathogenesis. A number of recurrent structural and numerical chromosomal aberrations have been described in MALT lymphoma, but

  4. Investigating and correcting plasma DNA sequencing coverage bias to enhance aneuploidy discovery.

    Directory of Open Access Journals (Sweden)

    Dineika Chandrananda

    Full Text Available Pregnant women carry a mixture of cell-free DNA fragments from self and fetus (non-self in their circulation. In recent years multiple independent studies have demonstrated the ability to detect fetal trisomies such as trisomy 21, the cause of Down syndrome, by Next-Generation Sequencing of maternal plasma. The current clinical tests based on this approach show very high sensitivity and specificity, although as yet they have not become the standard diagnostic test. Here we describe improvements to the analysis of the sequencing data by reducing GC bias and better handling of the genomic repeats. We show substantial improvements in the sensitivity of the standard trisomy 21 statistical tests, which we measure by artificially reducing read coverage. We also explore the bias stemming from the natural cleavage of plasma DNA by examining DNA motifs and position specific base distributions. We propose a model to correct this fragmentation bias and observe that incorporating this bias does not lead to any further improvements in the detection of fetal trisomy. The improved bias corrections that we demonstrate in this work can be readily adopted into existing fetal trisomy detection protocols and should also lead to improvements in sub-chromosomal copy number variation detection.

  5. Epidemiology of double aneuploidies involving chromosome 21 and the sex chromosomes.

    Science.gov (United States)

    Kovaleva, Natalia V; Mutton, David E

    2005-04-01

    The chance of two chromosome abnormalities occurring in one conceptus is very small. However, some authors have suggested that double aneuplodies (DAs) might be more common than the product of their individual frequencies. The nonrandomness of such DA events was considered to be evidence that nondisjunction (NDJ) may be genetically determined. Data collected from the National Down syndrome Cytogenetic Register (NDSCR) in England and Wales and from the literature indicate that the frequencies of all nonmosaic DAs, except for 48,XXY,+21, are lower than expected, probably because of strong intrauterine selection against such pregnancies. Collectively, we identified 52 cases of nonmosaic 48,XXY,+21; 28 cases of 48,XYY,+21; and 14 cases of 48,XXX,+21 in liveborns and 13 cases of 48,XXY,+21; four cases of 48,XYY,+21; and two cases of 48,XXX,+21 after prenatal diagnoses. Among these cases, analysis of the published unbiased cytogenetic surveys of liveborn DS revealed 24 cases of 48,XXY,+21; nine cases of 48,XYY,+21; and seven cases of 48,XXX,+21. These figures are different from the expected proportion of 1:1:1 (P XYY,+21 DA, with a mean maternal age of 24.7 (P XYY,+21 cases (P genetic predisposition, may play a more important role in the etiology of the most common DA, 48,XXY,+21.

  6. Linking Sister Chromatid Cohesion to Apoptosis and Aneuploidy in the Development of Breast Cancer

    Science.gov (United States)

    2005-07-01

    instead ofa pituitary isograft as in the original specific optical filters TRI, TR2, and TR3 (Chroma Technology, Brattleboro, experiment. A pituitary... isograft results in marked increases in the circulating VT). Quantitative evaluation of the hybridization was performed using a levels of prolactin and...transcription start sites Untreated 9/50(18) 49.2 16 6/10 Pituitary isograft 7/50(14) 41.4 14 7/7using Genomatix Suite and a neural network promoter prediction

  7. DNA damage, somatic aneuploidy, and malignant sarcoma susceptibility in muscular dystrophies.

    Science.gov (United States)

    Schmidt, Wolfgang M; Uddin, Mohammed H; Dysek, Sandra; Moser-Thier, Karin; Pirker, Christine; Höger, Harald; Ambros, Inge M; Ambros, Peter F; Berger, Walter; Bittner, Reginald E

    2011-04-01

    Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD-pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD-gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases.

  8. DNA Damage, Somatic Aneuploidy, and Malignant Sarcoma Susceptibility in Muscular Dystrophies

    OpenAIRE

    2011-01-01

    Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD-pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD-gene defects and strain background stro...

  9. Cytogenetic Mechanism for the Aneuploidy and Mosaicism Found in Tetraploid Pacific Oyster Crassostrea gigas (Thunberg)

    Institute of Scientific and Technical Information of China (English)

    ZHANG Zhengrui; WANG Xinglian; ZHANG Quanqi; Standish Allen Jr

    2014-01-01

    Chromosome constitution was investigated in adult tetraploid Pacific oyster produced by blocking the first polar body of triploid eggs which were fertilized with haploid sperms. A high incidence of aneuploid and heteroploid mosaics were found among the offspring. Of 20 individuals identified, only 9 (45%) were eutetraploid which contained 40 chromosomes; 2 (10%) were ane-uploid (hypotetraploid), which contained 39 and 38 chromosomes, respectively;and 9 (45%) were heteroploid mosaics. One mosaic was consisted of cells containing 40 and 39 chromosomes, respectiovely (1:1 in cell number), while the other 8 were consisted of cells containing chromosomes varying between tetraploid and triploid. It was also interesting to note that 3 mosaics even contained some diploid cells with 20 chromosomes. A certain number of cells of 2 tetraploids and 8 mosaics spread with 32-37 well-scattered and some clumped chromosomes at metaphase. The percentage of aneuploid cells with chromosomes varying between triploid and tetraploid correlated significantly with that of heteroploid mosaics cells with clumping chromosomes (P<0.05). Our findings sug-gested that reversion existed in both tetraploid and triploid oyster and chromosome clumping may underline the chromosome elimi-nation in tetraploid oyster. It seems that the reversing cells, at least some of them, continuously eliminate their chromosomes until the most stable diploid state is established.

  10. Counseling parents before prenatal diagnosis: do we need to say more about the sex chromosome aneuploidies?

    Science.gov (United States)

    Lalatta, Faustina; Tint, G Stephen

    2013-11-01

    Sex chromosome trisomies (SCT), an extra X chromosome in females (triple X, XXX), males with an extra X chromosome (Klinefelter syndrome, XXY) or an extra Y chromosome (XYY) occur because of errors during meiosis and are relatively frequent in humans. Their identification has never been the goal of prenatal diagnosis (PD) but they almost never escape detection by any of the methods commonly in use. Despite recommendations and guide-lines which emphasize the importance of structured counseling before and after PD, most women remain unaware that testing for serious genetic abnormalities is more likely to uncover these trisomies. With the increasing use of PD more and more prospective parents receive a diagnosis of sex chromosome trisomies and are faced with the dilemma of whether to terminate the pregnancy or to carry it to term. Despite the dramatic and emotionally devastating consequences of having to make such a decision, they have little opportunity to consider in advance the possible outcomes of such a pregnancy and, rather than relying on their own feelings and judgements, are forced to depend on the advice of counseling professionals who may or may not themselves be fully aware of what having an extra sex chromosome can mean to the development of a child. We address here the principles of reproductive autonomy together with an analysis of the major issues that ought to be discussed with the parents before a PD is carried out in order to minimize detrimental effects caused by this unexpected finding.

  11. Ectopia cordis in a first-trimester sonographic screening program for aneuploidy.

    Science.gov (United States)

    Sepulveda, Waldo; Wong, Amy E; Simonetti, Luis; Gomez, Enrique; Dezerega, Victor; Gutierrez, Jorge

    2013-05-01

    We review the sonographic features, antenatal course, and perinatal outcomes in 7 cases of ectopia cordis diagnosed in the first trimester. Four cases were associated with a large omphalocele (pentalogy of Cantrell) and 2 with a body stalk anomaly. The remaining fetus had isolated thoracic ectopia cordis. Two pregnancies were terminated; 2 fetuses died in utero; 2 infants died after delivery; and 1 died at 3 months of age. We conclude that the diagnosis of ectopia cordis can easily be established during the first trimester. In agreement with the currently available literature, the prognosis of ectopia cordis in our series was uniformly poor.

  12. Analysing the Influence of the Spontaneous Aneuploidy Frequency on the Cell Population System Cultivation

    Directory of Open Access Journals (Sweden)

    G. A. Nefedov

    2015-01-01

    Full Text Available The paper provides a qualitative analysis of M.S. Vinogradova's nonlinear model for dynamics of the cell population system. This system describes the stem cells cultivation in vitro under resource constraints. The system consists of two populations, namely: population of normal cells and population of abnormal cells. Resource constraints are considered as linear dependences of mitosis parameters on the normalized densities of each population.One of the key parameters that effects on the realization of the system evolution scenarios is a parameter that determines a share of the normal cells, which pass, when dividing, into population of the abnormal cells. The paper analyses both the existence conditions of the rest points and the changes of the evolution scenarios of population system with changing abovementioned parameter and other system parameters held fixed. It is shown that there is a saddle-node bifurcation in the system; the bifurcation value of the parameter is found. The paper shows the interval of parameter values in which the favorable scenarios of population system evolution are implemented. It also presents results of mathematical modeling.

  13. DNA Aneuploidy by Flow Cytometry Is an Independent Prognostic Factor in Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Mar Abad

    1998-01-01

    Full Text Available In the present study the prognostic value of both DNA ploidy and the proliferative activity of tomour cells were studied in a series of 76 consecutive patients suffering from gastric tumours. DNA ploidy and the proliferative index (as measured by the percentage of S-phase cells were determined by flow cytometry using fresh tumour specimens.

  14. DNA damage, somatic aneuploidy, and malignant sarcoma susceptibility in muscular dystrophies.

    Directory of Open Access Journals (Sweden)

    Wolfgang M Schmidt

    2011-04-01

    Full Text Available Albeit genetically highly heterogeneous, muscular dystrophies (MDs share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD-pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD-gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1, amplification of oncogenes (Met, Jun, recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases.

  15. Investigating and correcting plasma DNA sequencing coverage bias to enhance aneuploidy discovery.

    Science.gov (United States)

    Chandrananda, Dineika; Thorne, Natalie P; Ganesamoorthy, Devika; Bruno, Damien L; Benjamini, Yuval; Speed, Terence P; Slater, Howard R; Bahlo, Melanie

    2014-01-01

    Pregnant women carry a mixture of cell-free DNA fragments from self and fetus (non-self) in their circulation. In recent years multiple independent studies have demonstrated the ability to detect fetal trisomies such as trisomy 21, the cause of Down syndrome, by Next-Generation Sequencing of maternal plasma. The current clinical tests based on this approach show very high sensitivity and specificity, although as yet they have not become the standard diagnostic test. Here we describe improvements to the analysis of the sequencing data by reducing GC bias and better handling of the genomic repeats. We show substantial improvements in the sensitivity of the standard trisomy 21 statistical tests, which we measure by artificially reducing read coverage. We also explore the bias stemming from the natural cleavage of plasma DNA by examining DNA motifs and position specific base distributions. We propose a model to correct this fragmentation bias and observe that incorporating this bias does not lead to any further improvements in the detection of fetal trisomy. The improved bias corrections that we demonstrate in this work can be readily adopted into existing fetal trisomy detection protocols and should also lead to improvements in sub-chromosomal copy number variation detection.

  16. Confined trisomy 8 mosaicism of meiotic origin: a rare cause of aneuploidy in childhood cancer.

    Science.gov (United States)

    Valind, Anders; Pal, Niklas; Asmundsson, Jurate; Gisselsson, David; Holmquist Mengelbier, Linda

    2014-07-01

    Whether chromosome abnormalities observed in tumor cells may in some cases reflect low-grade somatic mosaicism for anomalies present already at zygote formation, rather than acquired somatic mutations, has for long remained a speculation. We here report a patient with Wilms tumor, where constitutional somatic mosaicism of trisomy 8 was detected in a previously healthy 2 ½-year-old boy. Single Nucleotide Polymorphism (SNP) array analysis of tumor tissue revealed a complex distribution of allele frequencies for chromosome 8 that could not be explained solely by mitotic events. Combined analysis of allele frequencies, chromosome banding, and fluorescence in situ hybridization revealed that the majority of tumor cells contained four copies of chromosome 8, with three distinct haplotypes at a 2:1:1 ratio. Because the patient had not been subject to organ transplantation, these findings indicated that the tumor karyotype evolved from a cell with trisomy 8 of meiotic origin, with subsequent somatic gain of one additional chromosome copy. Haplotype analysis was consistent with trisomy 8 through nondisjunction at meiosis I. Matched normal renal tissue or peripheral blood did not contain detectable amounts of cells with trisomy 8, consistent with the complete lack of mosaic trisomy 8 syndrome features in the patient. This case provides proof of principle for the hypothesis that tumor genotypes may in rare cases reflect meiotic rather than mitotic events, also in patients lacking syndromic features. © 2014 Wiley Periodicals, Inc.

  17. Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development.

    Directory of Open Access Journals (Sweden)

    Rajiv C McCoy

    2015-10-01

    Full Text Available Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4-8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos provides insight into the cytogenetic mechanisms underlying their formation and the consequences for human fertility.

  18. EFFECT OF GOSSYPOL ACETIC ACID ON CHROMOSOME ABERRATIONS AND ANEUPLOIDIES IN OOCYTES AND ZYGOTES OF MICE

    Institute of Scientific and Technical Information of China (English)

    WANGRen-Li; ZHANGZhong-Shu

    1989-01-01

    It was reported that gossypol acetic acid could effectively inhibit th~ implantation in ratA. This finding indicated that gossypol acet/c acid might also be used as a female contraceptive. The Present study further investigated the genetic effect of gossypol acetic

  19. Application of Molecular Cytogenetic Technique for Rapid Prenatal Diagnosis of Aneuploidies in Iranian Population

    Directory of Open Access Journals (Sweden)

    Habib Nasiri

    2009-06-01

    Full Text Available Objective: Classic cell culture and karyotyping is routinely used for prenatal detection of different chromosomal abnormalities. Molecular cytogenetic techniques have also recently been developed and used for this purpose. Quantitative florescence PCR using short tandem repeat (STR markers has more potential for high throughput diagnosis. Marker heterozygosity in short tandem repeats (STR is of critical importance in the clinical applicablity of this method. Materials and Methods: Different STR markers on chromosomes 13, 18, 21, X and Y  were analysed from  amniotic samples to detect related disorders such as Down, Edward, Patau,  Klinefelter sundromes , as well as sex chromosomes numerical abnormalities . Results: In our population some markers (D18S976, DXS6854, D21S11, and D21S1411 showed alleles with sizes out of expected ranges. But others occupied narrower range of predicted distribution. Most markers have enough heterozygosity (66.3-94.7 to be used for prenatal diagnosis. Furthermore, results obtained from full karyotype for all samples were in concordance with results of molecular cytogenetic testing. Conclusion: It is concluded that, in urgent situations, if proper markers used, molecular cytogenetic testing (QF-PCR could be a useful method for rapid prenatal diagnosis (PND in populations with high rate of consanguinity such as Iran.  

  20. Investigation of QF-PCR Application for Rapid Prenatal Diagnosis of Chromosomal Aneuploidies in Iranian Population

    Directory of Open Access Journals (Sweden)

    Jila Dastan

    2011-03-01

    Full Text Available Objective:G-Banding followed by standard chromosome analysis is routinely used for prenatal detection of chromosomal abnormalities. In recent years, molecular cytogenetic techniques have been developed for rapid diagnosis of chromosomal abnormalities. Among these methods Quantitative Florescence Polymerase Chain Reaction (QF-PCR has been widely used for this purpose. HHeterozygosity of short tandem repeat (STR markers which leads to informativity is the most critical requirement for feasibility of QF-PCR. Methods:In this study we analyzed several short tandem repeats on chromosomes 13, 18, 21, X and Y on amniotic fluid samples obtained from PND candidates to diagnose conditions such as Down, Edward and Patau syndromes and also numerical sex chromosome abnormalities such as Klinefelter and Turner syndromes. Findings:Most of the analyzed STRs had acceptable heterozygosity (66.3-94.7 to be used in QF-PCR based prenatal diagnosis. Moreover, results obtained from both methods (standard karyotype and QF-PCR for all samples were in accordance with each other. Conclusion:In case of using appropriate STR markers, and in certain clinical indications, QF-PCR could be used as useful technique for prenatal diagnosis even in consanguine populations such as Iranians.

  1. Mustard Gas Surrogate, 2-Chloroethyl Ethylsulfide (2-CEES), Induces Centrosome Amplification and Aneuploidy in Human and Mouse Cells

    Science.gov (United States)

    2014-03-01

    permeabilization    with 1%  Nonidet   P ‐ 40  (Fisher) in PBS for 10 minutes at room temperature.  Cells were blocked   in 15% NGS (Life Technologies) for 1 hour and...in each of at least 100 cells.  p  < 0.05  comparing  treated to untreated cells with more  than 2 centrosomes per cell, except for 50 μM,  which was...00537‐1 [pii]  10.1016/j.freeradbiomed.2009.09.011  Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry  P , Doxsey SJ. 1998. Centrosome

  2. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo : a randomized controlled trial

    NARCIS (Netherlands)

    Baart, Esther B.; Martini, Elena; Eijkemans, Marinus J.; Van Opstal, Diane; Beckers, Nicole G. M.; Verhoeff, Arie; Macklon, Nicolas S.; Fauser, Bart C. J. M.

    2007-01-01

    To test whether ovarian stimulation for in-vitro fertilization (IVF) affects oocyte quality and thus chromosome segregation behaviour during meiosis and early embryo development, preimplantation genetic screening of embryos was employed in a prospective, randomized controlled trial, comparing two ov

  3. Nuclei size in relation to nuclear status and aneuploidy rate for 13 chromosomes in donated four cells embryos

    DEFF Research Database (Denmark)

    Agerholm, I E; Hnida, C; Crüger, D G;

    2008-01-01

    PURPOSE: The aim was to elucidate if the nuclear size and number are indicative of aberrant chromosome content in human blastomeres and embryos. METHODS: The number of nuclei and the nucleus and blastomere size were measured by a computer controlled system for multilevel analysis. Then the nuclei...... were enumerated for 13 chromosomes by a combination of PNA and DNA probes. RESULTS: In the mononucleated embryos there was no difference in the mean size of chromosomally normal and abnormal nuclei but a significant difference in the mean nuclei size of nuclei that had gained chromosomes compared...... to nuclei that had lost chromosomes. The nuclei from multinucleated blastomeres had a significant smaller mean size and the frequency of chromosomally aberrant blastomeres was significantly higher. CONCLUSION: The mean nuclear size is not a marker for the chromosome content in mononucleated embryos. However...

  4. FISH analysis of 15 chromosomes in human day 4 and 5 preimplantation embryos : the added value of extended aneuploidy detection

    NARCIS (Netherlands)

    Baart, E. B.; van den Berg, I.; Martini, E.; Eussen, H. J.; Fauser, B. C. J. M.; Van Opstal, D.

    2007-01-01

    Objective Screening for an increased number of chromosomes may improve the detection of abnormal embryos and thus contribute to the capability of preimplantation genetic screening (PGS) to detect the embryo(s) for transfer in IVF with the best chance for a healthy child. Good-quality day 4 and 5 emb

  5. Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: Report of five infants

    NARCIS (Netherlands)

    M.M. van Haelst (Mieke); J. Hoogeboom (Jeanette); R-J.H. Galjaard (Robert-Jan); W.J. Kleijer (Wim); N.S. den Hollander (Nicolette); R.R. de Krijger (Ronald); R.C.M. Hennekam (Raoul); M.F. Niermeijer (Martinus)

    2001-01-01

    textabstractFive infants (two girls and three boys) from four families all had severe pre- and post-natal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and developed uncontrollable clonic seiz

  6. The CIN4 chromosomal instability qPCR classifier defines tumor aneuploidy and stratifies outcome in grade 2 breast cancer

    DEFF Research Database (Denmark)

    Szász, Attila Marcell; Li, Qiyuan; Eklund, Aron Charles

    2013-01-01

    Purpose: Quantifying chromosomal instability (CIN) has both prognostic and predictive clinical utility in breast cancer. In order to establish a robust and clinically applicable gene expression-based measure of CIN, we assessed the ability of four qPCR quantified genes selected from the 70-gene...... Chromosomal Instability (CIN70) expression signature to stratify outcome in patients with grade 2 breast cancer. Methods: AURKA, FOXM1, TOP2A and TPX2 (CIN4), were selected from the CIN70 signature due to their high level of correlation with histological grade and mean CIN70 signature expression in silico. We...... assessed the ability of CIN4 to stratify outcome in an independent cohort of patients diagnosed between 1999 and 2002. 185 formalin-fixed, paraffin-embedded (FFPE) samples were included in the qPCR measurement of CIN4 expression. In parallel, ploidy status of tumors was assessed by flow cytometry. We...

  7. Total globozoospermia associated with increased frequency of immature spermatozoa with chromatin defects and aneuploidy: a case report.

    Science.gov (United States)

    Vozdova, M; Rybar, R; Kloudova, S; Prinosilova, P; Texl, P; Rubes, J

    2014-10-01

    Globozoospermia, characterised by the presence of round spermatozoa lacking acrosomes in an ejaculate, is a known cause of male infertility. Semen analysis, including sperm chromatin structure assay, toluidine blue, chromomycin A3 and aniline blue staining and fluorescence in situ hybridisation, was performed in an infertile globozoospermic patient to establish to which extent these genetic factors contributed to his infertility. No spermatozoa capable of hyaluronan (HA) binding were detected in the HA binding assay. Increased rates of immature spermatozoa with defective replacement of histones by protamines, DNA breaks and disturbed chromatin integrity and sperm aneuploid for the sex chromosomes were observed. Intracytoplasmic sperm injection (ICSI) was used in three in vitro fertilisation (IVF) cycles, and enough morphologically well-developing embryos were obtained in each cycle. However, no pregnancy was achieved. The infertility of our couple, resistant to IVF/ICSI treatment, was most probably caused by a combination of male and female factors.

  8. Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management

    NARCIS (Netherlands)

    Bayindir, Baran; Dehaspe, Luc; Brison, Nathalie; Brady, Paul; Ardui, Simon; Kammoun, Molka; van der Veken, Lars; Lichtenbelt, Klaske; van den Bogaert, Kris; van Houdt, Jeroen; Peeters, Hilde; van Esch, Hilde; de Ravel, Thomy; Legius, Eric; Devriendt, Koen; Vermeesch, Joris R.

    2015-01-01

    Noninvasive prenatal testing by massive parallel sequencing of maternal plasma DNA has rapidly been adopted as a mainstream method for detection of fetal trisomy 21, 18 and 13. Despite the relative high accuracy of current NIPT testing, a substantial number of false-positive and false-negative test

  9. Relationship of isolated single umbilical artery to fetal growth, aneuploidy and perinatal mortality : systematic review and meta-analysis

    NARCIS (Netherlands)

    Voskamp, B. J.; Fleurke-Rozema, H.; Oude-Rengerink, K.; Snijders, R. J. M.; Bilardo, C. M.; Mol, B. W. J.; Pajkrt, E.

    2013-01-01

    ObjectiveTo review the available literature on outcome of pregnancy when an isolated single umbilical artery (iSUA) is diagnosed at the time of the mid-trimester anomaly scan. MethodsWe searched MEDLINE (1948-2012), EMBASE (1980-2012) and the Cochrane Library (until 2012) for relevant citations repo

  10. A qualitative study looking at informed choice in the context of non‐invasive prenatal testing for aneuploidy

    Science.gov (United States)

    Hill, Melissa; Chitty, Lyn S.

    2016-01-01

    Abstract Objective To explore women's attitudes towards non‐invasive prenatal testing (NIPT) and determine factors influencing their decisions around uptake of NIPT. Method We conducted qualitative interviews to assess knowledge, attitude and deliberation amongst women offered NIPT in a public health service. In total, 45 women took part in telephone interviews (79% participation rate). Results Most women could recount the key aspects of NIPT discussed during pre‐test counselling but had variable knowledge about Down syndrome. Analysis of women's attitudes towards undergoing NIPT revealed three dominant factors they considered when reflecting on the test: (1) how NIPT compared with alternative testing options, (2) reflections on coping and (3) moral or religious values. Exploring the deliberative process revealed the different paths women take when making decisions. For some, it was an extension of the decision to have Down syndrome screening; some considered it early on following the booking‐in appointment; others made step‐wise decisions about NIPT when it became relevant to them. Conclusion Our findings support the importance of personalised counselling, whereby women and their partners have the opportunity to reflect on the implications of the test results in the context of their own lives and values. Our data highlight the influence of personal circumstances on decision‐making. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd. PMID:27477537

  11. Fetal Aneuploidy Detection by Cell-Free DNA Sequencing for Multiple Pregnancies and Quality Issues with Vanishing Twins

    Directory of Open Access Journals (Sweden)

    Sebastian Grömminger

    2014-06-01

    Full Text Available Non-invasive prenatal testing (NIPT by random massively parallel sequencing of maternal plasma DNA for multiple pregnancies is a promising new option for prenatal care since conventional non-invasive screening for fetal trisomies 21, 18 and 13 has limitations and invasive diagnostic methods bear a higher risk for procedure related fetal losses in the case of multiple gestations compared to singletons. In this study, in a retrospective blinded analysis of stored twin samples, all 16 samples have been determined correctly, with four trisomy 21 positive and 12 trisomy negative samples. In the prospective part of the study, 40 blood samples from women with multiple pregnancies have been analyzed (two triplets and 38 twins, with two correctly identified trisomy 21 cases, confirmed by karyotyping. The remaining 38 samples, including the two triplet pregnancies, had trisomy negative results. However, NIPT is also prone to quality issues in case of multiple gestations: the minimum total amount of cell-free fetal DNA must be higher to reach a comparable sensitivity and vanishing twins may cause results that do not represent the genetics of the living sibling, as described in two case reports.

  12. Bacterial artificial chromosomes (BACs)-on-Beads™ as a diagnostic platform for the rapid aneuploidy screening of products of conception.

    Science.gov (United States)

    Sheath, Karen L; Duffy, Lisa; Asquith, Philip; Love, Donald R; George, Alice M

    2013-08-01

    The aim of the present study was to evaluate the use of KaryoLite™ bacterial artificial chromosomes (BACs)‑on‑Beads™ (BoBs) technology for the rapid screening of products of conception (POC). Validation and prospective studies were carried out on 85 and 95 patient samples, respectively. Validation studies had previously been analyzed using routine culture and G-banded karyotyping. BoBs resulted in an abnormality detection frequency of 27%, with a failure rate of <3%. The time required for processing was significantly lower compared with that of tissue culture. In conclusion, BoBs technology decreased the failure rate, while increasing the analytical sensitivity compared with G-banded karyotype analysis alone. Additionally, significant cost savings may be achieved with regard to the time of processing and analysis of specimens.

  13. Chromosome-wide aneuploidy study of cultured circulating myeloid progenitor cells from workers occupationally exposed to formaldehyde

    NARCIS (Netherlands)

    Lan, Qing; Smith, Martyn T; Tang, Xiaojiang; Guo, Weihong; Vermeulen, Roel; Ji, Zhiying; Hu, Wei; Hubbard, Alan E; Shen, Min; McHale, Cliona M; Qiu, Chuangyi; Liu, Songwang; Reiss, Boris; Beane-Freeman, Laura; Blair, Aaron; Ge, Yichen; Xiong, Jun; Li, Laiyu; Rappaport, Stephen M; Huang, Hanlin; Rothman, Nathaniel; Zhang, Luoping

    2015-01-01

    Formaldehyde (FA) is an economically important industrial chemical to which millions of people worldwide are exposed environmentally and occupationally. Recently, the International Agency for Cancer Research concluded that there is sufficient evidence that FA causes leukemia, particularly myeloid le

  14. BubbleTree: an intuitive visualization to elucidate tumoral aneuploidy and clonality using next generation sequencing data.

    Science.gov (United States)

    Zhu, Wei; Kuziora, Michael; Creasy, Todd; Lai, Zhongwu; Morehouse, Christopher; Guo, Xiang; Sebastian, Yinong; Shen, Dong; Huang, Jiaqi; Dry, Jonathan R; Xue, Feng; Jiang, Liyan; Yao, Yihong; Higgs, Brandon W

    2016-02-29

    Tumors are characterized by properties of genetic instability, heterogeneity, and significant oligoclonality. Elucidating this intratumoral heterogeneity is challenging but important. In this study, we propose a framework, BubbleTree, to characterize the tumor clonality using next generation sequencing (NGS) data. BubbleTree simultaneously elucidates the complexity of a tumor biopsy, estimating cancerous cell purity, tumor ploidy, allele-specific copy number, and clonality and represents this in an intuitive graph. We further developed a three-step heuristic method to automate the interpretation of the BubbleTree graph, using a divide-and-conquer strategy. In this study, we demonstrated the performance of BubbleTree with comparisons to similar commonly used tools such as THetA2, ABSOLUTE, AbsCN-seq and ASCAT, using both simulated and patient-derived data. BubbleTree outperformed these tools, particularly in identifying tumor subclonal populations and polyploidy. We further demonstrated BubbleTree's utility in tracking clonality changes from patients' primary to metastatic tumor and dating somatic single nucleotide and copy number variants along the tumor clonal evolution. Overall, the BubbleTree graph and corresponding model is a powerful approach to provide a comprehensive spectrum of the heterogeneous tumor karyotype in human tumors. BubbleTree is R-based and freely available to the research community (https://www.bioconductor.org/packages/release/bioc/html/BubbleTree.html).

  15. Mitotic defects lead to pervasive aneuploidy and accompany loss of RB1 activity in mouse LmnaDhe dermal fibroblasts.

    Directory of Open Access Journals (Sweden)

    C Herbert Pratt

    Full Text Available BACKGROUND: Lamin A (LMNA is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350 and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670. Cells from progeria patients exhibit cell cycle defects in both interphase and mitosis. Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1 activity, leading to aberrant cell cycle control in interphase, but how mitosis is affected by LMNA is not well understood. RESULTS: We examined the cell cycle and structural phenotypes of cells from mice with the Lmna allele, Disheveled hair and ears (Lmna(Dhe. We found that dermal fibroblasts from heterozygous Lmna(Dhe (Lmna(Dhe/+ mice exhibit many phenotypes of human laminopathy cells. These include severe perturbations to the nuclear shape and lamina, increased DNA damage, and slow growth rates due to mitotic delay. Interestingly, Lmna(Dhe/+ fibroblasts also had reduced levels of hypophosphorylated RB1 and the non-SMC condensin II-subunit D3 (NCAP-D3, a mitosis specific centromere condensin subunit that depends on RB1 activity. Mitotic check point control by mitotic arrest deficient-like 1 (MAD2L1 also was perturbed in Lmna(Dhe/+ cells. Lmna(Dhe/+ fibroblasts were consistently aneuploid and had higher levels of micronuclei and anaphase bridges than normal fibroblasts, consistent with chromosome segregation defects. CONCLUSIONS: These data indicate that RB1 may be a key regulator of cellular phenotype in laminopathy-related cells, and suggest that the effects of LMNA on RB1 include both interphase and mitotic cell cycle control.

  16. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: A randomized controlled trial

    NARCIS (Netherlands)

    E.B. Baart (Esther); E. Martini (Elena); M.J.C. Eijkemans (René); D. van Opstal (Diane); N.G.M. Beckers (Nicole); A. Verhoeff (Arie); N.S. Macklon (Nick); B.C.J.M. Fauser (Bart)

    2007-01-01

    textabstractBACKGROUND: To test whether ovarian stimulation for in-vitro fertilization (IVF) affects oocyte quality and thus chromosome segregation behaviour during meiosis and early embryo development, preimplantation genetic screening of embryos was employed in a prospective, randomized controlled

  17. Nuclei size in relation to nuclear status and aneuploidy rate for 13 chromosomes in donated four cells embryos

    DEFF Research Database (Denmark)

    Agerholm, I.E.; Hnida, C.; Cruger, D.G.

    2008-01-01

    Purpose The aim was to elucidate if the nuclear size and number are indicative of aberrant chromosome content in human blastomeres and embryos. Methods The number of nuclei and the nucleus and blastomere size were measured by a computer controlled system for multilevel analysis. Then the nuclei...

  18. Non-invasive aneuploidy detection using free fetal DNA and RNA in maternal plasma: recent progress and future possibilities.

    NARCIS (Netherlands)

    Go, A.T.; Vugt, J.M.G. van; Oudejans, C.B.

    2011-01-01

    BACKGROUND: Cell-free fetal DNA (cff DNA) and RNA can be detected in maternal plasma and used for non-invasive prenatal diagnostics. Recent technical advances have led to a drastic change in the clinical applicability and potential uses of free fetal DNA and RNA. This review summarizes the latest cl

  19. A simple screening method for detection of Klinefelter syndrome and other X-chromosome aneuploidies based on copy number of the androgen receptor gene

    DEFF Research Database (Denmark)

    Ottesen, A M; Garn, I D; Aksglaede, L;

    2007-01-01

    -gene expression. The XIST-expression based assay was correct in only 29/36 samples (81%). Our findings demonstrated that the AR-qPCR technique is a simple and reliable screening method for diagnosis of patients with Klinefelter syndrome or other chromosomal disorders involving an aberrant number of X-chromosomes.......Due to the high prevalence and variable phenotype of patients with Klinefelter syndrome, there is a need for a robust and rapid screening method allowing early diagnosis. Here, we report on the development and detailed clinical validation of a quantitative real-time PCR (qPCR)-based method...... chromosome abnormalities (46,XX males; 47,XYY)(n = 4) and normal karyotypes (46,XY) (n = 13). The reference range for the AR-copy number was established as 0.8-1.2 for one copy and 1.7-2.3 for two copies. The qPCR results were within the reference range in 17/18 samples (94%) or 30/31 (97%) samples with one...

  20. A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes.

    Science.gov (United States)

    Peiris, Heshan; Duffield, Michael D; Fadista, Joao; Jessup, Claire F; Kashmir, Vinder; Genders, Amanda J; McGee, Sean L; Martin, Alyce M; Saiedi, Madiha; Morton, Nicholas; Carter, Roderick; Cousin, Michael A; Kokotos, Alexandros C; Oskolkov, Nikolay; Volkov, Petr; Hough, Tertius A; Fisher, Elizabeth M C; Tybulewicz, Victor L J; Busciglio, Jorge; Coskun, Pinar E; Becker, Ann; Belichenko, Pavel V; Mobley, William C; Ryan, Michael T; Chan, Jeng Yie; Laybutt, D Ross; Coates, P Toby; Yang, Sijun; Ling, Charlotte; Groop, Leif; Pritchard, Melanie A; Keating, Damien J

    2016-05-01

    Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.

  1. A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes.

    Directory of Open Access Journals (Sweden)

    Heshan Peiris

    2016-05-01

    Full Text Available Type 2 diabetes (T2D is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21. To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.

  2. Experimental Population Genetics of Meiotic Drive Systems. III. Neutralization of Sex-Ratio Distortion in Drosophila through Sex-Chromosome Aneuploidy

    OpenAIRE

    Lyttle, Terrence W.

    1981-01-01

    Laboratory populations of Drosophila melanogaster were challenged by pseudo-Y drive, which mimics true Y-chromosome meiotic drive through the incorporation of Segregation Distorter (SD) in a T(Y;2) complex. This causes extreme sex-ratio distrotion and can ultimately lead to population extinction. Populations normally respond by the gradual accumulation of drive suppressors, and this reduction in strength of distortion allows the sex ratio to move closer to the optimal value of 1:1. One popula...

  3. A simple screening method for detection of Klinefelter syndrome and other X-chromosome aneuploidies based on copy number of the androgen receptor gene

    DEFF Research Database (Denmark)

    Ottesen, A M; Garn, I D; Aksglaede, L;

    2007-01-01

    Due to the high prevalence and variable phenotype of patients with Klinefelter syndrome, there is a need for a robust and rapid screening method allowing early diagnosis. Here, we report on the development and detailed clinical validation of a quantitative real-time PCR (qPCR)-based method...... of the copy number assessment of the androgen receptor (AR) gene, located to Xq11.2-q12. We analysed samples from 50 individuals, including a healthy male and female controls and patients with Klinefelter syndrome (47,XXY; 48,XXXY) (n = 28), mosaicisms (46,XX/47,XXY/48XXYY; 45,X/46,XY) (n = 3), other sex......-gene expression. The XIST-expression based assay was correct in only 29/36 samples (81%). Our findings demonstrated that the AR-qPCR technique is a simple and reliable screening method for diagnosis of patients with Klinefelter syndrome or other chromosomal disorders involving an aberrant number of X-chromosomes....

  4. A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes

    Science.gov (United States)

    Peiris, Heshan; Duffield, Michael D.; Fadista, Joao; Kashmir, Vinder; Genders, Amanda J.; McGee, Sean L.; Martin, Alyce M.; Saiedi, Madiha; Morton, Nicholas; Carter, Roderick; Cousin, Michael A.; Oskolkov, Nikolay; Volkov, Petr; Hough, Tertius A.; Fisher, Elizabeth M. C.; Tybulewicz, Victor L. J.; Busciglio, Jorge; Coskun, Pinar E.; Becker, Ann; Belichenko, Pavel V.; Mobley, William C.; Ryan, Michael T.; Chan, Jeng Yie; Laybutt, D. Ross; Coates, P. Toby; Yang, Sijun; Ling, Charlotte; Groop, Leif; Pritchard, Melanie A.; Keating, Damien J.

    2016-01-01

    Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D. PMID:27195491

  5. 胎儿染色体非整倍体产前筛查进展%Advances in antenatal screening for fetal aneuploidy

    Institute of Scientific and Technical Information of China (English)

    黄赛琼; 宋亦军; 刘俊涛

    2014-01-01

    过去30年里,胎儿染色体非整倍体产前筛查从单纯的孕妇年龄筛查到不同模式的母血清学筛查,检出率和准确度均逐渐提高.近三年,采用大规模平行测序技术对母血浆胎儿游离DNA进行测序的无创产前检测(noninvasive prenatal testing,NIPT)被用于胎儿染色体非整倍体产前筛查领域.本文回顾了传统血清学筛查方案的进展,并阐述了无创DNA产前检测方法的发现、临床应用、局限性及应用前景.

  6. Acceptance of non-invasive prenatal testing by cell free foetal DNA for foetal aneuploidy in a developing country: experience at a tertiary care centre in India

    Directory of Open Access Journals (Sweden)

    Namrata Kashyap

    2016-03-01

    Conclusions: Newer genomic technology involving cell free maternal DNA is a new storm in prenatal diagnosis. Its application in clinical practice is the need of the hour, however, the lack of awareness, high cost and unavailability of the test in the country appears to be a major limiting factor for its poor acceptability. [Int J Reprod Contracept Obstet Gynecol 2016; 5(3.000: 705-710

  7. New techniqe of screening chromosome aneuploidy in prenatal%产前筛查染色体非整倍体的新技术

    Institute of Scientific and Technical Information of China (English)

    王芳; 乔福元

    2004-01-01

    染色体非整倍体主要是指13、18、21三体及Turner综合征、三倍体综合征。XYY综合征及Klinefelter综合征,它是各种先天畸形的重要原因。产前诊断染色体非整体具有重要价值。目前已在临床中应用的筛查21三体征的方法为使用酶联免疫法检测孕妇外周血中妊娠相关血浆蛋白(PAPP—A)、甲胎蛋白(AFP—α),人绒毛膜促性腺激素(HCG-β)浓度值,

  8. 染色体非整倍体畸变的产前诊断研究进展%Study Progress of Chromosome Aneuploidy in Prenatal Diagnosis

    Institute of Scientific and Technical Information of China (English)

    唐宁

    2008-01-01

    染色体非整倍体是指细胞的染色体数目多或少了一条或多条。非整倍体畸变可分为单体型、三体型、多体型、嵌合体。临床上常见的非整倍体畸变包括了21三体综合征(Down综合征)、18三体综合征(Edwards综合征)、13三体综合征(Patau综合征),以及一些性染色体畸变,例如X单体(Turner综合征),或性染色体三体,如47XXX(X三体综合征)、47XXY(K linefelter综合征)、47XYY(XYY综合征)等。多年研究表明13、18、21及X,Y非整倍体占新生儿染色体数目异常的95%。在这类遗传病中,在胎儿期常有流产、死胎、畸胎等,患儿可表现为先天智力低下、生长发育迟缓,常伴有五官、四肢、内脏等方面畸形,对家庭和社会造成重大危害。基于这点,学者们在不断地寻求各种诊断方法来避免这类患儿的出生。近年来,随着多学科不断发展并相互渗透,使得产前诊断技术不断提高,快捷和准确是发展方向。目前常用的有非浸入性产前诊断方法和浸入性产前诊断方法。1非浸入性产前诊断方法1.1孕妇外周血中胎儿游离的DNA和RNA 1997年Lo[1]等利用PCR技术在妊娠12周~40周孕期男性胎儿的孕妇血浆和血清中检测到睾丸决定基因(SR...

  9. Study on clincal application of non-invasive prental genetic testing for fetal chromosomal aneuploidy%无创产前DNA检测胎儿染色体非整倍的临床应用分析

    Institute of Scientific and Technical Information of China (English)

    王杰; 董弘; 冀云鹏; 郭志远; 周燕; 周雪原; 侯丽青; 王晓华

    2016-01-01

    目的 探讨无创产前DNA检测技术在产前诊断中的应用价值.方法 针对2012年1月~ 2015年2月在内蒙古妇幼保健院产前诊断中心就诊的1115例孕妇,采集孕妇外周静脉血,提取血浆DNA,制备测序文库,应用Ion Proton半导体测序平台得的基因序列,并与人类的参考基因组比对,进行统计分析.对检测结果为高风险者行羊水穿刺,以羊水或脐血核型分析作为实验对照以及检测标准;对检测结果为低风险的孕妇随访妊娠结局.结果 1115例样本中,提示胎儿高风险有14例,其中21-三体高风险3例,18三体高风险4例,13三体高风险2例,性染色体异常2例,低风险为1101例;高风险孕妇行羊水或脐血穿刺及染色体核型分析,以其为金标准进行结果对照,结果显示存在2例13-三体高风险患者为假阳性,1例X染色体高风险患者,其羊水细胞核型分析结果为47,XYY;其余11例染色体核型分析结果均与无创产前DNA检测的结果相符.对检查结果为低风险的孕妇进行产后随访,无漏诊病例.胎儿游离DNA高通量基因测序技术的敏感度为100% (12/12),特异度为99.82% (1103/1105).结论 应用无创产前DNA检测技术对孕妇血浆游离DNA进行胎儿染色体非整倍体检测,具有无创、快速、敏感度高、特异度高等优势,具有重要的临床应用价值.

  10. Genetic analysis of sex chromosomal aneuploidies and Robertsonian translocation%性染色体非整倍体合并罗氏易位患者的遗传学分析

    Institute of Scientific and Technical Information of China (English)

    邵敏杰; 高雪峰; 黄瑾; 张小为

    2010-01-01

    目的 应用细胞遗传学和分子生物学技术分析1例少弱精子患者的核型,确定其少弱精子的原因.方法 应用实验室常规染色体标本制备方法进行G-显带和C-显带,并应用Yq12区DYZ1探针和Yp11.1-q11.1区DYZ3探针与病例的中期分裂相进行荧光原位杂交(fluorescence in situ hybridization,FISH),同时对患者进行了Y染色体微缺失的检测.结果 结合G-显带、C-显带和FISH检测结果,确定该患者核型为46,XYY,dic(13,22)(p11.1;p11.1).Yq11区生精基因微缺失检测未发现该患者存在缺失.结论 细胞遗传学检测结合FISH可以明确诊断复杂的染色体异常,为患者提供正确的遗传咨询和生育指导.和C-显带,并应用Yq12区DYZ1探针和Yp11.1-q11.1区DYZ3探针与病例的中期分裂相进行荧光原位杂交(fluorescence in situ hybridization,FISH),同时对患者进行了Y染色体微缺失的检测.结果 结合G-显带、C-显带和FISH检测结果,确定该患者核型为46,XYY,dic(13,22)(p11.1;p11.1).Yqll区生精因微

  11. Clinical application of non-invasive prenatal testing for detecting chromosome aneuploidy%产前检测胎儿染色体非整倍体临床应用分析

    Institute of Scientific and Technical Information of China (English)

    文萍; 王挺; 李琼; 李海波; 李红

    2014-01-01

    目的 评价基于第二代高通量测序技术(HTS)的无创产前检测(NIPT)胎儿染色体非整倍体的临床应用价值.方法 收集要求NIPT的单胎孕妇2932例,抽取外周血,富集血清中的胎儿游离DNA,经HTS二次测序检测21、18、13号染色体非整倍体及性染色体异常.对检测提示高危的孕妇,根据孕周行羊膜腔或者脐静脉穿刺,行胎儿核型分析,随访妊娠结局.最后将NIPT与核型分析、妊娠结局综合进行统计学分析.结果 (1)2932例孕妇中,共检出25例21三体高危,6例18三体高危,2例13三体高危,15例提示性染色体异常.(2)随访妊娠结局2716例,结果显示NIPT检测阴性中无21三体、18三体、13三体综合征.根据目前随访资料,NIPT检测T21/T18/T13的综合阳性率1.13%,灵敏度100%,特异度99.85%,假阳性率0.15%,阳性预测值87.88%,阴性预测值100%;NIPT检测T21灵敏度100%,特异度99.9%,假阳性率0.1%,阳性预测值92%,阴性预测值100%;NIPT检测T18灵敏度100%,特异度100%,假阳性率0,阳性预测值100%,阴性预测值100%.结论 NIPT可作为高危人群21、18号染色体非整倍体的“二次筛查”方案;13号染色体非整倍体检测及性染色体异常检测尚需要提高其特异度.NIPT有望成为产前高危人群筛查染色体非整倍体的一种新模式.

  12. Application of noninvasive prenatal testing in the screening of fetal aneuploidy%无创产前基因检测在胎儿染色体非整倍体筛查中的应用

    Institute of Scientific and Technical Information of China (English)

    梅瑾; 王小华; 王昊; 杨晓楠; 方锴; 韩渭

    2014-01-01

    目的 评估无创产前基因检测技术(noninvasive prenatal testing,NIPT)在胎儿染色体非整倍体产前筛查与诊断中的临床应用价值.方法 针对2012年5月至2013年4月在杭州市第一人民医院集团产前诊断中心就诊的高龄、唐氏生化筛查高风险和中等风险孕妇,采用高通量大规模平行测序方法进行胎儿染色体非整倍体的无创产前检测.对检测结果为高风险者进一步进行染色体核型分析,对检测结果为低风险的孕妇随访妊娠结局,评估NIPT对染色体非整倍体检测的敏感性和特异性.结果 2 358例检测孕妇中,高风险23例,染色体核型分析结果显示,NIPT检测21三体、18三体的敏感性为100%,检测13三体的敏感性为0.2 335例低风险妊娠结局随访,B超检查胎儿结构异常7例,未发现21三体综合征患儿出生.结论 NIPT对21三体、18三体综合征检测具有较高的敏感性和特异性.NIPT作为唐氏筛查的一种常规补充手段,可避免95%以上的唐氏生化筛查假阳性病例进行有创性的产前诊断.

  13. NIPT应用于胎儿非整倍体畸形诊断的研究进展%Current progress on the application of NIPT in diagnosis of fetal aneuploidy

    Institute of Scientific and Technical Information of China (English)

    滕月; 刘丹; 黄谱; 李旭; 李春芳

    2016-01-01

    伴随着1997年于孕妇的外周血中发现胎儿来源的基因片段(cfDNA)以及基因组测序技术、生物信息学技术的不断进步,无创性产前诊断技术(non-invasive prenatal testing,NIPT)得以迅速发展.NIPT是一项通过分析母血中胎儿染色体成分的分子诊断技术,目前主要应用于胎儿非整倍体畸形(21-三体综合征、18-三体综合征及13-三体综合征)的产前诊断.该文就NIPT技术在产前诊断,特别是在胎儿非整倍体畸形中的研究进展及面临的挑战进行总结,以期为产科及遗传咨询等相关专业人员提供有益的理论参考.

  14. Noninvasive prenatal testing of fetal chromosomal aneuploidy diseases in twin pregnancies%无创产前检测技术在双胎染色体非整倍体疾病筛查中应用研究

    Institute of Scientific and Technical Information of China (English)

    于文倩; 吕远; 尹少尉; 刘浩; 刘彩霞

    2016-01-01

    目的 探讨无创产前检测技术在双胎染色体非整倍体疾病筛查中的临床应用价值.方法 对2015年10月1日至2016年8月1日在中国医科大学附属盛京医院就诊,自愿接受无创产前检测的423例妊娠12~31周双胎孕妇,抽取外周血获取胎儿游离DNA,应用高通量测序技术检测胎儿非整倍体的情况.无创检测的结果由羊水细胞及分娩时脐血核型分析进行验证.结果 无创产前检测异常者8例,4例提示21-三体高风险,2例提示18-三体高风险,2例提示X染色体单体(45,X).6例三体高风险胎儿经羊水或脐血穿刺检查结果确认无误.1例X染色体单体的羊水结果与检测结果一致,另1例羊水检测结果正常,但随后确认该孕妇核型为46,XX[36]/45,X[64].经验证的低风险者176例,均与其一致.结论 无创产前检测作为一种快速、安全的产前筛查手段,在双胎的非整倍体疾病筛查中有较高的灵敏度和特异度,具有临床应用价值.

  15. Current status and challenges of fetal aneuploidy technology by non-invasive prenatal testing%无创产前检测胎儿非整倍体技术:现状与挑战

    Institute of Scientific and Technical Information of China (English)

    曹东华; 邱广斌

    2015-01-01

    本文结合产前筛查技术的发展历程、目前高通量测序技术主流平台间的比较、无创产前检测胎儿非整倍体技术的优势与局限性等方面,讨论无创产前检测胎儿非整倍体技术当前的现状与及面临的挑战.

  16. Correlation between repeated IVF-ET failure and oocyte aneuploidy%反复IVF-ET失败与卵细胞染色体的非整倍体异常

    Institute of Scientific and Technical Information of China (English)

    陈雯; 朱桂金; Mettler L

    2004-01-01

    目的:研究反复试管婴儿(IVF-ET)失败与卵细胞染色体非整倍体间的相关关系.方法:取反复IVF-ET失败和初次行IVF-ET患者助孕技术后未能受精成功的卵母细胞,采用多色荧光原位杂交方法检测两组卵母细胞13、16、18、21和22号染色体的核型情况.结果:反复IVF-ET失败组卵母细胞的非整倍体率为66.67%,明显高于初次行IVF-ET患者的未受精卵母细胞的非整倍体率为30.77%(P<0.025).结论:卵细胞的非整倍体异常可能是导致反复IVF-ET失败的一个重要原因.

  17. CIN-ful cancers.

    Science.gov (United States)

    Rajagopalan, Harith; Lengauer, Christoph

    2004-09-01

    Aneuploidy has long been recognized to be a cardinal feature of many neoplasias. However, the role of aneuploidy in tumorigenesis continues to be a matter of debate. We believe that aneuploidy in cancers is the result of chromosomal instability, a process in which dividing cancer cells segregate their chromosomes with decreased fidelity. Here we discuss our definition of chromosomal instability, evidence for its causal role in tumor development, and suggestions regarding the mechanisms that initiate chromosomal instability in cancer cells.

  18. Microarray-based analysis of methylation of 1st trimester trisomic placentas from down syndrome, edwards syndrome and patau syndrome

    DEFF Research Database (Denmark)

    Hatt, L.; M. Aagaard, Mads; Bach, C

    2016-01-01

    Methylation-based non-invasive prenatal testing of fetal aneuploidies is an alternative method that could possibly improve fetal aneuploidy diagnosis, especially for trisomy 13 (T13) and trisomy 18(T18). Our aim was to study the methylation landscape in placenta DNA from trisomy 13, 18 and 21 pre...

  19. The role of BUBR1 in the maintenance of chromosomal stability

    NARCIS (Netherlands)

    Suijkerbuijk, S.J.E.

    2012-01-01

    The majority of solid tumours contain an incorrect number of chromosomes. This state, called aneuploidy, can be caused by defects in chromosome segregation during the division of cells. Prevention against aneuploidy is dependent on BUBR1. This protein is an essential component of a surveillance mech

  20. Studying chromosome instability in the mouse

    NARCIS (Netherlands)

    Foijer, Floris; Draviam, Viji M; Sorger, Peter K

    2008-01-01

    Aneuploidy has long been recognized as one of the hallmarks of cancer. It nonetheless remains uncertain whether aneuploidy occurring early in the development of a cancer is a primary cause of oncogenic transformation, or whether it is an epiphenomenon that arises from a general breakdown in cell cyc

  1. Induction of genomic instability and activation of autophagy in artificial human aneuploid cells

    Energy Technology Data Exchange (ETDEWEB)

    Ariyoshi, Kentaro [Hirosaki University, Institute of Radiation Emergency Medicine, 66-1 Hon-cho, Hirosaki 036-8564 (Japan); Miura, Tomisato; Kasai, Kosuke; Fujishima, Yohei [Department of Biomedical Sciences, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki 036-8564 (Japan); Oshimura, Mitsuo [Chromosome Engineering Research Center (CERC), Tottori University, Nishicho 86, Yonago, Tottori 683-8503 (Japan); Yoshida, Mitsuaki A., E-mail: ariyoshi@hirosaki-u.ac.jp [Hirosaki University, Institute of Radiation Emergency Medicine, 66-1 Hon-cho, Hirosaki 036-8564 (Japan)

    2016-08-15

    Highlights: • Clones with artificial aneuploidy of chromosome 8 or chromosome 22 both show inhibited proliferation and genomic instability. • Increased autophagy was observed in the artificially aneuploid clones. • Inhibition of autophagy resulted in increased genomic instability and DNA damage. • Intracellular levels of reactive oxygen species were up-regulated in the artificially aneuploid clones. - Abstract: Chromosome missegregation can lead to a change in chromosome number known as aneuploidy. Although aneuploidy is a known hallmark of cancer cells, the various mechanisms by which altered gene and/or DNA copy number facilitate tumorigenesis remain unclear. To understand the effect of aneuploidy occurring in non-tumorigenic human breast epithelial cells, we generated clones harboring artificial aneuploidy using microcell-mediated chromosome transfer. Our results demonstrate that clones with artificial aneuploidy of chromosome 8 or chromosome 22 both show inhibited proliferation and genomic instability. Also, the increased autophagy was observed in the artificially aneuploidy clones, and inhibition of autophagy resulted in increased genomic instability and DNA damage. In addition, the intracellular levels of reactive oxygen species were up-regulated in the artificially aneuploid clones, and inhibition of autophagy further increased the production of reactive oxygen species. Together, these results suggest that even a single extraneous chromosome can induce genomic instability, and that autophagy triggered by aneuploidy-induced stress is a mechanism to protect cells bearing abnormal chromosome number.

  2. Gross genomic damage measured by DNA image cytometry independently predicts gastric cancer patient survival

    NARCIS (Netherlands)

    Belien, J.A.M.; Buffart, T.E.; Gill, A.; Broeckaert, M.A.M.; Quirke, P.; Meijer, G.A.; Grabsch, H.

    2009-01-01

    BACKGROUND: DNA aneuploidy reflects gross genomic changes. It can be measured by flow cytometry (FCM-DNA) or image cytometry (ICM-DNA). In gastric cancer, the prevalence of DNA aneuploidy has been reported to range from 27 to 100%, with conflicting associations with clinicopathological variables. Th

  3. [Spontaneous chromosome aberrations in the oogenesis of laboratory rats].

    Science.gov (United States)

    Dyban, A P; Chebotar', N A

    1975-08-01

    Cytological preparations were made by Tarkovsky's method from 2335 rat oocytes obtained after an induced superodulation. The chromosomes could be counted exactly in 861 oocytes. In 797 oocytes (92.7%) euploidy (metaphase II with 21 chromosomes) and in 64 oocytes (7.5%) aneuploidy was found. 60 oocytes were hypoploid, but only 4 oocytes (0.4%) were hyperploid (with 22 chromosomes). Hypoploidy can often be due to the presence of artefacts. Probably the rate of spontaneous aneuploidy in rat oogenesis is about 0.8%, this being significantly lower than the rate of spontaneous aneuploidy in mice oogenesis.

  4. Application of FISH in analyzing sperm aneuploidy of Klinefelter's syndrome and assisted reproductive treatment with first case report of delivery%FISH检测精子非整倍体率在Klinefelter综合征辅助生育治疗的应用首例分娩报告

    Institute of Scientific and Technical Information of China (English)

    欧建平; 彭文林; 陈宝江; 庄广伦

    2004-01-01

    目的分析Klinefelter综合征病人精子X,Y,18染色体的非整倍体率(aneuploid),指导其辅助生育治疗.方法应用荧光原位杂交(FISH)检测1例射出的少量精子X,Y和18号染色体,计算精子染色体非整倍体率,用卵胞浆内单精子注射(ICSI)治疗.结果ICSI前后拾取形态正常的精子,进行FISH后有荧光信号的精子数为156条,其中正常18/X精子有82条(52.6%),18/Y精子有74条(47.4%),未发现异常的精子信号.ICSI治疗后获得双胎妊娠,孕19w产前诊断,2个胎儿的染色体核型分别是46,XY和46,XX.孕36w分娩1男婴和1女婴.结论ISH分析证实Klinefelter综合征病人可以产生正常精子,有精子的克氏征病人可以通过ICSI获得正常婴儿.

  5. Doble aneuploidía en un niño Colombiano: síndrome de Down–Klinefelter, con fenotipo de síndrome de Down = Double aneuploidy in a Colombian child: Down-Klinefelter syndrome with Down syndrome phenotype

    OpenAIRE

    Pachajoa Londoño, Harry; Perilla Duque, Diana; Isaza de Lourido, Carolina

    2011-01-01

    La ocurrencia de una doble aneuploidía en una misma persona es un evento relativamente raro. Se presenta el caso de un niño de siete meses de edad, de padres no consanguíneos con características clínicas de síndrome de Down y cariotipo 48XXY.

  6. Detection of chromosome aneuploidy and copy number variation in abortion fetus or chorionic villi using NGS technology%NGS技术检测自然流产胚胎或绒毛染色体非整倍体及拷贝数变异的研究

    Institute of Scientific and Technical Information of China (English)

    赵佳; 毕川; 高雅; 季刚; 汪凌云; 张红云; 李云; 王军; 王威

    2015-01-01

    目的 探索新一代测序技术(NGS)在检测自然流产胚胎或绒毛组织染色体非整倍体和拷贝数变异(CNV)应用中的价值.方法 选择20例自然流产患者的绒毛进行染色体核型分析,同时应用NGS技术进行染色体非整倍体和拷贝数变异的检测,并以染色体核型分析结果为“金标准”进行NGS方法的评估.后于201 3年共收集1 074例自然流产胚胎或绒毛组织,应用NGS技术完成染色体非整倍体和CNV的检测,并对检测结果进行分析.结果 20例自然流产样本的NGS结果与核型分析结果对比,检测灵敏度和特异性均为100%.临床检测的1 074例流产组织样本中,42例样本DNA不符合质控标准,实际完成检测1032例.1 032例组织样本中阳性445例(43.12%),其中非整倍体369例(82.92%),以16、X、22、21、15、1 8号染色体高发;CNV共76例(17.08%),阳性样本集中发生在8-12w.阴性587例(56.88%).根据孕妇年龄将样本分为三组比较,差异有统计学意义(P<0.01).结论 NGS技术用于检测流产组织的非整倍体和拷贝数变异具有较高的灵敏度和特异性,是适用于临床的有效检测方法.

  7. Doble aneuploidía en un niño Colombiano: síndrome de Down–Klinefelter, con fenotipo de síndrome de Down = Double aneuploidy in a Colombian child: Down-Klinefelter syndrome with Down syndrome phenotype

    Directory of Open Access Journals (Sweden)

    Pachajoa Londoño, Harry

    2011-03-01

    Full Text Available La ocurrencia de una doble aneuploidía en una misma persona es un evento relativamente raro. Se presenta el caso de un niño de siete meses de edad, de padres no consanguíneos con características clínicas de síndrome de Down y cariotipo 48XXY.

  8. 多重荧光定量PCR方法的建立及其在快速产前诊断中的应用%Establishment of multiple quantitative fluorescent polymerase chain reaction assay and its application in rapid prenatal diagnosis of common chromosome aneuploidies

    Institute of Scientific and Technical Information of China (English)

    徐爱群; 边旭明; 刘俊涛; 姚凤霞; 张为民; 郝娜; 周京

    2010-01-01

    目的 探讨用于快速产前诊断的多重荧光定量PCR(QF-PCR)方法的建立并评价其临床应用价值.方法 2008年5月到2009年7月在北京协和医院产前诊断中心进行产前诊断的孕妇170例,其中收集羊水123例,新鲜绒毛9例,脐血20例,自然流产绒毛18例.孕妇均为汉族,平均年龄(34.1±4.6)岁,平均孕周为(19.6±1.0)周.采用基因组DNA提取试剂盒提取羊水、绒毛及脐血标本中DNA.采用3种荧光素标记的引物,针对人类染色体中的短串联重复序列(STR)位点参照基因库(GenBank)和文献资料设计并合成20对引物,其中21号染色体6对引物,18号染色体4对引物,13号染色体4对引物,X和Y染色体1对通用引物,另有X染色体4对引物,Y染色体1对引物.设计检测方案为每份标本均进行两套8重QF-PCR(8×QF-PCR),共检测21、18、13号染色体及性染色体各4个位点;如果无法达到诊断要求,再追加第3套4个位点.同时与染色体核型分析结果进行对照.结果 (1)核型分析:170例标本均成功进行了核型分析,其中正常核型151例(89%,151/170),异常核型19例(11%,19/170).(2)QF-PCR检测:170例标本中,QF-PCR成功检测167例(98%),失败3例,QF-PCR检测均在2~3 d得出结果.QF-PCR检测结果正常134例,均与核型分析结果一致;核型分析异常的19例中,QF-PCR检测出异常18例(其中8例21三体及3例18三体).167例QF-PCR成功检测标本中,第1套+第2套引物组合共确诊150例(90%,150/167),加用第3套引物组合共检测3例(2%,3/167),另有14例不提供信息(8%,14/167).(3)QF-PCR诊断效率:QF-PCR用于常见非整倍体异常产前诊断的敏感度为95%(18/19),特异度为100%(134/134),假阳性率0(0/134),假阴性率5%(1/19),阳性预测值为100%(18/18),阴性预测值为99%(134/135).(4)QF-PCR检测常染色体及性染色体结果:21号常染色体STR位点中D21S1270和D21S1411杂合度最高,性染色体中DXS8377杂合度最高,扩增较稳定.结论 多重QF-PCR技术能成功用于常见非整倍体异常的快速产前诊断,检测结果准确,适合于规模较大的产前诊断中心进行大样本检测.%Objective To establish the multiple quantitative fluorescent polymerase chain reaction (QF-PCR)assay and evaluate its clinical application in prenatal diagnosis.Methods Totally 170 samples Were collected between May 2008 and July 2009 in prenatal center of Peking Union Medical College Hospital:123 of them were amniotic fluid,9 were chofionic villous samples,20 were fetal blood and 18 were villi from aborted fetuses.All samples were from women of Han nationality,with mean age of (34.1±4.6) years old,and with mean gestational age of(19.6±1.0)weeks.Cytogenetic cultures and karyotyping were made to every sample.Genomic DNA wag extracted from the samples.The sequences of twenty short tandem repeat (STR) markers were designed according to the GenBank and references,including 6 STR markers in chromosome 21.4 in chromosome 18.4 in chromosome 13,4 in chromosome X,1 in chromosome Y and 1 universal marker in both X and Y chromosome.Each sample was amplified by two sets of multiple QF-PCR,which included 4 STR markers in each of 21,18,13 and sex chromosomes. If the result was uninformative,the third set of anotherd 4 STR markers was added. Results ( 1 ) Karyotyping. Cytogenetic analysis were made for all the 170 samples, 151 (89%) of which were normal, and 19 (11% ) were abnormal (2)QF-PCR assay. 167(98% ) samples were detected by QF-PCR. The results were obtained within 2 -3 days after sampling. 134 samples were proved normal by QF-PCR, which was consistent with karyotyping. Among the 19 abnormal karyotype samples, 18 were detected as abnormal( eight were 21-trisomy, three were 18-trisomy)by QF-PCR. Among the 167 samples, 150(90% ) were detected using the first and second set of STR mixtures, and 3(2% ) were detected when the third set of STR was added. The remain 14(8% ) were uninformative. (3) The diagnostic efficiency of QF-PCR. The sensitivity of QF-PCR in prenatal diagnosis of common aneuploidities was 95%, the specifici

  9. Clinical application of multiplex quantitative fluorescent polymerase chain reaction for the diagnosis of trisomy 21 and sex chromosome aneuploidies%多重定量荧光PCR在21-三体及性染色体多倍体畸变诊断中的应用

    Institute of Scientific and Technical Information of China (English)

    唐宁; 蔡稔; 梁昕; 陈华云; 丁渭; 潘莉珍; 罗颖花; 许泽辉; 韦小妮

    2007-01-01

    目的 探讨多重定量荧光PCR(QF-PCR)技术在染色体非整倍体畸变诊断中的应用价值.方法 抽取脐血样本16份,羊水样本73份,21、X、Y染色体数目异常患者及其父母外周静脉血71份,针对21号染色体和X、Y染色体上7个基因位点21S1435、D21S11、D21S1411、AMXY、DXS981、DXS6809和X22应用QF-PCR方法进行多重扩增,毛细管电泳法检测并分析结果.所有样本同时进行染色体核型分析.结果 染色体核型分析中有129例为正常核型46,XX(XY);26例21-三体(其中1例为易位型,余为标准型);1例45,XO/46,XX;2例47,XXX;1例47,XXY;1例45,XX,der(13,21).QF-PCR结果中,确诊1例47,XXY,26例21-三体征中23例确诊,2例47,XXX被提示可能存在性染色体数目异常,其余为阴性结果.结论 多重定量荧光技术可用于染色体非整倍体畸变的快速诊断.

  10. 沈阳地区无创产前基因检测胎儿染色体非整倍体技术应用结果分析%Analysis of the use of noninvasive prenatal tests for detecting infant aneuploidy

    Institute of Scientific and Technical Information of China (English)

    孟培; 李晓琳; 闫素文; 徐斌

    2014-01-01

    目的 对1134例要求无创产前基因检测的孕妇进行检测,以检出胎儿染色体非整倍体高风险者.方法 通过母体外周血中的胎儿游离DNA,应用高通量测序技术,检测胎儿T21、T18和T13三种染色体疾病.结果 检出高风险4例,占调查资料总数0.35% (4/1134),其中T21高风险3例,T18高风险1例,均经介入性诊断确认并实施引产.4例高风险孕妇中因唐筛高风险来诊1例,占唐筛高风险来诊的0.42% (1/239),其他3例高风险均为高龄孕妇.结论 无创产前基因检测技术在孕早期即能进行;安全,可避免很多不必要的介入性有创检查;准确率高;是未来产前筛查领域的发展趋势.

  11. 孕11~13周+6胎儿多个超声指标联合母血清学指标在筛查染色体异常胎儿中的价值%Study on several ultrasound markers combined maternal serum biochemical markers to screen fetal chromosomal aneuploidy at 11 to 13+6 weeks of gestation

    Institute of Scientific and Technical Information of China (English)

    陈叙; 常颖; 崔洪艳; 任晨春; 于炳颖

    2013-01-01

    Objective To evaluate the efficiency of combined screening for chromosomal abnormalities in the first trimester and the ultrasound characteristics of these fetuses.Methods Retrospective study for 5000 singleton pregnancies by combined screening of trisomies 21,18,13 and Turner syndrome.Risk algorithms were developed for calculation of patient-specific risks for each of the three trisomies based on maternal age,fetal nuchal translucency,free β human chorionic gonadotropin and serum pregnancy associated plasma protein A at 11 to 13 +6 weeks of pregnant.The value of nuchal translucency (NT) and β-hCG and pregnancy-associated plasma protein A (PAPP-A) level were inputted computer,and calculate the risk value (≥ 1 ∶ 270) by automatic analysis software.Two hundred and four cases with high risk were performed transabdominal chorionic villus biopsy to detect the fetal chromosomal karyotypes.Meanwhile,other ultrasonic characteristics of fetal were elevated.Results (1) Five thousand cases of pregnant women were detected,including 4983 normal cases,62 cases were induced labor for a variety of reasons in the second trimester,including 40 cases with normal karyotype but with congenital heart disease,17 cases of chromosome abnormalities (9 cases trisomy 21,2 cases trisomy 18,1 cases trisomy 13,4 cases 45X),2 cases spina bifida,2 cases digestive tract obstruction,1 cases giant bladder.One case with low risk of fetal chromosomal abnormalities in combined screening,but high risk of age (maternal age were over 40 years old),it was 21 trisomy syndrome after the prenatal diagnosis.(2) Five cases of nasal bone loss in 9 cases of trisomy 21 (5/9),5 cases with three tricuspid regurgitation (5/9),4 cases of venous ductus a wave flow reverse (4/9),3 cases of fetal nasal bone loss accompanied by tricuspid regurgitation and venous ductus a wave flow reverse (3/9).One case of nasal bone loss in 2 cases of trisomy 18,2 cases were tricuspid regurgitation and venous ductus a wave flow reverse.Two cases in 4 cases of 45X had venous ductus a wave flow reverse.There were 8 cases (0.16%) nasal bone absence in 4983 cases of normal karyotype fetus,48 cases (0.96%) of tricuspid regurgitation and 44 cases (0.88%) of venous ductus a wave flow reverse.Thirty-two cases in 40 cases (80%) of fetal congenital heart disease were tricuspid regurgitation,30 cases of venous ductus a wave flow reverse (75%).Eight cases of nasal bone absence normal karyotype fetus were found the nasal bone at 20 weeks gestation.Conclusion Combination screening of nuchal translucency with serum markers in the first trimester were high detection rate and low false positive rate; a wave reversion and fetal nasal bone absence accompanied by tricuspid regurgitation can improve the detection rate of abnormal karyotype; abnormalities ultrasound marker may be associated with fetal congenital heart disease at 11-13 +6 weeks of pregnancy.%目的 探讨孕11 ~13周+6胎儿多个超声指标联合母血清学指标在筛查染色体异常胎儿中的临床效果.方法 选择2010年1月1日至2011年12月31日天津市中心妇产科医院进行联合筛查的单胎孕妇5000例(筛查孕周为11 ~13周+6).采用超声仪对胎儿颈项透明层(NT)厚度,鼻骨缺失与否,静脉导管a波血流反向及三尖瓣反流情况进行检测;同时检测孕妇血清妊娠相关蛋白A(PAPP-A)和游离β绒毛膜促性腺激素(β-hCG)水平.将NT值和β-hCG及PAPP-A水平输入计算机,计算风险值(≥1∶270).联合筛查的5000例孕妇中筛查出高风险204例,对这204例孕妇进行绒毛组织活检,检测胎儿染色体核型,对染色体异常胎儿的超声特征进行分析.结果 (1) 5000例单胎孕妇中,正常染色体核型胎儿4983例,活产儿4938例,62例胎儿因各种原因于孕中期引产,其中40例染色体核型正常但伴先天性心脏病,17例为染色体异常(其中21三体9例、18三体2例、13 三体1例、45X 4例),2例脊柱裂,2例消化道梗阻,1例巨膀胱.染色体核型异常胎儿中有1例联合筛查为低风险,年龄高风险(孕妇年龄均≥40岁),后经产前诊断证实胎儿为21三体综合征.(2)9例21 三体胎儿中有5例为鼻骨缺失(5/9)、5例有三尖瓣反流(5/9)、4例为静脉导管a波反向(4/9)、3例胎儿鼻骨缺失伴有三尖瓣反流及静脉导管a波血流反向(3/9).2例18 三体胎儿中有l例鼻骨缺失、2例均为三尖瓣反流及静脉导管a波血流反向.4例45X胎儿中有2例为静脉导管a波血流反向.4983例正常核型胎儿中有8例鼻骨缺失(0.16%)、48例三尖瓣反流(0.96%)以及44例静脉导管a波血流反向(0.88%).40例先天性心脏病胎儿中有32例为三尖瓣反流(80%),30例静脉导管a波血流反向(75%).8例孕早期发现的鼻骨缺失的正常核型胎儿,于孕20周时超声检测均发现鼻骨.结论 孕11 ~13周+6胎儿联合筛查检出率高,假阳性率低;异常核型胎儿往往伴有三尖瓣反流、静脉导管的a波反向及鼻骨缺失,增加超声标记有提高异常胎儿检出率的作用;孕11 ~13周+6超声标记物异常可能与胎儿先天性心脏病有关.

  12. Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome

    NARCIS (Netherlands)

    Bruining, Hilgo; Swaab, Hanna; Kas, Martien; van Engeland, Herman

    2009-01-01

    BACKGROUND: Klinefelter syndrome is the most frequent chromosomal aneuploidy with a prevalence of 1 in 700. Klinefelter syndrome has been widely associated with cognitive impairment and language problems. No previous studies have systematically investigated the association of Klinefelter syndrome wi

  13. Disease: H00032 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available aneuploidy and the high prevalence of RAS mutations and PAX8-PPAR{gamma} rearrang... PTC and may be found in early stages. The most distinctive molecular features of FTC are the prominence of

  14. DNA ploidy of primary and recurrent irradiated laryngeal tumors

    NARCIS (Netherlands)

    Struikmans, H; Hordijk, GJ; Kal, HB

    2002-01-01

    Purpose: Radiosensitivity of diploid laryngeal cancers, as compared with that of aneuploid ones, appears to be increased. However, no conclusive data exist. If a causal relationship exists, then recurrent laryngeal cancer after irradiation should predominantly be characterized by aneuploidy. Patient

  15. Prenatal diagnosis of a trisomy 7/trisomy 13 mosaicism

    OpenAIRE

    Huijsdens-van Amsterdam Karin; Barge-Schaapveld Daniela QCM; Mathijssen Inge B; Alders Mariëlle; Pajkrt Eva; Knegt Alida C

    2012-01-01

    Abstract Double aneuploidy mosaicism of two different aneuploidy cell lines is rare. We describe for the first time a double trisomy mosaicism, involving chromosomes 7 and 13 in a fetus presenting with multiple congenital anomalies. No evidence for chimerism was found by DNA genotyping. The origin of both trisomies are consistent with isodisomy of maternal origin. Therefore, it is most likely that the double trisomy mosaicism arose from two independent events very early in embryonic developme...

  16. Chromosomal disorders and male infertility

    Institute of Scientific and Technical Information of China (English)

    Gary L Harton; Helen G Tempest

    2012-01-01

    infertility in humans is surprisingly common occurring in approximately 15% of the population wishing to start a family.Despite this,the molecular and genetic factors underlying the cause of infertility remain largely undiscovered.Nevertheless,more and more genetic factors associated with infertility are being identified.This review will focus on our current understanding of the chromosomal basis of male infertility specifically:chromosomal aneuploidy,structural and numerical karyotype abnormalities and Y chromosomal microdeletions.Chromosomal aneuploidy is the leading cause of pregnancy loss and developmental disabilities in humans.Aneuploidy is predominantly maternal in origin,but concerns have been raised regarding the safety of intracytoplasmic sperm injection as infertile men have significantly higher levels of sperm aneuploidy compared to their fertile counterparts.Males with numerical or structural karyotype abnormalities are also at an increased risk of producing aneuploid sperm.Our current understanding of how sperm aneuploidy translates to embryo aneuploidy will be reviewed,as well as the application of preimplantation genetic diagnosis (PGD) in such cases.Clinical recommendations where possible will be made,as well as discussion of the use of emerging array technology in PGD and its potential applications in male infertility.

  17. Analysis on 580 Cases of Ultrasonic NT, Serological Screening and Non-invasive Prenatal Genetic Testing to Combined Screening High-risk Pregnant Women of Fetal Chromosome Aneuploidy%超声NT、血清学筛查与无创产前基因检测联合筛查高危孕妇胎儿染色体非整倍体580例分析

    Institute of Scientific and Technical Information of China (English)

    侯桂玉; 郭跃文; 蒋丽江; 何小红; 欧阳晓红

    2016-01-01

    目的:探讨应用超声颈部半透明层厚度(NT)、血清学筛查与无创产前基因检测(NIPT)联合筛查高危孕妇胎儿染色体非整倍体的风险及追踪妊娠结局情况.方法:选取2013年1月-2014年12月本院门诊产科高危孕妇共580例,对其进行超声NT、血清学筛查与NIPT联合筛查.结果:其中NIPT提示异常8例(其中21-三体高风险:2例;18-三体高风险:3例;可疑47,XYY:1例;染色体多态改变2例).妊娠结局:1例胚胎停止发育,终止妊娠;4例引产;3例继续妊娠,新生儿表现健康.需行侵入性产前诊断的高危孕妇仅1.4%,避免了95%以上的唐氏筛查假阳性病例进行侵入性的产前诊断.结论:应用超声NT、血清学筛查与NIPT联合筛查高危孕妇胎儿染色体非整倍体,有效降低了进行侵入性产前诊断的孕妇数量,减轻孕妇的心理压力和减少胎儿丢失的风险.

  18. Dysregulation of gene expression in the artificial human trisomy cells of chromosome 8 associated with transformed cell phenotypes.

    Directory of Open Access Journals (Sweden)

    Hisakatsu Nawata

    Full Text Available A change in chromosome number, known as aneuploidy, is a common characteristic of cancer. Aneuploidy disrupts gene expression in human cancer cells and immortalized human epithelial cells, but not in normal human cells. However, the relationship between aneuploidy and cancer remains unclear. To study the effects of aneuploidy in normal human cells, we generated artificial cells of human primary fibroblast having three chromosome 8 (trisomy 8 cells by using microcell-mediated chromosome transfer technique. In addition to decreased proliferation, the trisomy 8 cells lost contact inhibition and reproliferated after exhibiting senescence-like characteristics that are typical of transformed cells. Furthermore, the trisomy 8 cells exhibited chromosome instability, and the overall gene expression profile based on microarray analyses was significantly different from that of diploid human primary fibroblasts. Our data suggest that aneuploidy, even a single chromosome gain, can be introduced into normal human cells and causes, in some cases, a partial cancer phenotype due to a disruption in overall gene expression.

  19. Molecular cytogenetic analysis of human blastocysts andcytotrophoblasts by multi-color FISH and Spectra Imaging analyses

    Energy Technology Data Exchange (ETDEWEB)

    Weier, Jingly F.; Ferlatte, Christy; Baumgartner, Adolf; Jung,Christine J.; Nguyen, Ha-Nam; Chu, Lisa W.; Pedersen, Roger A.; Fisher,Susan J.; Weier, Heinz-Ulrich G.

    2006-02-08

    Numerical chromosome aberrations in gametes typically lead to failed fertilization, spontaneous abortion or a chromosomally abnormal fetus. By means of preimplantation genetic diagnosis (PGD), we now can screen human embryos in vitro for aneuploidy before transferring the embryos to the uterus. PGD allows us to select unaffected embryos for transfer and increases the implantation rate in in vitro fertilization programs. Molecular cytogenetic analyses using multi-color fluorescence in situ hybridization (FISH) of blastomeres have become the major tool for preimplantation genetic screening of aneuploidy. However, current FISH technology can test for only a small number of chromosome abnormalities and hitherto failed to increase the pregnancy rates as expected. We are in the process of developing technologies to score all 24 chromosomes in single cells within a 3 day time limit, which we believe is vital to the clinical setting. Also, human placental cytotrophoblasts (CTBs) at the fetal-maternal interface acquire aneuploidies as they differentiate to an invasive phenotype. About 20-50% of invasive CTB cells from uncomplicated pregnancies were found aneuploidy, suggesting that the acquisition of aneuploidy is an important component of normal placentation, perhaps limiting the proliferative and invasive potential of CTBs. Since most invasive CTBs are interphase cells and possess extreme heterogeneity, we applied multi-color FISH and repeated hybridizations to investigate individual CTBs. In summary, this study demonstrates the strength of Spectral Imaging analysis and repeated hybridizations, which provides a basis for full karyotype analysis of single interphase cells.

  20. Human oocytes. Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes.

    Science.gov (United States)

    Holubcová, Zuzana; Blayney, Martyn; Elder, Kay; Schuh, Melina

    2015-06-05

    Aneuploidy in human eggs is the leading cause of pregnancy loss and several genetic disorders such as Down syndrome. Most aneuploidy results from chromosome segregation errors during the meiotic divisions of an oocyte, the egg's progenitor cell. The basis for particularly error-prone chromosome segregation in human oocytes is not known. We analyzed meiosis in more than 100 live human oocytes and identified an error-prone chromosome-mediated spindle assembly mechanism as a major contributor to chromosome segregation defects. Human oocytes assembled a meiotic spindle independently of either centrosomes or other microtubule organizing centers. Instead, spindle assembly was mediated by chromosomes and the small guanosine triphosphatase Ran in a process requiring ~16 hours. This unusually long spindle assembly period was marked by intrinsic spindle instability and abnormal kinetochore-microtubule attachments, which favor chromosome segregation errors and provide a possible explanation for high rates of aneuploidy in human eggs.

  1. Reduced ability to recover from spindle disruption and loss of kinetochore spindle assembly checkpoint proteins in oocytes from aged mice.

    Science.gov (United States)

    Yun, Yan; Holt, Janet E; Lane, Simon I R; McLaughlin, Eileen A; Merriman, Julie A; Jones, Keith T

    2014-01-01

    Currently, maternal aging in women, based on mouse models, is thought to raise oocyte aneuploidy rates, because chromosome cohesion deteriorates during prophase arrest, and Sgo2, a protector of centromeric cohesion, is lost. Here we show that the most common mouse strain, C57Bl6/J, is resistant to maternal aging, showing little increase in aneuploidy or Sgo2 loss. Instead it demonstrates significant kinetochore-associated loss in the spindle assembly checkpoint protein Mad2 and phosphorylated Aurora C, which is involved in microtubule-kinetochore error correction. Their loss affects the fidelity of bivalent segregation but only when spindle organization is impaired during oocyte maturation. These findings have an impact clinically regarding the handling of human oocytes ex vivo during assisted reproductive techniques and suggest there is a genetic basis to aneuploidy susceptibility.

  2. [Down-Turner syndrome (45,X/47,XY,+21): case report and review].

    Science.gov (United States)

    Ryu, Sook Won; Lee, Goeun; Baik, Cheong Soon; Shim, Sung Han; Kim, Jin Tack; Lee, Jung Soo; Lee, Kyung A

    2010-04-01

    We report the case of a 3-yr-old boy with Down-Turner mosaicism and review the previous reports of Down-Turner syndrome with documented karyotyping and clinical features. The patient showed clinical features of Down syndrome without significant stigma of Turner syndrome. Cytogenetic analysis of peripheral blood preparations by using G-banding revealed mosaicism with 2 cell lines (45,X[29]/47,XY,+21[4]). FISH analysis revealed that 87.5% of the cells had monosomy X karyotype and 12.5% of the cells had XY karyotype; trisomy 21 was only detected in the Y-positive cells. We suggest that additional cells should be analyzed and molecular genetic studies should be conducted to rule out double aneuploidy when karyotypes with sex chromosome aneuploidies and mosaicism are encountered, as in our case of Down syndrome mosaic with sex chromosome aneuploidy.

  3. New Advances of Preimplantation and Prenatal Genetic Screening and Noninvasive Testing as a Potential Predictor of Health Status of Babies

    Directory of Open Access Journals (Sweden)

    Tanya Milachich

    2014-01-01

    Full Text Available The current morphologically based selection of human embryos for transfer cannot detect chromosome aneuploidies. So far, only biopsy techniques have been able to screen for chromosomal aneuploidies in the in vitro fertilization (IVF embryos. Preimplantation genetic diagnosis (PGD or screening (PGS involves the biopsy of oocyte polar bodies or embryonic cells and has become a routine clinical procedure in many IVF clinics worldwide, including recent development of comprehensive chromosome screening of all 23 pairs of chromosomes by microarrays for aneuploidy screening. The routine preimplantation and prenatal genetic diagnosis (PND require testing in an aggressive manner. These procedures may be invasive to the growing embryo and fetus and potentially could compromise the clinical outcome. Therefore the aim of this review is to summarize not only the new knowledge on preimplantation and prenatal genetic diagnosis in humans, but also on the development of potential noninvasive embryo and fetal testing that might play an important role in the future.

  4. An Overview of the Spindle Assembly Checkpoint Status in Oral Cancer

    Directory of Open Access Journals (Sweden)

    José Henrique Teixeira

    2014-01-01

    Full Text Available Abnormal chromosome number, or aneuploidy, is a common feature of human solid tumors, including oral cancer. Deregulated spindle assembly checkpoint (SAC is thought as one of the mechanisms that drive aneuploidy. In normal cells, SAC prevents anaphase onset until all chromosomes are correctly aligned at the metaphase plate thereby ensuring genomic stability. Significantly, the activity of this checkpoint is compromised in many cancers. While mutations are rather rare, many tumors show altered expression levels of SAC components. Genomic alterations such as aneuploidy indicate a high risk of oral cancer and cancer-related mortality, and the molecular basis of these alterations is largely unknown. Yet, our knowledge on the status of SAC components in oral cancer remains sparse. In this review, we address the state of our knowledge regarding the SAC defects and the underlying molecular mechanisms in oral cancer, and discuss their therapeutic relevance, focusing our analysis on the core components of SAC and its target Cdc20.

  5. No difference in high-magnification morphology and hyaluronic acid binding in the selection of euploid spermatozoa with intact DNA

    Institute of Scientific and Technical Information of China (English)

    Suchada Mongkolchaipak; Teraporn Vutyavanich

    2013-01-01

    In this study,we compared conventional sperm selection with high-magnification morphology based on the motile sperm organellar morphology examination (MSOME) criteria,and hyaluronic acid (HA) binding for sperm chromosome aneuploidy and DNA fragmentation rates.Semen from 50 severe male factor cases was processed through density gradient centrifugation,and subjected to sperm selection by using the conventional method (control),high magnification at x 6650 or HA binding.Aneuploidy was detected by fluorescence in situ hybridization with probes for chromosomes 13,18,21,X and Y,and DNA fragmentation by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method.Spermatozoa selected under high-magnification had a lower DNA fragmentation rate (2.6% vs.1.7%; P=0.032),with no significant difference in aneuploidy rate (0.8% vs 0.7%; P=0.583),than those selected by the HA binding method.Spermatozoa selected by both methods had much lower aneuploidy and DNA fragmentation rate than the controls (7% aneuploidy and 26.8% DNA fragmentation rates,respectively).In the high-magnification group,the aneuploidy rate was lower when the best spermatozoa were selected than when only the second-best spermatozoa were available for selection,but the DNA fragmentation rate was not different.In conclusion,sperm selection under high magnification was more effective than under HA binding in selecting spermatozoa with low DNA fragmentation rate,but the small difference (0.9%) might not be clinically meaningful.Both methods were better than the conventional method of sperm selection.

  6. The aberrant asynchronous replication — characterizing lymphocytes of cancer patients — is erased following stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Korenstein-Ilan Avital

    2010-05-01

    Full Text Available Abstract Background Aberrations of allelic replication timing are epigenetic markers observed in peripheral blood cells of cancer patients. The aberrant markers are non-cancer-type-specific and are accompanied by increased levels of sporadic aneuploidy. The study aimed at following the epigenetic markers and aneuploidy levels in cells of patients with haematological malignancies from diagnosis to full remission, as achieved by allogeneic stem cell transplantation (alloSCT. Methods TP53 (a tumor suppressor gene assigned to chromosome 17, AML1 (a gene assigned to chromosome 21 and involved in the leukaemia-abundant 8;21 translocation and the pericentomeric satellite sequence of chromosome 17 (CEN17 were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosomes 17 and 21. Replication timing and aneuploidy were detected cytogenetically using fluorescence in situ hybridization (FISH technology applied to phytohemagglutinin (PHA-stimulated lymphocytes. Results We show that aberrant epigenetic markers are detected in patients with hematological malignancies from the time of diagnosis through to when they are scheduled to undergo alloSCT. These aberrations are unaffected by the clinical status of the disease and are displayed both during accelerated stages as well as in remission. Yet, these markers are eradicated completely following stem cell transplantation. In contrast, the increased levels of aneuploidy (irreversible genetic alterations displayed in blood lymphocytes at various stages of disease are not eliminated following transplantation. However, they do not elevate and remain unchanged (stable state. A demethylating anti-cancer drug, 5-azacytidine, applied in vitro to lymphocytes of patients prior to transplantation mimics the effect of transplantation: the epigenetic aberrations disappear while aneuploidy stays unchanged. Conclusions The reversible nature of the replication aberrations may

  7. Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis.

    Directory of Open Access Journals (Sweden)

    Antoneta Granic

    Full Text Available Elevated low-density lipoprotein (LDL-cholesterol is a risk factor for both Alzheimer's disease (AD and Atherosclerosis (CVD, suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy-in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1 high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis' first prediction, 2 Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3 oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL, induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4 LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5 cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6 ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol's aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol

  8. Current applications of molecular cytogenetic technologies.

    Science.gov (United States)

    Mark, H F; Jenkins, R; Miller, W A

    1997-01-01

    This review discusses select current applications of fluorescent in situ hybridization (FISH) which may be of utility for the average clinical cytogenetic laboratory. Owing to the large number of men and women affected, the applications chosen to illustrate the use of FISH technology in cancer focus on two diseases: breast cancer and prostate cancer. The applicability of FISH to detect common aneuploidies, such as trisomy 21, trisomy 18, trisomy 13 and the sex chromosome aneuploidies in prenatal diagnosis, is discussed, as well as FISH for the detection of microdeletions and microduplications. Quality assurance/quality control issues and standards and guidelines relating to laboratory practices in molecular cytogenetic testing are reviewed.

  9. Turner syndrome and 45,X/47,XXX mosaicism.

    Science.gov (United States)

    Akbas, E; Mutluhan, H; Savasoglu, K; Soylemez, F; Ozturk, I; Yazici, G

    2009-01-01

    The occurrence of double aneuploidy is a relatively rare phenomenon. We report on a 17-year-old woman with short stature, minimal pubic and axillar hair and short hands. In cultured lymphocyte a double aneuploidy mosaicism was detected, consisting of a cell line with trisomy for X chromosome and a cell line with monosomy for the X-chromosome and no cell line with a normal karyotype. To our knowledge, this is the first case of mosaic 45,X/47,XXX in Turkey.

  10. Numerically abnormal chromosome constitutions in humans

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-12-31

    Chapter 24, discusses numerically abnormal chromosome constitutions in humans. This involves abnormalities of human chromosome number, including polyploidy (when the number of sets of chromosomes increases) and aneuploidy (when the number of individual normal chromosomes changes). Chapter sections discuss the following chromosomal abnormalities: human triploids, imprinting and uniparental disomy, human tetraploids, hydatidiform moles, anomalies caused by chromosomal imbalance, 13 trisomy (D{sub 1} trisomy, Patau syndrome), 21 trisomy (Down syndrome), 18 trisomy syndrome (Edwards syndrome), other autosomal aneuploidy syndromes, and spontaneous abortions. The chapter concludes with remarks on the nonrandom participation of chromosomes in trisomy. 69 refs., 3 figs., 4 tabs.

  11. Subcellular localization of the mitotic checkpoint kinase MPS1: Mechanisms and regulation

    NARCIS (Netherlands)

    Nijenhuis, W.

    2014-01-01

    Faithful segregation of chromosomes during mitosis is required for the maintenance of genomic stability. The missegregation of chromosomes during mitosis causes aneuploidy and may be an initial step in the development of cancer. To ensure that both daughter cells are endowed with a complete set of c

  12. Potential diagnostic consequences of applying non-invasive prenatal testing

    DEFF Research Database (Denmark)

    Petersen, Olav Bjørn; Vogel, I; Ekelund, C

    2014-01-01

    OBJECTIVES: Targeted non-invasive prenatal testing (NIPT) tests for trisomies 21, 18 and 13 and sex chromosome aneuploidies and could be an alternative to traditional karyotyping. The aim of this study was to determine the risk of missing other abnormal karyotypes of probable phenotypic...

  13. Karyotype Analysis Activity: A Constructivist Learning Design

    Science.gov (United States)

    Ahmed, Noveera T.

    2015-01-01

    This classroom activity is based on a constructivist learning design and engages students in physically constructing a karyotype of three mock patients. Students then diagnose the chromosomal aneuploidy based on the karyotype, list the symptoms associated with the disorder, and discuss the implications of the diagnosis. This activity is targeted…

  14. Nuclear DNA-Content in Mesenchymal Lesions in Dogs: Its Value as Marker of Malignancy and Extent of Genomic Instability

    Energy Technology Data Exchange (ETDEWEB)

    Boerkamp, Kim M., E-mail: K.M.Boerkamp@uu.nl; Rutteman, Gerard R. [Department of Clinical Science of Companion Animals, Faculty of Veterinary Medicine, UU, Yalelaan 104, 3584 CM, Utrecht (Netherlands); Kik, Marja J. L. [Department of Pathobiology, Faculty of Veterinary Medicine, UU, Yalelaan 1, 3508 TD, Utrecht (Netherlands); Kirpensteijn, Jolle [Department of Clinical Science of Companion Animals, Faculty of Veterinary Medicine, UU, Yalelaan 104, 3584 CM, Utrecht (Netherlands); Schulze, Christoph; Grinwis, Guy C. M. [Department of Pathobiology, Faculty of Veterinary Medicine, UU, Yalelaan 1, 3508 TD, Utrecht (Netherlands)

    2012-12-03

    DNA-aneuploidy may reflect the malignant nature of mesenchymal proliferations and herald gross genomic instability as a mechanistic factor in tumor genesis. DNA-ploidy and -index were determined by flow cytometry in canine inflammatory or neoplastic mesenchymal tissues and related to clinico-pathological features, biological behavior and p53 gene mutational status. Half of all sarcomas were aneuploid. Benign mesenchymal neoplasms were rarely aneuploid and inflammatory lesions not at all. The aneuploidy rate was comparable to that reported for human sarcomas with significant variation amongst subtypes. DNA-ploidy status in canines lacked a relation with histological grade of malignancy, in contrast to human sarcomas. While aneuploidy was related to the development of metastases in soft tissue sarcomas it was not in osteosarcomas. No relation amongst sarcomas was found between ploidy status and presence of P53 gene mutations. Heterogeneity of the DNA index between primary and metastatic sarcoma sites was present in half of the cases examined. Hypoploidy is more common in canine sarcomas and hyperploid cases have less deviation of the DNA index than human sarcomas. The variation in the presence and extent of aneuploidy amongst sarcoma subtypes indicates variation in genomic instability. This study strengthens the concept of interspecies variation in the evolution of gross chromosomal aberrations during cancer development.

  15. Nuclear DNA-Content in Mesenchymal Lesions in Dogs: Its Value as Marker of Malignancy and Extent of Genomic Instability

    Directory of Open Access Journals (Sweden)

    Christoph Schulze

    2012-12-01

    Full Text Available DNA-aneuploidy may reflect the malignant nature of mesenchymal proliferations and herald gross genomic instability as a mechanistic factor in tumor genesis. DNA-ploidy and -index were determined by flow cytometry in canine inflammatory or neoplastic mesenchymal tissues and related to clinico-pathological features, biological behavior and p53 gene mutational status. Half of all sarcomas were aneuploid. Benign mesenchymal neoplasms were rarely aneuploid and inflammatory lesions not at all. The aneuploidy rate was comparable to that reported for human sarcomas with significant variation amongst subtypes. DNA-ploidy status in canines lacked a relation with histological grade of malignancy, in contrast to human sarcomas. While aneuploidy was related to the development of metastases in soft tissue sarcomas it was not in osteosarcomas. No relation amongst sarcomas was found between ploidy status and presence of P53 gene mutations. Heterogeneity of the DNA index between primary and metastatic sarcoma sites was present in half of the cases examined. Hypoploidy is more common in canine sarcomas and hyperploid cases have less deviation of the DNA index than human sarcomas. The variation in the presence and extent of aneuploidy amongst sarcoma subtypes indicates variation in genomic instability. This study strengthens the concept of interspecies variation in the evolution of gross chromosomal aberrations during cancer development.

  16. Interphase cytogenetics of workers exposed to benzene

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, L.; Wang, Yunxia; Venkatesh, P. [Univ. of California, Berkeley, CA (United States)] [and others

    1996-12-01

    Fluorescence in situ hybridization (FISH) is a powerful new technique that allows numerical chromosome aberrations (aneuploidy) to be detected in interphase cells. In previous studies, FISH has been used to demonstrate that the benzene metabolites hydroquinone and 1,2,4-benzenetriol induce aneuploidy of chromosomes 7 and 9 in cultures of human cells. In the present study, we used an interphase FISH procedure to perform cytogenetic analyses on the blood cells of 43 workers exposed to benzene (median=31 ppm, 8-hr time-weighted average) and 44 matched controls from Shanghai, China. High benzene exposure (>31 ppm, n=22) increased the hyperdiploid frequency of chromosome 9 (p<0.01), but lower exposure (<31 ppm, n=21) did not. Trisomy 9 was the major form of benzene-induced hyperdiploidy. The level of hyperdiploidy in exposed workers correlated with their urinary phenol level (r= 0.58, p < 0.0001), a measure of internal benzene close. A significant correlation was also found between hyperdiploicly and decreased absolute lymphocyte count, an indicator of benzene hematotoxicity, in the exposed group (r=-0.44, p=0.003) but not in controls (r=-0.09, P=0.58). These results show that high benzene exposure induces aneuploidy of chromosome 9 in nondiseased individuals, with trisomy being the most prevalent form. They further highlight the usefulness of interphase cytogenetics and FISH for the rapid and sensitive detection of aneuploidy in exposed human populations. 35 refs., 3 figs., 2 tabs.

  17. A chromosome 21-specific cosmid cocktail for the detection of chromosome 21 aberrations in interphase nuclei

    NARCIS (Netherlands)

    A.R.M. van Opstal (Diane); J.O. van Hmel (J.); H.J.F.M.M. Eussen (Bert); A. van der Heide (Annette); C.D.F. van den Berg (Cardi); P.A. In't Veld (Peter); F.J. Los

    1995-01-01

    textabstractFluorescent in situ hybridization (FISH) with a 21q11-specific probe (CB21c1) consisting of three non-overlapping cosmids has been applied to interphase amniocytes of pregnancies at increased risk for fetal aneuploidy (N = 78) and to interphase lymphocytes, cultured and uncultured, of pa

  18. Hepatic artery Doppler in trisomy 21 and euploid fetuses at 11-13 weeks

    NARCIS (Netherlands)

    Zvanca, Mona; Gielchinsky, Yuval; Abdeljawad, Firas; Bilardo, Caterina M.; Nicolaides, Kypros H.

    2011-01-01

    Objective To determine possible differences in hepatic artery flow between trisomy 21 and euploid fetuses at 11-13 weeks' gestation. Methods Hepatic artery pulsatility index (PI) and peak systolic velocity (PSV) were measured in fetuses at low risk of aneuploidies (n = 350) and another group at high

  19. [Benefit of human gamete cytogenetics: results and perspectives].

    Science.gov (United States)

    Vialard, F; Pellestor, F

    2008-09-01

    In man, the incidence of reproductive failures is high and chromosomal abnormalities remains the major cause of pregnancy wastage. The advent of molecular cytogenetic techniques and assisted reproduction technology have brought forth new approaches for the chromosomal analysis of human oocytes and spermatozoa. The oocyte analyses have evidenced the high rate of chromosomal abnormalities in women and identified premature separation of sister chromatid as a major mechanism in aneuploidy occurrence. High frequencies of aneuploidy have been found in various groups of women, such as patients over 35 or 38 years old, patients with recurrent implantation failures or recurrent miscarriages. The polar body analysis has confirmed the major contribution of premature separation of sister chromatids in aneuploidies and the effect of maternal ageing on its occurrence. In spermatozoa, the efficient adaptation of in situ chromosomal detection techniques has facilitated the segregation analysis of chromosomal abnormalities. Despite the consensus observed in sperm studies of robertsonnian translocations and inversions, new data are required for accurate estimates of imbalances in various types of structural rearrangements. For infertile patients with normal karyotypes, there is significant increase in aneuploidy frequencies, which can be extremely elevated in some groups of subjects, such as patients with large headed spermatozoa syndrome.

  20. Abnormal fetal head shape: aetiology and management

    DEFF Research Database (Denmark)

    Petersen, Olav Bjørn; David, Anna; Thomasson, Louise;

    2007-01-01

    (lemon-shaped), 18.4% with aneuploidy (mostly strawberry-shaped). 19.5% were dolicocephalic, most secondary to fetal position or oligohydramnios (see table). 13 had confirmed craniosynostosis, including thanatophoric dysplasia, Craniofrontonasal dysplasia, Aperts syndrome, Baller-Gerold syndrome, I...

  1. Social Function in Multiple X and Y Chromosome Disorders: XXY, XYY, XXYY, XXXY

    Science.gov (United States)

    Visootsak, Jeannie; Graham, John M., Jr.

    2009-01-01

    Klinefelter syndrome (47,XXY) was initially described in the context of its endocrinologic and physical features; however, subsequent studies have revealed specific impairments in verbal skills and social functioning. Males with sex chromosomal aneuploidies are known to have variability in their developmental profile with the majority presenting…

  2. 47,XYY karyotype in acute myeloid leukemia.

    Science.gov (United States)

    Palanduz, S; Aktan, M; Ozturk, S; Tutkan, G; Cefle, K; Pekcelen, Y

    1998-10-01

    A case of acute myelomonocytic leukemia (AMMoL; M4) with a 47,XYY karyotype is reported. This chromosome aneuploidy was found in both bone marrow cells and mitogen-stimulated lymphocytes. The contribution of XYY chromosomal constitution in the pathogenesis of AMMoL is controversial.

  3. Structural and Functional Neuroimaging in Klinefelter (47,XXY) Syndrome: A Review of the Literature and Preliminary Results from a Functional Magnetic Resonance Imaging Study of Language

    Science.gov (United States)

    Steinman, Kyle; Ross, Judith; Lai, Song; Reiss, Allan; Hoeft, Fumiko

    2009-01-01

    Klinefelter (47,XXY) syndrome (KS), the most common form of sex-chromosomal aneuploidy, is characterized by physical, endocrinologic, and reproductive abnormalities. Individuals with KS also exhibit a cognitive/behavioral phenotype characterized by language and language-based learning disabilities and executive and attentional dysfunction in the…

  4. Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Callinice D. Capo-chichi; Kathy Q. Car; Jennifer Smedberg; Parvin Ganjei-Azar; Andrew K. Godwin; Xiang-Xi Xu

    2011-01-01

    Through advances in technology, the genetic basis of cancer has been investigated at the genomic level, and many fundamental questions have begun to be addressed. Among several key unresolved questions in cancer biology, the molecular basis for the link between nuclear deformation and malignancy has not been determined. Another hallmark of human cancer is aneuploidy; however, the causes and consequences of aneuploidy are unanswered and are hotly contested topics. We found that nuclear lamina proteins lamin A/C are absent in a significant fraction (38%) of human breast cancer tissues. Even in lamin A/C-positive breast cancer, lamin A/C expression is heterogeneous or aberrant (such as nonnuclear distribution) in the population of tumor cells, as determined by immunohistology and immunofluorescence microscopy. In most breast cancer cell lines, a significant fraction of the lamin A/Cnegative population was observed. To determine the consequences of the loss of lamin A/C, we suppressed their expression by shRNA in non-cancerous primary breast epithelial cells. Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation, resembling that of cancer cells, as observed by immunofluorescence microscopy. The lamin A/C-suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization. We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.

  5. Hypoxia-induced reactive oxygen species cause chromosomal abnormalities in endothelial cells in the tumor microenvironment.

    Directory of Open Access Journals (Sweden)

    Miyako Kondoh

    Full Text Available There is much evidence that hypoxia in the tumor microenvironment enhances tumor progression. In an earlier study, we reported abnormal phenotypes of tumor-associated endothelial cells such as those resistant to chemotherapy and chromosomal instability. Here we investigated the role of hypoxia in the acquisition of chromosomal abnormalities in endothelial cells. Tumor-associated endothelial cells isolated from human tumor xenografts showed chromosomal abnormalities, >30% of which were aneuploidy. Aneuploidy of the tumor-associated endothelial cells was also shown by simultaneous in-situ hybridization for chromosome 17 and by immunohistochemistry with anti-CD31 antibody for endothelial staining. The aneuploid cells were surrounded by a pimonidazole-positive area, indicating hypoxia. Human microvascular endothelial cells expressed hypoxia-inducible factor 1 and vascular endothelial growth factor A in response to either hypoxia or hypoxia-reoxygenation, and in these conditions, they acquired aneuploidy in 7 days. Induction of aneuploidy was inhibited by either inhibition of vascular endothelial growth factor signaling with vascular endothelial growth factor receptor 2 inhibitor or by inhibition of reactive oxygen species by N-acetyl-L-cysteine. These results indicate that hypoxia induces chromosomal abnormalities in endothelial cells through the induction of reactive oxygen species and excess signaling of vascular endothelial growth factor in the tumor microenvironment.

  6. Human-chromosome alterations induced by argon laser treatment

    Energy Technology Data Exchange (ETDEWEB)

    Simi, S.; Colella, C. (Consiglio Nazionale delle Ricerche, Pisa (Italy). Lab. di Mutagenesi e Differenziamento); Agati, G.; Fusi, F. (Florence Univ. (Italy). Ist. di Farmacologia); Corsi, M.F.; Pratesi, R. (Consiglio Nazionale delle Ricerche, Florence (Italy). Lab. di Elettronica Quantistica); Tocco, G.A. (Naples Univ. (Italy). Ist. di Istologia ed Embrilogia)

    1984-07-01

    The possible occurrence of genetic damage arising from exposure of human cells to visible laser light has been evaluated in PHA-stimulated human lymphocytes. Aneuploidy and chromosome aberrations have been observed after exposure to an argon laser. These findings appear of special interest in view of the possible role of these chromosome alterations in carcinogenesis.

  7. Prediction of miscarriage and stillbirth at 11-13 weeks and the contribution of chorionic villus sampling

    NARCIS (Netherlands)

    Akolekar, Ranjit; Bower, Sarah; Flack, Nicola; Bilardo, Caterina M.; Nicolaides, Kypros H.

    2011-01-01

    Objectives To derive models for estimating risk of miscarriage and stillbirth from maternal characteristics and findings of first-trimester screening for aneuploidies and to define the procedure-related risk of chorionic villus sampling (CVS) after adjusting for these factors. Method We examined 33

  8. A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.

    Directory of Open Access Journals (Sweden)

    Benjamin D Harrison

    2014-03-01

    Full Text Available Candida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50% of isolates that are resistant to fluconazole (FLC, the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneuploidy, we analyzed diploid strains during exposure to FLC using flow cytometry and epifluorescence microscopy. FLC exposure caused a consistent deviation from normal cell cycle regulation: nuclear and spindle cycles initiated prior to bud emergence, leading to "trimeras," three connected cells composed of a mother, daughter, and granddaughter bud. Initially binucleate, trimeras underwent coordinated nuclear division yielding four daughter nuclei, two of which underwent mitotic collapse to form a tetraploid cell with extra spindle components. In subsequent cell cycles, the abnormal number of spindles resulted in unequal DNA segregation and viable aneuploid progeny. The process of aneuploid formation in C. albicans is highly reminiscent of early stages in human tumorigenesis in that aneuploidy arises through a tetraploid intermediate and subsequent unequal DNA segregation driven by multiple spindles coupled with a subsequent selective advantage conferred by at least some aneuploidies during growth under stress. Finally, trimera formation was detected in response to other azole antifungals, in related Candida species, and in an in vivo model for Candida infection, suggesting that aneuploids arise due to azole treatment of several pathogenic yeasts and that this can occur during the infection process.

  9. Investigation of Gene Expression Correlating With Centrosome Amplification in Development and Progression of Breast Cancer

    Science.gov (United States)

    2004-09-01

    Endocrinology 142, 4006-4014. 9. Colditz, G. A., Stampfer , M. J., Willett, W. C., Hennekens, C. H., Rosner, B. 37. Li, J. J., Hou, X., Banerjee, S. K...overexpression induces centrosome amplification, mitotic spindle abnormalities, and aneuploidy Christopher J. Nelsen,Ŗ Ryoko Kuriyama,3𔃾 Betsy Hirsch,4𔃿

  10. Uniparental disomy in the human blastocyst is exceedingly rare

    NARCIS (Netherlands)

    Gueye, N.A.; Devkota, B.; Taylor, D.; Pfundt, R.P.; Scott jr, R.T.; Treff, N.R.

    2014-01-01

    OBJECTIVE: To establish whether uniparental disomy (UPD) could represent an outcome of embryonic aneuploidy self-correction and its relevance to preimplantation genetic diagnosis, and to validate a method of UPD detection in limited quantities of cells and determine the frequency of UPD in a large s

  11. Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention

    OpenAIRE

    Lissa, Delphine; Senovilla, Laura; Rello-Varona, Santiago; Vitale, Ilio; Michaud, Mickaël; Pietrocola, Federico; Boilève, Alice; Obrist, Florine; Bordenave, Chloé; Garcia, Pauline; Michels, Judith; Jemaà, Mohamed; Kepp, Oliver; Castedo, Maria; Kroemer, Guido

    2014-01-01

    One hypothetical pathway leading to oncogenic transformation involves a transient phase of tetraploidization, followed by asymmetric cell divisions, aneuploidy, and genomic instability. By means of a pharmacological screen, we identified resveratrol and salicylate as compounds that kill tetraploid cells more efficiently than their parental diploid counterparts. Resveratrol and salicylate reduced the frequency of tetraploid cells arising from primary epithelial cell cultures exposed to mitotic...

  12. A tetraploid intermediate precedes aneuploid formation in yeasts exposed to fluconazole.

    Science.gov (United States)

    Harrison, Benjamin D; Hashemi, Jordan; Bibi, Maayan; Pulver, Rebecca; Bavli, Danny; Nahmias, Yaakov; Wellington, Melanie; Sapiro, Guillermo; Berman, Judith

    2014-03-01

    Candida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50% of isolates that are resistant to fluconazole (FLC), the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneuploidy, we analyzed diploid strains during exposure to FLC using flow cytometry and epifluorescence microscopy. FLC exposure caused a consistent deviation from normal cell cycle regulation: nuclear and spindle cycles initiated prior to bud emergence, leading to "trimeras," three connected cells composed of a mother, daughter, and granddaughter bud. Initially binucleate, trimeras underwent coordinated nuclear division yielding four daughter nuclei, two of which underwent mitotic collapse to form a tetraploid cell with extra spindle components. In subsequent cell cycles, the abnormal number of spindles resulted in unequal DNA segregation and viable aneuploid progeny. The process of aneuploid formation in C. albicans is highly reminiscent of early stages in human tumorigenesis in that aneuploidy arises through a tetraploid intermediate and subsequent unequal DNA segregation driven by multiple spindles coupled with a subsequent selective advantage conferred by at least some aneuploidies during growth under stress. Finally, trimera formation was detected in response to other azole antifungals, in related Candida species, and in an in vivo model for Candida infection, suggesting that aneuploids arise due to azole treatment of several pathogenic yeasts and that this can occur during the infection process.

  13. Interobserver Reproducibility of Dna-Image-Cytometry in Ascus or Higher Cervical Cytology

    Directory of Open Access Journals (Sweden)

    Vu Quoc Huy Nguyen

    2004-01-01

    Full Text Available In the present study, the aim has been to investigate the interobserver reproducibility of DNA‐image‐cytometry (DNA‐ICM applied to routine Pap smears classified as Atypical Squamous Cells of Undetermined Significance (ASCUS or higher lesions (ASCUS+. 202 Pap smears diagnosed as ASCUS or higher were included in the study. After cytological assessment, smears underwent restaining according to Feulgen. First measurements were performed as routine workup. The second measurements were blinded to the result of the first and consecutively performed. DNA‐ICM met the consensus statements of the European Society of Analytical Cellular Pathology (ESACP. Interobserver agreement was assessed by calculating Kappa statistics. The diagnosis of DNA‐aneuploidy in the first measurements was confirmed in all cases. Second measurement detected 12 additional cases with aneuploidy. Nine out of these cases were classified as aneuploidy by detection of 9c Exceeding Events (9cEE. In three cases stemline‐aneuploidy was disclosed. The overall proportion of observed agreement was 94.1%, κ=0.87, 95% CI=0.74–0.99. Our study shows a good interobserver reproducibility of DNA‐ICM performed on cervical smears with ASCUS or higher lesions. DNA‐ICM thus represents a highly reproducible diagnostic procedure.

  14. Genome stability in Caenorhabditis elegans

    NARCIS (Netherlands)

    Haaften, G.W. van

    2006-01-01

    Genome stability is closely linked to cancer. Most, if not all tumor cells show some form of genome instability, mutations can range from single point mutations to gross chromosomal rearrangements and aneuploidy. Genome instability is believed to be the driving force behind tumorigenesis. In order t

  15. NON-INVASIVE PRENATAL DIAGNOSIS: A REVIEW

    Directory of Open Access Journals (Sweden)

    Madhusudan Dey, Sumita Agarwal and Sumedha Sharma

    2013-04-01

    Full Text Available ABSTRACT: Aneuploidies are one of the important causes of perinatal morbidity and mortality. Initially screening for aneuploidies started with maternal age risk estimation. Later on, serum testing for biochemical markers and ultrasound markers were added. Women detected to be at high risk for aneuploidies were offered invasive testing. Recently, various methods including non-invasive prenatal testing (NIPT by analysis of cell-free fetal DNA (cffDNA in maternal blood has shown promise for highly accurate detection of common fetal autosomal trisomies. Incorporating these new non-invasive technologies into clinical practice will impact the current prenatal screening paradigm for fetal aneuploidy, in which genetic counselling plays an integral role. The advantage of the technique being elimination of risks such as miscarriage associated with invasive diagnostic procedures. But then this new technique has its own set of technical limitations and ethical issues at present and further research is required before implementation. Data was obtained through a literature search via Pubmed and Google as well as detailed search of our library database.

  16. Implementation of whole genome massively parallel sequencing for noninvasive prenatal testing in laboratories

    NARCIS (Netherlands)

    Thung, G.W.D.T.; Beulen, L.; Hehir-Kwa, J.Y.; Faas, B.H.W.

    2015-01-01

    Noninvasive prenatal testing (NIPT) for fetal aneuploidies using cell-free fetal DNA in maternal plasma has revolutionized the field of prenatal care and methods using massively parallel sequencing are now being implemented almost worldwide. Substantial progress has been made from initially testing

  17. BACs-on-beads: a new robust and rapid detection method for prenatal diagnosis.

    Science.gov (United States)

    Choy, Richard Kwong Wai; Chen, Ying; Sun, Xiao-Fang; Kwok, Yvonne Ka Yin; Leung, Tak Yeung

    2014-04-01

    Karyotyping, the gold standard used for diagnosis of chromosomal abnormalities, is being progressively replaced by rapid aneuploidy testing (RAT) techniques such as quantitative fluorescence-PCR, FISH and multiplex ligation-dependent probe amplification for diagnosing the common aneuploidies or chromosomal microarray analysis for comprehensive genome-wide testing. However, due to technical limitations, current RATs are confined to the detection of common aneuploidies 13, 18, 21 and sex chromosomes. To overcome the limitations of RATs, a bacterial artificial chromosomes-on-beads (BoBs™) assay technology has been introduced for the detection of the common aneuploidies as well as specific microdeletion syndromes. The BoBs assay is a bead-based multiplex assay using polystyrene beads impregnated with two spectrally distinct infrared fluorochromes to create a liquid array of up to 100 unique spectral signatures that supports the analysis of that scale of simultaneous hybridization assays on a minute DNA sample. This review gives an overview on the collective experiences of BoBs applications in prenatal diagnosis.

  18. Chromosomal mosaicism goes global

    Directory of Open Access Journals (Sweden)

    Yurov Yuri B

    2008-11-01

    Full Text Available Intercellular differences of chromosomal content in the same individual are defined as chromosomal mosaicism (alias intercellular or somatic genomic variations or, in a number of publications, mosaic aneuploidy. It has long been suggested that this phenomenon poorly contributes both to intercellular (interindividual diversity and to human disease. However, our views have recently become to change due to a series of communications demonstrated a higher incidence of chromosomal mosaicism in diseased individuals (major psychiatric disorders and autoimmune diseases as well as depicted chromosomal mosaicism contribution to genetic diversity, the central nervous system development, and aging. The later has been produced by significant achievements in the field of molecular cytogenetics. Recently, Molecular Cytogenetics has published an article by Maj Hulten and colleagues that has provided evidences for chromosomal mosaicism to underlie formation of germline aneuploidy in human female gametes using trisomy 21 (Down syndrome as a model. Since meiotic aneuploidy is suggested to be the leading genetic cause of human prenatal mortality and postnatal morbidity, these data together with previous findings define chromosomal mosaicism not as a casual finding during cytogenetic analyses but as a more significant biological phenomenon than previously recognized. Finally, the significance of chromosomal mosaicism can be drawn from the fact, that this phenomenon is involved in genetic diversity, normal and abnormal prenatal development, human diseases, aging, and meiotic aneuploidy, the intrinsic cause of which remains, as yet, unknown.

  19. [Non-invasive Genetic Prenatal Testing - A Serious Challenge for Society as a Whole].

    Science.gov (United States)

    Zerres, K

    2015-04-01

    Non-invasive genetic prenatal tests nowadays allow a highly reliable identification of pregnancies with foetal aneuploidies. Due to the general availability of these tests for all pregnant women, non-invasive genetic prenatal testing raises many ethical questions whieh can only be answered by a debate focused on society as a whole.

  20. Pallister-Killian syndrome: case report with pineal tumor.

    Science.gov (United States)

    Mauceri, L; Sorge, G; Incorpora, G; Pavone, L

    2000-11-06

    Pallister-Killian syndrome, an aneuploidy syndrome, comprises a characteristic facial appearance, mental retardation, and multiple other anomalies. It is caused by mosaicism with a supernumerary isochromosome 12p. This chromosomal abnormality has been reported also in human germ cell tumors. We report on a 15-year-old girl with Pallister-Killian syndrome and pineal tumor.

  1. Pallister-Killian syndrome presenting through nuchal translucency screening for trisomy 21.

    Science.gov (United States)

    Langford, K; Hodgson, S; Seller, M; Maxwell, D

    2000-08-01

    Pallister-Killian syndrome (tetrasomy 12p) is an uncommon aneuploidy, which may present in the prenatal period with an ultrasonographically detected fetal abnormality or following karyotyping for maternal age. We report a case that presented with increased nuchal translucency and hydrops at a first trimester screening scan for trisomy 21.

  2. A new marker set that identifies fetal cells in maternal circulation with high specificity

    DEFF Research Database (Denmark)

    Hatt, Lotte; Brinch, Marie; Singh, Ripudaman;

    2014-01-01

    OBJECTIVE: Fetal cells from the maternal circulation (FCMBs) have the potential to replace cells from amniotic fluid or chorionic villi in a diagnosis of common chromosomal aneuploidies. Good markers for enrichment and identification are lacking. METHOD: Blood samples from 78 normal pregnancies...

  3. First-trimester septated cystic hygroma and cavum velum interpositum cyst.

    Science.gov (United States)

    Sherer, David M; Dalloul, Mudar; Miller, Michelle J; Kheyman, Mila; Zinn, Harry L; Abulafia, Ovadia

    2011-07-01

    First-trimester septated cystic hygroma, frequently noted during general obstetric first-trimester screening, is strongly associated with fetal aneuploidy and structural anomalies and is considered an ominous finding. We present the case of a fetus with a first-trimester septated cystic hygroma and cavum velum interpositum cyst.

  4. Hypoxia-Induced Reactive Oxygen Species Cause Chromosomal Abnormalities in Endothelial Cells in the Tumor Microenvironment

    Science.gov (United States)

    Hida, Yasuhiro; Maishi, Nako; Towfik, Alam Mohammad; Inoue, Nobuo; Shindoh, Masanobu; Hida, Kyoko

    2013-01-01

    There is much evidence that hypoxia in the tumor microenvironment enhances tumor progression. In an earlier study, we reported abnormal phenotypes of tumor-associated endothelial cells such as those resistant to chemotherapy and chromosomal instability. Here we investigated the role of hypoxia in the acquisition of chromosomal abnormalities in endothelial cells. Tumor-associated endothelial cells isolated from human tumor xenografts showed chromosomal abnormalities, >30% of which were aneuploidy. Aneuploidy of the tumor-associated endothelial cells was also shown by simultaneous in-situ hybridization for chromosome 17 and by immunohistochemistry with anti-CD31 antibody for endothelial staining. The aneuploid cells were surrounded by a pimonidazole-positive area, indicating hypoxia. Human microvascular endothelial cells expressed hypoxia-inducible factor 1 and vascular endothelial growth factor A in response to either hypoxia or hypoxia-reoxygenation, and in these conditions, they acquired aneuploidy in 7 days. Induction of aneuploidy was inhibited by either inhibition of vascular endothelial growth factor signaling with vascular endothelial growth factor receptor 2 inhibitor or by inhibition of reactive oxygen species by N-acetyl-L-cysteine. These results indicate that hypoxia induces chromosomal abnormalities in endothelial cells through the induction of reactive oxygen species and excess signaling of vascular endothelial growth factor in the tumor microenvironment. PMID:24260373

  5. Elevated frequencies of hyperhaploid sperm were detected in a man with a history of multiple aneuploid pregnancies

    Energy Technology Data Exchange (ETDEWEB)

    Chuu, Y.J.; Wyrobek, A.J. [Lawrence Livermore National Lab., CA (United States); Kidd, S. [Univ. of California, Berkeley, CA (United States)] [and others

    1997-10-01

    The goal of this research is to determine the heritable risk associated with elevations in the proportion of hyperhaploid human sperm. A case family presented with a history of four aneuploid pregnancies: two with autosomal trisomies (47,+ 22 and 47, +15) which were non-viable and two children with sex chromosomal aneuploidies (47, XYY and Klinefelter syndrome, 47, XXY). The father consumed {approximately}{1/2} pack of cigarettes and 1 alcoholic drink per day. He had no notable occupational or environmental exposures. Paternal origin of extra X chromosomes in the boy with Klinefelter syndrome was confirmed by DNA analyses of blood using polymorphic X-linked microsatellite markers. The inheritance pattern was established by {ge}2 informative loci using PCR products analyzed on an automatic DNA sequencer. Multi-probe sperm FISH was employed to determine the proportion of sperm with aneuploidies involving chromosome 21, X, and Y. Sperm aneuploidy frequencies of hyper-haploid sperm; XY ({approximately}6 fold, p < 0.001), 21-21 ({approximately}6 fold, p< 0.001), XX and YY ({approximately}2 fold, p<0.02). These findings suggest that elevated proportions of aneuploid sperm may be associated with an increased risk of fathering an aneuploid offspring. These findings are also relevant for future studies of heritable risk for men with elevations in sperm aneuploidy after exposures to therapeutic or environmental agents.

  6. DNA ploidy and c-Kit mutation in gastrointestinal stromal tumors

    Institute of Scientific and Technical Information of China (English)

    Ju Han Lee; Xianglan Zhang; Woon Yong Jung; Yang Seok Chae; Jong-Jae Park; Insun Kim

    2004-01-01

    AIM: To investigate the prognostic significance of c-Kit gene mutation and DNA ploidy in gastointestinal stromal tumors (GISTs).METHODS: A total of 55 cases of GISTs were studied for the expression of c-Kit by immunohistochemistry, and the c-Kit gene mutations in exons 9, 11, 13, and 17 were detected by polymerase chain reaction-single strand confirmation polymarphism (PCR-SSCP) and denaturing high performance liquid chromatography (D-HPLC)techniques. DNA ploidy was determined by flow cytometry.RESULTS: Of the 55 cases of GISTs, 53 cases (96.4%)expressed c-Kit protein. The c-Kit gene mutations of exons 11 and 9 were found in 30 (54.5%) and 7 cases (12.7%),respectively. No mutations were found in exons 13 and 17.DNA aneuploidy was seen in 10 cases (18.2%). The c-Kit mutation positive GISTs were larger in size than the negative GISTs. The aneuploidy tumors were statistically associated with large size, high mitotic counts, high risk groups, high cellularity and severe nuclear atypia, and epithelioid type.There was a tendency that c-Kit mutations were more frequently found in aneuploidy GISTs.CONCLUSION: DNA aneuploidy and c-Kit mutations can be considered as prognostic factors in GISTs.

  7. Genetic alterations in benign lesions: Chronic gastritis and gastric ulcer

    Institute of Scientific and Technical Information of China (English)

    Ana Cristina Gobbo César; Marília de Freitas Calmon; Patrícia Maluf Cury; Alaor Caetano; Aldenis Albaneze Borim; Ana Elizabete Silva

    2006-01-01

    AIM: To investigate the occurrence of chromosome 3, 7,8, 9, and 17 aneuploidies, TP53 gene deletion and p53 protein expression in chronic gastritis, atrophic gastritis and gastric ulcer, and their association with H pylori infection.METHODS: Gastric biopsies from normal mucosa (NM,n = 10), chronic gastritis (CG,n =38), atrophic gastritis (CAG, n=13) and gastric ulcer (GU, n = 21) were studied using fluorescence in situ hybridization (FISH) and immunohistochemical assay. A modified Giemsa staining technique and PCR were used to detect H pylori. An association of the gastric pathologies and aneuploidies with H pylori infection was assessed.RESULTS: Aneuploidies were increasingly found from CG (21%) to CAG (31%) and to GU (62%), involving mainly monosomy and trisomy 7, trisomies 7 and 8, and trisornies 7, 8 and 17, respectively. A significant association was found between H pylori infection and aneuploidies in CAG (P= 0.0143) and GU (P= 0.0498). No TP53 deletion was found in these gastric lesions, but p53-positive immunoreactivity was detected in 45% (5/11) and 12% (2/17) of CG and GU cases, respectively. However, there was no significant association between p53 expression and H pylori infection.CONCLUSION: The occurrence of aneuploidies in benign lesions evidences chromosomal instability in early stages of gastric carcinogenesis associated with H pylori infection, which may confer proliferative advantage. The increase of p53 protein expression in CG and GU may be due to overproduction of the wild-type protein related to an inflammatory response in mucosa.

  8. Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome.

    Science.gov (United States)

    Pessia, Eugénie; Makino, Takashi; Bailly-Bechet, Marc; McLysaght, Aoife; Marais, Gabriel A B

    2012-04-03

    How and why female somatic X-chromosome inactivation (XCI) evolved in mammals remains poorly understood. It has been proposed that XCI is a dosage-compensation mechanism that evolved to equalize expression levels of X-linked genes in females (2X) and males (1X), with a prior twofold increase in expression of X-linked genes in both sexes ("Ohno's hypothesis"). Whereas the parity of X chromosome expression between the sexes has been clearly demonstrated, tests for the doubling of expression levels globally along the X chromosome have returned contradictory results. However, changes in gene dosage during sex-chromosome evolution are not expected to impact on all genes equally, and should have greater consequences for dosage-sensitive genes. We show that, for genes encoding components of large protein complexes (≥ 7 members)--a class of genes that is expected to be dosage-sensitive--expression of X-linked genes is similar to that of autosomal genes within the complex. These data support Ohno's hypothesis that XCI acts as a dosage-compensation mechanism, and allow us to refine Ohno's model of XCI evolution. We also explore the contribution of dosage-sensitive genes to X aneuploidy phenotypes in humans, such as Turner (X0) and Klinefelter (XXY) syndromes. X aneuploidy in humans is common and is known to have mild effects because most of the supernumerary X genes are inactivated and not affected by aneuploidy. Only genes escaping XCI experience dosage changes in X-aneuploidy patients. We combined data on dosage sensitivity and XCI to compute a list of candidate genes for X-aneuploidy syndromes.

  9. Selenium, selenoenzymes, oxidative stress and risk of neoplastic progression from Barrett's esophagus: results from biomarkers and genetic variants.

    Directory of Open Access Journals (Sweden)

    Yumie Takata

    Full Text Available Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1 concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85. SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR = 3.95, 95% confidence intervals (CI = 1.42-10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31-32.58, but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12-0.69. Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1

  10. Incidence of chromosome abnormalities at a second-trimester genetic amniocentesis for Mainland Chinese women of advanced maternal age: a study of 6, 584 cases

    Institute of Scientific and Technical Information of China (English)

    Qi Qing-wei; Jiang Yu-lin; Zhou Xi-ya; Liu Jun-tao; Bian Xu-ming

    2012-01-01

    Objective: The aim of this study was to calculate the expected incidence of chromosomal aneuploidy at second trimester genetic amniocentesis in Mainland China in women aged 35 and older.Methods: We reviewed the genetic amniocenteses data in Peking Union Medical College Hospital between January 2001 to June 2011.The indication for genetic amniocentesis was solely advanced maternal age (AMA).A total of 6,584 cases were included in this study.The AMA women was divided into two groups by maternal age,the group of 35-39 years old and the group of ≥40 years old.The incidence of fetal Down syndrome was compared between the two groups by chi-square test.Results: A total of 121 cases were diagnosed to be chromosomally abnormal,giving an overall incidence of 18.38‰ (121/6,584).The abnormal karyotypes included 111 cases of various aneuploidies and 10 cases with various structural abnormalities.The aneuploidies(mosaicism included)were 59 cases of (47,+ 21),25 cases of (47,+ 18),2 cases of (47,+ 13),8 cases of (45,X),3 cases of (47,XXX),13 cases of (47,XXY) and 1 case of (47,XYY).The karyotype of (47,+21) was the most frequent chromosomal abnormality,with an overall incidence of 8.96‰,account for 53.1% of all aneuploidies.Sex chromosome aneuploidies were the next most common,with a total incidence of 3.80‰.The incidence of fetal Down syndrome was significantly higher in the group of ≥40 years old than that of the group of 35-39 years old (P=0.047).Conclusions: The incidence of chromosomal aneuploidy found in this study is the first data published for Mainland China and will be helpful for the counseling of pregnant women in this age group.Consideration may be given to prenatal screening versus prenatal diagnosis in women of advanced maternal age in Mainland China.

  11. [The induction of chromosome loss and gain by colchicine (author's transl)].

    Science.gov (United States)

    Traut, H; Sommer, U

    1976-09-03

    The fruit fly Drosophila melanogaster is one of the standard systems used for mutagen screening. The colchicine-containing drugs Colchicum-Dispert and Colchysat Burger were fed at extremely low concentrations (1:300 000 and 1:50 000 respectively) to Drosophila females. Among their offspring a remarkably high frequency of aneuploid individuals (XO and XXY flies) were found. These aneuploids correspond karyotypically to the human Ullrich-Turner (XO) and Klinefelter's (XXY) syndromes and result from chromosome loss (XO) and chromosome gain (XXY). The maximum aneuploidy frequency observed after colchicine feeding was 24 times the control value. Depending on their size the aneuploidy frequencies are as great as those obtained by X-irradiation with some hundred or some thousand R.

  12. Self-correction in human embryos%胚胎自我修复

    Institute of Scientific and Technical Information of China (English)

    徐艳文

    2013-01-01

    Reanalysis of aneuploid embryos diagnosed by preimplantation genetic screening (PGS) using fluorescence in situ hybridization(FISH) showed that part or all cells in some human cleavage-stage embryos may undergo self-correction during preimplantation development. Putative embryo self-correction mechanisms include embryonic mosaicism, preferential segregation of chromosomal abnormalities to the trophectoderm and extrusion or duplication of aneuploid chromosomes resulting in uniparental disomy. However, embryo self-correction has not been proved in the study using a single nucleotide polymorphism (SNP)microarray-based 24 chromosome aneuploidy screening technology. Neither preferential segregation of aneuploidy to trophectoderm nor uniparental disomy was found. Further study to improve the accuracy of karyotyping on cleavage-stage embryos is definitely needed.

  13. Changes in metal levels and chromosome aberrations in the peripheral blood of patients after metal-on-metal hip arthroplasty.

    Science.gov (United States)

    Ladon, Dariusz; Doherty, Ann; Newson, Roger; Turner, Justine; Bhamra, Manjit; Case, C Patrick

    2004-12-01

    A prospective study was performed to investigate changes in metal levels and chromosome aberrations in patients within 2 years of receiving metal-on-metal hip arthroplasties. There was a statistically significant increase of cobalt and chromium concentrations, with a small increase in molybdenum, in whole blood at 6, 12, and 24 months after surgery. There was also a statistically significant increase of both chromosome translocations and aneuploidy in peripheral blood lymphocytes at 6, 12, and 24 months after surgery. The changes were generally progressive with time, but the change in aneuploidy was much greater than in chromosome translocations. No statistically significant correlations were found in secondary analyses between chromosome translocation indices and cobalt or chromium concentration in whole blood. Although the clinical consequences of these changes, if any, are unknown, future epidemiological studies could usefully include direct comparisons of patients with implants of different composition.

  14. Cytogenetic analysis of chromosomal abnormalities in Sri Lankan children

    Institute of Scientific and Technical Information of China (English)

    Colombo; Sri Lanka

    2015-01-01

    Background: Cytogenetic analysis is a valuable investigation in the diagnostic work up of children with suspected chromosomal disorders. The objective of this study was to describe the prevalence of various types of chromosomal abnormalities in Sri Lankan children undergoing cytogenetic analysis. Methods: Cytogenetic reports of 1554 consecutive children with suspected chromosomal disorders who underwent karyotyping in two genetic centers in Sri Lanka from January 2006 to December 2011 were reviewed retrospectively. Results: A total of 1548 children were successfully karyotyped. Abnormal karyotypes were found in 783 (50.6%) children. Numerical and structural abnormalities accounted for 90.8% and 9.2%, respectively. Down syndrome was the commonest aneuploidy identifi ed. Other various autosomal and sex chromosomal aneuploidies as well as micro-deletion syndromes were also detected. Conclusions: The prevalence of chromosomal abnormalities in Sri Lankan children undergoing cytogenetic analysis for suspected chromosomal disorders was relatively higher than that in Caucasian and other Asian populations.

  15. Cytogenetics of Premature Ovarian Failure: An Investigation on 269 Affected Women

    Directory of Open Access Journals (Sweden)

    Simona Baronchelli

    2011-01-01

    Full Text Available The importance of X chromosome in the aetiology of premature ovarian failure (POF is well-known but in many cases POF still remains idiopathic. Chromosome aneuploidy increase is a physiological phenomenon related to aging, but the role of low-level sex chromosome mosaicism in ovarian function is still undiscovered. Standard cytogenetic analysis was carried out in a total of 269 patients affected by POF: 27 chromosomal abnormalities were identified, including X chromosome and autosomal structural and numerical abnormalities. In 47 patients with 46,XX karyotype we performed interphase FISH using X alpha-satellite probe in order to identify X chromosome mosaicism rate. Aneuploidy rate in the patient group was significantly higher than the general population group. These findings underline the importance of X chromosome in the aetiology of POF and highlight the potential role of low-level sex chromosome mosaicism in ovarian aging that may lead to a premature onset of menopause.

  16. Statistical analysis of clone formation in cultures of human stem cells.

    Science.gov (United States)

    Bochkov, N P; Vinogradova, M S; Volkov, I K; Voronina, E S; Kuleshov, N P

    2011-08-01

    We performed a statistical analysis of clone formation from aneuploid cells (chromosomes 6, 8, 11, X) in cultures of bone marrow-derived human multipotent mesenchymal stromal cells by spontaneous level of aneuploidy at different terms of culturing (from 2 to 19 cell cycles). It was found that the duration of cell cycle increased from 65.6 h at passages 2-3 to 164.5 h at passage 12. The expected ratio of aneuploid cells was calculated using modeled 5, 10, 20 and 30% selective preference in reproduction. The size of samples for detecting 10, 25, and 50% increased level of aneuploidy was calculated. The presented principles for evaluation of aneuploid clone formation may be used to distinguish clones of any abnormal cells.

  17. Triploidy mosaicism (45,X/68,XX) in an infant presenting with failure to thrive.

    Science.gov (United States)

    Posey, Jennifer E; Mohrbacher, Nikki; Smith, Janice L; Patel, Ankita; Potocki, Lorraine; Breman, Amy M

    2016-03-01

    Triploid mosaicism is a rare aneuploidy syndrome characterized by growth retardation, developmental delay, 3-4 syndactyly, microphthalmia, coloboma, cleft lip and/or palate, genitourinary anomalies, and facial or body asymmetry. In the present report, we describe a 3-month-old female presenting with failure to thrive, growth retardation, and developmental delay. A chromosomal microarray demonstrated monosomy X, but her atypical phenotype prompted further evaluation with a chromosome analysis, which demonstrated 45,X/68,XX mixoploidy. To our knowledge, this is the first report of a patient with this chromosome complement. Mosaicism in chromosomal aneuploidies is likely under-recognized and may obscure the clinical diagnosis. At a time when comparative genomic hybridization and genome sequencing are increasingly used as diagnostic tools, this report highlights the clinical utility of chromosome analysis when a molecular diagnosis is not consistent with the observed phenotype.

  18. Meiotic recombination and male infertility:from basic science to clinical reality?%减数分裂重组和男性不育:从基础研究到临床实践

    Institute of Scientific and Technical Information of China (English)

    Michael C Hann; Patricio E Lau; Helen G Tempest

    2011-01-01

    Infertility is a common problem that affects approximately 15% of the population. Although many advances have been made in the treatment of infertility, the molecular and genetic causes of male infertility remain largely elusive. This review will present a summary of our current knowledge on the genetic origin of male infertility and the key events of male meiosis. It focuses on chromosome synapsis and meiotic recombination and the problems that arise when errors in these processes occur, specifically meiotic arrest and chromosome aneuploidy, the leading cause of pregnancy loss in humans. In addition, meiosis-specific candidate genes will be discussed, including a discussion on why we have been largely unsuccessful at identifying disease-causing mutations in infertile men.Finally clinical applications of sperm aneuploidy screening will be touched upon along with future prospective clinical tests to better characterize male infertility in a move towards personalized medicine.

  19. Mad revival of cancer

    Institute of Scientific and Technical Information of China (English)

    Hong Liu; Hongtao Yu

    2010-01-01

    @@ Aneuploidy (wrong numbers of chromosomes) is a hallmark of cancer cells and arises from chromosome missegregation in mitosis. To prevent aneuploidy, cells employ surveillance systems to monitor mitosis. The spindle checkpoint (also known as the mitotic checkpoint) is one such surveillance system conserved from yeast to man [1, 2]. During each mitosis, this check-point detects aberrant kinetochore-microtubule attachments, inhibits the anaphase-promoting complex or cy-closome (APC/C), stabilizes cyclin B1 and securin, and delays anaphase onset until all sister chromatids reach proper microtubule attachment. Mad2 is a criti-cal player of the spindle checkpoint and contributes to the inhibition of APC/C directly [3].

  20. Fetal Sonography for the Detection of Chromosomal Abnormality

    Energy Technology Data Exchange (ETDEWEB)

    Song, Mi Jin [Cheil General Hospital and Women' s Healthcare Center, Kwandong University College of Medicine, Gangneung (Korea, Republic of)

    2011-06-15

    Over the past decade, women's health clinicians have witnessed a shift of the paradigm for the approach to prenatal screening for chromosomal abnormalities. From an emphasis on age-based invasive diagnostic tests, women are now being offered a variety of noninvasive screening tests. Although there is exciting research and innovation in the field of noninvasive testing for fetal aneuploidy, there are currently two tests, and both are invasive, that are used in a routine manner to determine the presence of fetal aneuploidy: chorionic villous sampling and amniocentesis. The aim of this review was to investigate the effectiveness of prenatal sonography, including first trimester nuchal translucency screening and second trimester genetic sonography, for obtaining valid chromosomal abnormality screening test results

  1. Partial duplication 2p as the sole abnormality in two cases with anencephaly.

    Science.gov (United States)

    Thangavelu, Maya; Frolich, Gary; Rogers, David

    2004-01-15

    Anencephaly/NTD has been observed in aneuploid and non-aneuploid individuals. We present two cases of anencephaly diagnosed prenatally with partial duplication of the short arm of chromosome 2 as the sole abnormality. The absence of aneuploidy involving other regions of the genome in these cases, further substantiates suggestions of the existence of a gene or genes on the short arm of chromosome 2 critical in the development of the central nervous system.

  2. Kinetochore microtubule establishment is defective in oocytes from aged mice.

    Science.gov (United States)

    Shomper, Maria; Lappa, Christina; FitzHarris, Greg

    2014-01-01

    Errors in chromosome segregation in mammalian oocytes increase in number with advancing maternal age, and are a major cause of pregnancy loss. Why chromosome segregation errors are more common in oocytes from older females remains poorly understood. In mitosis, accurate chromosome segregation is enabled by attachment of kinetochores to microtubules from appropriate spindle poles, and erroneous attachments increase the likelihood of mis-segregation. Whether attachment errors are responsible for age-related oocyte aneuploidy is unknown. Here we report that oocytes from naturally aged mice exhibit substantially increased chromosome misalignment, and fewer kinetochore pairs that make stable end-on attachments to the appropriate spindle poles compared with younger oocytes. The profile of mis-attachments exhibited is consistent with the types of chromosome segregation error observed in aged oocytes. Loss of chromosome cohesion, which is a feature of oocytes from older females, causes altered kinetochore geometry in meiosis-I. However, this has only a minor impact upon MT attachment, indicating that cohesion loss is not the primary cause of aneuploidy in meiosis-I. In meiosis-II, on the other hand, age-related cohesion loss plays a direct role in errors, since prematurely individualized sister chromatids misalign and misattach to spindle MTs. Thus, whereas cohesion loss leading to precocious sister chromatid separation is a direct cause of errors in meiosis-II, cohesion loss plays a more minor role in the etiology of aneuploidy in meiosis-I. Our data introduce altered MT-kinetochore interactions as a lesion that explains aneuploidy in meiosis-I in older females.

  3. Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2

    Directory of Open Access Journals (Sweden)

    Juha K. Rantala

    2010-11-01

    Full Text Available Aneuploidy is among the most obvious differences between normal and cancer cells. However, mechanisms contributing to development and maintenance of aneuploid cell growth are diverse and incompletely understood. Functional genomics analyses have shown that aneuploidy in cancer cells is correlated with diffuse gene expression signatures and aneuploidy can arise by a variety of mechanisms, including cytokinesis failures, DNA endoreplication, and possibly through polyploid intermediate states. To identify molecular processes contributing to development of aneuploidy, we used a cell spot microarray technique to identify genes inducing polyploidy and/or allowing maintenance of polyploid cell growth in breast cancer cells. Of 5760 human genes screened, 177 were found to induce severe DNA content alterations on prolonged transient silencing. Association with response to DNA damage stimulus and DNA repair was found to be the most enriched cellular processes among the candidate genes. Functional validation analysis of these genes highlighted GINS2 as the highest ranking candidate inducing polyploidy, accumulation of endogenous DNA damage, and impairing cell proliferation on inhibition. The cell growth inhibition and induction of polyploidy by suppression of GINS2 was verified in a panel of breast cancer cell lines. Bioinformatic analysis of published gene expression and DNA copy number studies of clinical breast tumors suggested GINS2 to be associated with the aggressive characteristics of a subgroup of breast cancers in vivo. In addition, nuclear GINS2 protein levels distinguished actively proliferating cancer cells suggesting potential use of GINS2 staining as a biomarker of cell proliferation as well as a potential therapeutic target.

  4. The First Case Report in Italy of Di George Syndrome Detected by Noninvasive Prenatal Testing

    OpenAIRE

    Giuseppina Rapacchia; Cristina Lapucci; Maria Carla Pittalis; Aly Youssef; Antonio Farina

    2015-01-01

    Panorama Plus (Natera), a single-nucleotide polymorphism- (SNP-) based approach that relies on the identification of maternal and fetal allele distributions, allows the detection of common aneuploidies and also incorporates a panel of 5 microdeletions including Di George syndrome. We report here the first case of Di George syndrome detected by NIPT in Italy; blood was drawn at 12 weeks’ gestation. The patient had an amniocentesis to confirm the diagnosis by MLPA (multiplex ligation-dependent ...

  5. USSR Report, Life Sciences Biomedical and Behavioral Sciences.

    Science.gov (United States)

    1987-03-10

    arsenal of research techniques . Among those honored in this fashion is Valeriy Kazimirovich Lishko, director of the Institute of Biochemistry of the...cytogenetic stabilization, pollen fertility, aneuploidy and formation of productivity traits of plants in early generations (F..-F5) of new hexaploid...view of reports, some contested, that laser irradiation of crop seeds promotes germination and enhances yields, a statistical evaluation was conducted

  6. Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease.

    Science.gov (United States)

    Potter, Huntington; Granic, Antoneta; Caneus, Julbert

    2016-01-01

    Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer's disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.

  7. Evaluation of the mutagenic activity of leucinostatins, a novel class of antibiotic peptides produced by Paecilomyces marquandii, in the modul Aspergillus nidulans.

    Science.gov (United States)

    Crebelli, R; Carere, A; Conti, G; Conti, L; Rossi, C; Tuttobello, L

    1988-10-01

    Leucinostatins A, B, C, D, E, G, H, and K were thoroughly investigated for their genotoxic activity using the modul Aspergillus nidulans as the test organism. The results of assays for gene mutation (8-azaguanine resistance and methionine suppressors), gene conversion, mitotic crossing-over and mitotic aneuploidy induction suggest that these peptide antibiotics lack significant mutagenicity and that non-genotoxic mechanism(s) underlie their cytotoxic properties.

  8. Immunodeficiency in Patients With 49,XXXXY Chromosomal Variation

    OpenAIRE

    Keller, Michael D; Sadeghin, Teresa; Samango-Sprouse, Carole; Orange, Jordan S.

    2013-01-01

    Boys affected with 49,XXXXY sex chromosomal variation have been described to have high incidence of recurrent otitis media and asthma, the cause of which is unknown. We hypothesized that primary immunodeficiency occurs in patients with XXXXY aneuploidy. To investigate this, 31 boys with known 49,XXXXY were evaluated through a multidisciplinary clinic. Screening history was performed using the “10 Warning Signs of primary immunodeficiency” (Jeffrey Modell Foundation), as well as by history of ...

  9. Progression and survival in prostatic adenocarcinoma: a comparison of clinical stage, Gleason grade, S-phase fraction and DNA ploidy.

    OpenAIRE

    Vesalainen, S.; Nordling, S; Lipponen, P.; Talja, M.; Syrjänen, K

    1994-01-01

    Clinical data were reviewed in 325 patients with prostatic adenocarcinoma followed up for a mean of 13 years. Paraffin-embedded tumour biopsy specimens from the primary tumours were available for flow cytometry (FCM) in 273 cases. Intra-tumour heterogeneity in DNA index (DI) was found in 4% of the tumours (54 cases were analysed). S-phase fraction (SPF) and DNA ploidy were significantly interrelated. Aneuploidy and high SPF were significantly related to both a high T category and high Gleason...

  10. The accuracy of chromosomal microarray testing for identification of embryonic mosaicism in human blastocysts

    OpenAIRE

    2014-01-01

    Background Most previous studies of chromosomal mosaicism in IVF embryos were performed by fluorescence in situ hybridization (FISH) methods. While there are reports implicating chromosome aneuploidy in implantation failure following transfer and pregnancy loss by spontaneous miscarriage, the significance of mosaicism for the developmental potential of growing embryos is unknown. However, the low prevalence of chromosomal mosaicism in chorionic villus sampling and amniotic fluid specimens sug...

  11. Two subtelomeric chromosomal deletions in forty-six children with idiopathic mental retardation

    Institute of Scientific and Technical Information of China (English)

    李荣; 赵正言

    2004-01-01

    @@ Mental retardation (MR) affects approximately 3% of the population. In infancy and early childhood, mental retardation often presents as developmental delay. Unexplained MR is responsible for more than half of all cases.1,2 There is some evidence that subtle chromosomal rearrangements involved in subtelomeric regions (gene-rich regions), resulting in segmental aneuploidy and gene-dosage imbalance, are significant unrecognized causes of idiopathic mental retardation (IMR).3-10

  12. Hyperhaploid and tetraploid sperm detected in men who ingested ultra-high doses of diazepam

    Energy Technology Data Exchange (ETDEWEB)

    Baumgartner, A. [Lawrence Livermore National Lab., CA (United States)]|[GSF-Inst. Saeugetiergenetik, Neuherberg (Germany); Adler, I.D.; Schmid, T.E. [GSF-Inst. Saeugetiergenetik, Neuherberg (Germany)] [and others

    1997-10-01

    Diazepam is widely administered as a sedative, muscle relaxant and anxiolytic drug. Five young non-smoking men who were hospitalized after their suicide attempt using diazepam, {approximately}1-7 mg/kg (oral intake), provided semen samples 40-50 days and {approximately}100 days after exposure to assess drug effects on meiotic cells and to evaluate persistence. Five healthy men served as local clinical controls. A multicolor FISH assay was applied to detect aneuploidy for chromosome X, Y, and 21 in sperm. Sex ratios were not significantly different from 1:1 among 133,143 cells analyzed. The 40-day samples showed an increase in several sperm aneuploidy groups: disomy 21 (1.5 fold, p=0.04); disomy X (2.7 fold, p=0.0006), and XY aneuploidy (1.6 folk, p=0 0.017). The results for {approximately}100 days after exposure were similar to controls suggesting that hyperhaploidy effects may not persist. Phase contrast microscopy was used to identify flagellated tetraploid sperm, i.e., X-X-Y-Y-21-21-21-21. Tetraploid sperm were found among 8 semen samples provided by five patients (1.4 {+-} 1.2 per 10,000 cells; >80,000 cells) while none were detected among >50,000 cells from healthy men. Our findings are consistent with the possible aneuploidy-inducing effect of diazepam during male meiosis but further studies are needed before these results can be extrapolated to therapeutic dosing because suicide patients are a highly exposed cohort and other confounding factors (alcohol, drugs, antidotes) cannot be ruled out.

  13. Novel Roles for P53 in the Genesis and Targeting of Tetraploid Cancer Cells

    OpenAIRE

    Batzaya Davaadelger; Hong Shen; Maki, Carl G.

    2014-01-01

    Tetraploid (4N) cells are considered important in cancer because they can display increased tumorigenicity, resistance to conventional therapies, and are believed to be precursors to whole chromosome aneuploidy. It is therefore important to determine how tetraploid cancer cells arise, and how to target them. P53 is a tumor suppressor protein and key regulator of tetraploidy. As part of the "tetraploidy checkpoint", p53 inhibits tetraploid cell proliferation by promoting a G1-arrest in incipie...

  14. Guidelines for scanning twins and triplets with US and MRI

    Energy Technology Data Exchange (ETDEWEB)

    Calvo-Garcia, Maria A. [Cincinnati Children' s Hospital Medical Center, Department of Radiology, Cincinnati, OH (United States)

    2016-02-15

    Multiple-fetus gestations have an increased risk of discordant anomalies, aneuploidy and growth restriction compared to singleton pregnancies. In addition, twins sharing the same placenta are at risk for developing specific conditions that are potentially amenable to surgical management. In those scenarios, patients might need to be evaluated not only with US but with fetal MRI as well. This paper outlines basic guidelines to consider when imaging complicated multiple-fetus gestations during the 2nd and 3rd trimesters. (orig.)

  15. Rapid prenatal diagnosis of trisomy 21 by fluorescent quantitative multiplex polymerase chain reaction

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Trisomy 21, also named Down syndrome was the most frequent autosomal aneuploidy and the most common cause of mental retardation. Fifty percent patients had congenital heart malformation. Every 20 minutes one case of trisomy 21 was born, and the incidence rate was 1 in 600 to 800 newborns in China.1 In two thirds of cases with trisomy 21, there was a spontaneous abortion, so the actual incidence was higher than that obtained postnatally.

  16. Targeting the Synthetic Essential Kinases of Breast Cancers

    Science.gov (United States)

    2016-05-01

    robust and reproducible performance in identifying genes and pathways involved in such diverse processes as cancer cell proliferation, innate immune...343(6166):80-84. 3. Lucas JE, Kung HN, Chi JT: Latent factor analysis to discover pathway -associated putative segmental aneuploidies in human cancers ...AWARD NUMBER: W81XWH-15-1-0027 TITLE: Targeting the synthetic essential kinases of breast cancers PRINCIPAL INVESTIGATOR: Jen-Tsan

  17. Triple X Syndrome with Short Stature: Case Report and Literature Review

    OpenAIRE

    Mingyan Li; Chaochun Zou; Zhengyan Zhao

    2012-01-01

    Background: Triple X syndrome is a sex chromosomal aneuploidy condition characterized by tall stature, microcephaly, hypertelorism, congenital abnormalities, and motor and language delays. It is mainly derived from maternal nondisjunctional errors during meiosis. To highlight the clinical features and diagnosis of triple X syndrome, we present a rare phenotype of the syndrome.Case Presentation: A 5.9 year-old girl was admitted to our hospital because of short stature. Both her height and weig...

  18. Noninvasive prenatal testing using cell-free fetal DNA in maternal plasma.

    Science.gov (United States)

    Dharajiya, Nilesh; Zwiefelhofer, Tricia; Guan, Xiaojun; Angkachatchai, Vach; Saldivar, Juan-Sebastian

    2015-01-20

    Noninvasive prenatal testing (NIPT) represents an outstanding example of how novel scientific discoveries can be quickly and successfully developed into hugely impactful clinical diagnostic tests. Since the introduction of NIPT to detect trisomy 21 in late 2011, the technology has rapidly advanced to analyze other autosomal and sex chromosome aneuploidies, and now includes the detection of subchromosomal deletion and duplication events. Here we provide a brief overview of how noninvasive prenatal testing using next-generation sequencing is performed.

  19. Influence of the X-Chromosome on Neuroanatomy: Evidence from Turner and Klinefelter Syndromes

    OpenAIRE

    2014-01-01

    Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an addit...

  20. Hidden Markov models for the assessment of chromosomal alterations using high-throughput SNP arrays

    OpenAIRE

    2008-01-01

    Chromosomal DNA is characterized by variation between individuals at the level of entire chromosomes (e.g., aneuploidy in which the chromosome copy number is altered), segmental changes (including insertions, deletions, inversions, and translocations), and changes to small genomic regions (including single nucleotide polymorphisms). A variety of alterations that occur in chromosomal DNA, many of which can be detected using high density single nucleotide polymorphism (SNP)...

  1. Oxidative Stress and Mitochondrial Dysfunction in Down’s Syndrome: Relevance to Aging and Dementia

    OpenAIRE

    Coskun, Pinar E; Jorge Busciglio

    2012-01-01

    Genome-wide gene deregulation and oxidative stress appear to be critical factors determining the high variability of phenotypes in Down’s syndrome (DS). Even though individuals with trisomy 21 exhibit a higher survival rate compared to other aneuploidies, most of them die in utero or early during postnatal life. While the survivors are currently predicted to live past 60 years, they suffer higher incidence of age-related conditions including Alzheimer’s disease (AD). This paper is centered on...

  2. Modeling Human Epithelial Ovarian Cancer in Mice by Alteration of Expression of the BRCA1 and/or p53 Genes

    Science.gov (United States)

    2008-02-01

    including high level chromosome damage, variable chromosome counts, rearrangements and multiclonal populations ( dicentrics , translocations...sarcoma arising in the p53LoxP/LoxP group, while not normal, generally had patterns of whole chromosome gains and losses consistent with aneuploidy and...many fewer regions of interstitial chromosomal gains/losses detected by aCGH as compared to tumors isolated from Brca1LoxP/LoxP;p53LoxP/LoxP mice

  3. Cytogenetics in animal production

    OpenAIRE

    2010-01-01

    Cytogenetics applied to domestic animals is a useful biotechnology to be applied in the genetic improvement of livestock. Indeed, it can be used to select reproducers free chromosome abnormalities which are responsible for abnormal body conformation (aneuploidy), lower fertility (balanced chromosome abnormalities) or sterility (sex chromosome abnormalities). Cytogenetics may also be applied to assess environmental pollution by studying animals living in hazardous areas and using them as biolo...

  4. Centrosome Defects, Genetic Instability and Breast Cancer Progression

    Science.gov (United States)

    2006-08-01

    leads to multipolar spindles and aneuploidy by a mechanism different from pericentrin depletion. In conclusion, my work has focused on understanding...Components Localize to the Midbody Ring in a Centriolin-Dependent Manner Snapin was originally considered to be a neuron -spe- cific protein, but recent...Snapin as a ubiquitously expressed SNARE-binding protein hat interacts with SNAP23 in non- neuronal cells. Biochem. J. 375, 33–440. hen, C., and Contreras

  5. Histone H2AFX Links Meiotic Chromosome Asynapsis to Prophase I Oocyte Loss in Mammals.

    OpenAIRE

    Cloutier, Jeffrey M.; Mahadevaiah, Shantha K.; Elias ElInati; André Nussenzweig; Attila Tóth; James M A Turner

    2015-01-01

    Author Summary Chromosome abnormalities, such as aneuploidies and structural variants (i.e. translocations, inversions), are strikingly common in the human population, causing disorders such as Down syndrome and Turner syndrome. One important consequence of chromosome abnormalities in mammals is errors during meiosis, the specialized cell division that generates sperm and eggs for reproduction. As a result of these meiotic errors, patients with chromosome abnormalities oftentimes suffer from ...

  6. An adolescent with 48,xxyy syndrome with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder and renal malformations

    OpenAIRE

    Prasad Katulanda; Rajapakse, J. Rasika D. K.; Jayani Kariyawasam; Rohan Jayasekara; Vajira H.W. Dissanayake

    2012-01-01

    48,XXYY is a rare sex chromosome aneuploidy affecting 1 in 18,000 to 50,000 male births. They present with developmental delay, hypogonadism, gynecomastia, intention tremors, and a spectrum of neurodevelopmental and psychiatric disorders. At one time this condition was considered a variant of Klinefelter syndrome. In clinically suspected cases, 48,XXYY syndrome can be diagnosed by chromosome culture and karyotyping. This patient presented with hypergonadotrophic hypogonadism, attention defici...

  7. Association of MTHFR Polymorphisms and Chromosomal Abnormalities in Leukemia

    Directory of Open Access Journals (Sweden)

    Thivaratana Sinthuwiwat

    2012-01-01

    Full Text Available Genetic variation in MTHFR gene might explain the interindividual differences in the reduction of DNA repaired and the increase of chromosome breakage and damage. Nowadays, chromosomal rearrangement is recognized as a major cause of lymphoid malignancies. In addition, the association of MTHFR polymorphisms with aneuploidy was found in several studies, making the MTHFR gene as a good candidate for leukemia etiology. Therefore, in this study, we investigated the common sequence variation, 677C>T and 1298A>C in the MTHFR gene of 350 fixed cell specimens archived after chromosome analysis. The distribution of the MTHFR polymorphisms frequency was compared in leukemic patients with structural chromosome abnormality and chromosome aneuploidy, as well as in those with no evidence of chromosome abnormalities. We observed a significant decrease in the distribution of T allele in 677C>T polymorphisms among patients with chromosomal abnormalities including both structural aberration and aneuploidy. The same significance result also found in patients with structural aberration when compare with the normal karyotype patients. Suggesting that polymorphism in the MTHFR gene was involved in chromosome abnormalities of leukemia. However, further investigation on the correlation with the specific types of chromosomal aberrations is needed.

  8. Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance

    Institute of Scientific and Technical Information of China (English)

    Yoshiteru Kai; Teruhiko Wakayama; Mitsuo Oshimura; Chi Chiu Wang; Satoshi Kishigami; Yasuhiro Kazuki; Satoshi Abe; Masato Takiguchi; Yasuaki Shirayoshi; Toshiaki Inoue; Hisao Ito

    2009-01-01

    Although particular chromosomal syndromes are phenotypically and clinically distinct, the majority of individuals with autosomai imbalance, such as aneuploidy, manifest mental retardation. A common abnormal phenotype of Down syndrome (DS), the most prevalent autosomal aneuploidy, shows a reduction in both the number and the density of neurons in the brain. As a DS model, we have recently created chimeric mice from ES cells containing a single human chromosome 21. The mice mimicked the characteristic phenotypic features of DS, and ES cells showed a higher incidence of apoptosis during early neuronal differentiation in vitro. In this study, we examined the induction of anomalous early neural development by aneuploidy in mouse ES cells by transferring various human chromosomes or additional mouse chromosomes. Results showed an elevated incidence of apoptosis in all autosome-aneuploid clones examined during early neuronal differentiation in vitro. Further, cDNA microarray analysis revealed a common cluster of down-regulated genes, of which eight known genes are related to cell proliferation, neurite outgrowth and differentiation. Importantly, targeting of these genes by siRNA knockdown in normal mouse ES cells led to enhanced apoptosis during early neuronal differentiation. These findings strongly suggest that autosomal imbalance is associated with general neuronal loss through a common molecular mechanism for apoptosis.

  9. Simultaneous measurement of the frequencies of intrachromosomal recombination and chromosome gain using the yeast DEL assay.

    Science.gov (United States)

    Howlett, N G; Schiestl, R H

    2000-11-06

    The yeast DEL assay measures the frequency of intrachromosomal recombination between two partially-deleted his3 alleles on chromosome XV. The his3Delta alleles share approximately 400bp of overlapping homology, and are separated by an intervening LEU2 sequence. Homologous recombination between the his3Delta alleles results in deletion of the intervening LEU2 sequence (DEL), and reversion to histidine prototrophy. In this study we have attempted to further extend the use of the yeast DEL assay to measure the frequency of chromosome XV gain events. Reversion to His(+)Leu(+) in the haploid yeast DEL tester strain RSY6 occurs upon non-disjunction of chromosome XV sister chromatids, coupled with a subsequent DEL event. Here we have tested the ability of the yeast DEL assay to accurately predict the aneugenic potential of the diversely-acting, known or suspected aneugens actinomycin D, benomyl, chloral hydrate, ethyl methanesulfonate (EMS), methyl methanesulfonate (MMS), and methotrexate. Actinomycin D and benomyl strongly induced aneuploidy. EMS and methotrexate modestly induced aneuploidy, while chloral hydrate and MMS failed to illicit any significant induction. In addition, by FACS-analysis of DNA content it was shown that the majority of both spontaneous- and chemically-induced His(+)Leu(+) revertants were heterodiploid. Thus, our results indicate endoreduplication of almost entire chromosome sets as a major mechanism of aneuploidy induction in haploid Saccharomyces cerevisiae.

  10. Clinical utility of nuchal translucency screening

    Directory of Open Access Journals (Sweden)

    Stefanovic V

    2014-10-01

    Full Text Available Vedran Stefanovic,1 Outi Äyräs,1 Marianne Eronen,2 Jorma Paavonen,1 Minna Tikkanen1 1Department of Obstetrics and Gynecology, Helsinki University Central Hospital, 2Health Department, The Social Insurance Institution of Finland, Helsinki, Finland Abstract: The term nuchal translucency (NT is used to describe the accumulation of fluid behind the fetal neck visible on ultrasound in the first trimester of pregnancy. In singleton and dichorionic twin pregnancies, increased NT thickness is associated with trisomy 21 and other aneuploidies, major fetal anomalies (especially congenital heart disease, and genetic syndromes. The pathophysiology and significance of increased or discordant NT in monochorionic twin pregnancies is more complex and is associated with twin-to-twin transfusion syndrome and other pregnancy complications due to monochorionicity. The long-term neurological outcome of euploid children without structural anomalies after increased fetal NT seems to be favorable. Proper counseling is essential in the screening process. Special attention should be paid to the assessment of NT screening quality control. Even in the era of arising possibilities for non-invasive fetal karyotype determination from maternal blood, the role of NT screening is far from over. The association of this phenomenon with aneuploidies is only one of its utilities in modern obstetrics. Keywords: nuchal translucency, screening, aneuploidy, congenital anomaly, counseling, obstetrics

  11. Functional Inactivation of pRB Results in Aneuploid Mammalian Cells After Release From a Mitotic Block

    Directory of Open Access Journals (Sweden)

    Laura Lentini

    2002-01-01

    Full Text Available The widespread chromosome instability observed in tumors and in early stage carcinomas suggests that aneuploidy could be a prerequisite for cellular transformation and tumor initiation. Defects in tumor suppressers and genes that are part of mitotic checkpoints are likely candidates for the aneuploid phenotype. By using flow cytometric, cytogenetic, immunocytochemistry techniques we investigated whether pRB deficiency could drive perpetual aneuploidy in normal human and mouse fibroblasts after mitotic checkpoint challenge by microtubule-destabilizing drugs. Both mouse and human pRB-deficient primary fibroblasts resulted, upon release from a mitotic block, in proliferating aneuploid cells possessing supernumerary centrosomes. Aneuploid pRB-deficient cells show an elevated variation in chromosome numbers among cells of the same clone. In addition, these cells acquired the capability to grow in an anchorage-independent way at the same extent as tumor cells did suggesting aneuploidy as an initial mutational step in cell transformation. Normal Mouse Embryonic Fibroblasts. (MEFs harboring LoxP sites flanking exon 19 of the Rb gene arrested in G2/M with duplicated centrosomes after colcemid treatment. However, these cells escaped the arrest and became aneuploid upon pRB ablation by CRE recombinase, suggesting pRB as a major component of a checkpoint that controls cellular ploidy.

  12. Cytogenetics of Anodonta cygnea (Mollusca: Bivalvia) as possible indicator of environmental adversity

    Science.gov (United States)

    Carrilho, J.; Leitão, A.; Vicente, C.; Malheiro, I.

    2008-11-01

    Anodonta cygnea is a freshwater clam, belonging to the Unionidae family, which can be found in rivers and lagoons all over Europe and Northern America. As they appear as important case studies for ecological damage assessments, the various species of the Unionidae family have been submitted to a sort of recent studies on their chromosomal or cytogenetic status. In this study we confirmed the diploid chromosome number of 2 n = 38 for this species, and established for the first time the karyotype, which comprised six metacentric, 12 submetacentric and one subtelocentric chromosome pairs. We also found a high percentage of cells with an abnormal number of chromosomes. Considering that karyotype disturbances in Unionids have been previously related with exposure to chemicals, either natural or produced by human activity, we determined the aneuploidy index for our population. The aneuploidy index is an excellent marker for pollutant presence/effect. The animals acclimatized in tap water and in natural water from the lake where the individuals were collected showed different levels of aneuploidy. The higher values were found in tap water. Chromosome analysis techniques seem a suitable tool to study the impact of contaminants referred above, and making A. cygnea a suitable organism for assessment of an eugenic damage in aquatic systems. On the other hand, our results also point out to the importance of doing the acclimatizing process of the collected animals in their own natural water.

  13. Occupational risk factors and frequency of sex chromosome disomy.

    Science.gov (United States)

    Radwan, Michał; Jurewicz, Joanna; Radwan, Paweł; Ulańska, Anna; Jakubowski, Lucjusz; Hanke, Wojciech

    2015-09-01

    Possible reproductive toxicants such as occupational factors may affect the normal disjunction of chromosomes during meiosis, thereby altering the number of chromosomes in sperm nuclei. The purpose of the present analysis was to determine whether exposure to occupational factors existing in a contemporary work setting affected sperm aneuploidy. The study population consisted of 212 men who attended the infertility clinic for diagnostic purposes. The men either had a normal semen concentration of 20-300 million/ml or slight oligozoospermia (semen concentration of 15-20 million/ml) ( WHO 1999 ). All participants were interviewed and provided a semen sample. Sperm aneuploidy was assessed using multicolor FISH. After adjustment for potential confounders, positive associations were found between disomy XY18, 18, and sex chromosome disomy and exposure to mechanical vibrations (p = 0.03, p = 0.04, p = 0.03, respectively). In addition, sitting for more than 6 h at work increased X and Y disomy (p = 0.03, p = 0.04, respectively). To the best of our knowledge, this is the first study to show a significant effect of occupational factors on sperm aneuploidy. As such, the results need to be confirmed in larger studies.

  14. Production of Aneuploid Pinctada martensii Dunker in Tetraploid Induction

    Institute of Scientific and Technical Information of China (English)

    何毛贤; 林岳光; 沈琪; 胡建兴; 姜卫国

    2001-01-01

    Aneuploidy embryos of Pinctada martensii Dunker are produced during tetraploid induction by inhibiting the first polar body in eggs from triploid fertilized with haploid sperms with cytochalasin B treatment. Chromosome analysis reveals that there are 88.18 ±6.79% aneuploidy embryos, and 28.70% aneuploids in pearl oysters of one-year age These aneuploids have five chromosomal conditions, such as 2n + 1(29), 2n + 2 (30), 3n-2 (40), 3n-1(41) and 3n + 1 (43). Results of growth measurement show that there is no significant difference between aneuploids (as a group) and diploids in body size and weight (p > 0.10), but the aneuploide is obviously different from triploid (p < 0.01). The mean body size and weight of aneuploids in diploid condition (2n ± 1 and 2n ± 2) are significantly smaller than those of diploids (p < 0.01),but aneuploids within triploid condition (3n ± 1 and 3n ± 2) are not smaller than diploids in body size and weight (p > 0.1).This study indicates Pinctada martensii Dunker could tolerate aneuploidy by 7 ~ 14% of the haploid genome, and that aneuploids of this species are viable under certain conditions.

  15. Partial Hepatectomy in Acetylation-Deficient Mice Corroborates that Chromosome Missegregation Initiates Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Yoo-Kyung Lee

    2014-12-01

    Full Text Available BackgroundAneuploidy has been suggested as one of the major causes of cancer from the time of Boveri. In support of this notion, many studies have shown that cancer cells exhibit aneuploidy. However, there are evidences that do not support the aneuploidy hypothesis. We have previously reported that the spindle assembly checkpoint protein BubR1 is acetylated in mitosis and that the acetylation of BubR1 is crucial for checkpoint maintenance and chromosome-spindle attachment. Mice heterozygous for acetylation-deficient BubR1 (K243R/+ spontaneously develop cancer with chromosome instability. As K243R/+ mice develop hepatocellular carcinoma, we set out to test if chromosome mis-segregation was the cause of their liver cancer.MethodsPrimary hepatocytes in the regenerating liver after partial hepatectomy (PH were analyzed and compared for various mitotic parameters.ResultsPrimary hepatocytes isolated from K243R/+ mice after PH displayed a marked increase of chromosome misalignment, accompanied by an increase of micronuclei. In comparison, the number of nuclei per cell and the centrosome numbers were not different between wild-type and K243R/+ mice. Taken together, chromosome mis-segregation provokes tumorigenesis in mouse liver.ConclusionOur results corroborate that PH provides a reliable tool for assessing mitotic infidelity and cancer in mice.

  16. Chromatin structure and ATRX function in mouse oocytes.

    Science.gov (United States)

    De La Fuente, Rabindranath; Baumann, Claudia; Viveiros, Maria M

    2012-01-01

    Differentiation of chromatin structure and function during oogenesis is essential to confer the mammalian oocyte with meiotic and developmental potential. Errors in chromosome segregation during female meiosis and subsequent transmission of an abnormal chromosome complement (aneuploidy) to the early conceptus are one of the leading causes of pregnancy loss in women. The chromatin remodeling protein ATRX (α-thalassemia mental retardation X-linked) has recently emerged as a critical factor involved in heterochromatin formation at mammalian centromeres during meiosis. In mammalian oocytes, ATRX binds to centromeric heterochromatin domains where it is required for accurate chromosome segregation. Loss of ATRX function induces abnormal meiotic chromosome morphology, reduces histone H3 phosphorylation, and promotes a high incidence of aneuploidy associated with severely reduced fertility. The presence of centromeric breaks during the transition to the first mitosis in the early embryo indicates that the role of ATRX in chromosome segregation is mediated through an epigenetic mechanism involving the maintenance of chromatin modifications associated with pericentric heterochromatin (PCH) formation and chromosome condensation. This is consistent with the existence of a potential molecular link between centromeric and PCH in the epigenetic control of centromere function and maintenance of chromosome stability in mammalian oocytes. Dissecting the molecular mechanisms of ATRX function during meiosis will have important clinical implications towards uncovering the epigenetic factors contributing to the onset of aneuploidy in the human oocyte.

  17. Spindle assembly checkpoint signalling is uncoupled from chromosomal position in mouse oocytes.

    Science.gov (United States)

    Gui, Liming; Homer, Hayden

    2012-06-01

    The spindle assembly checkpoint (SAC) averts aneuploidy by coordinating proper bipolar chromosomal attachment with anaphase-promoting complex/cyclosome (APC/C)-mediated securin and cyclin B1 destruction required for anaphase onset. The generation of a Mad2-based signal at kinetochores is central to current models of SAC-based APC/C inhibition. During mitosis, kinetochores of polar-displaced chromosomes, which are at greatest risk of mis-segregating, recruit the highest levels of Mad2, thereby ensuring that SAC activation is proportionate to aneuploidy risk. Paradoxically, although an SAC operates in mammalian oocytes, meiosis I (MI) is notoriously error prone and polar-displaced chromosomes do not prevent anaphase onset. Here we find that Mad2 is not preferentially recruited to the kinetochores of polar chromosomes of wild-type mouse oocytes, in which polar chromosomes are rare, or of oocytes depleted of the kinesin-7 motor CENP-E, in which polar chromosomes are more abundant. Furthermore, in CENP-E-depleted oocytes, although polar chromosomal displacement intensified during MI and the capacity to form stable end-on attachments was severely compromised, all kinetochores nevertheless became devoid of Mad2. Thus, it is possible that the ability of the SAC to robustly discriminate chromosomal position might be compromised by the propensity of oocyte kinetochores to become saturated with unproductive attachments, thereby predisposing to aneuploidy. Our data also reveal novel functions for CENP-E in oocytes: first, CENP-E stabilises BubR1, thereby impacting MI progression; and second, CENP-E mediates bi-orientation by promoting kinetochore reorientation and preventing chromosomal drift towards the poles.

  18. Chromosome Bridges Maintain Kinetochore-Microtubule Attachment throughout Mitosis and Rarely Break during Anaphase.

    Directory of Open Access Journals (Sweden)

    Judit Pampalona

    Full Text Available Accurate chromosome segregation during cell division is essential to maintain genome stability, and chromosome segregation errors are causally linked to genetic disorders and cancer. An anaphase chromosome bridge is a particular chromosome segregation error observed in cells that enter mitosis with fused chromosomes/sister chromatids. The widely accepted Breakage/Fusion/Bridge cycle model proposes that anaphase chromosome bridges break during mitosis to generate chromosome ends that will fuse during the following cell cycle, thus forming new bridges that will break, and so on. However, various studies have also shown a link between chromosome bridges and aneuploidy and/or polyploidy. In this study, we investigated the behavior and properties of chromosome bridges during mitosis, with the idea to gain insight into the potential mechanism underlying chromosome bridge-induced aneuploidy. We find that only a small number of chromosome bridges break during anaphase, whereas the rest persist through mitosis into the subsequent cell cycle. We also find that the microtubule bundles (k-fibers bound to bridge kinetochores are not prone to breakage/detachment, thus supporting the conclusion that k-fiber detachment is not the cause of chromosome bridge-induced aneuploidy. Instead, our data suggest that while the microtubules bound to the kinetochores of normally segregating chromosomes shorten substantially during anaphase, the k-fibers bound to bridge kinetochores shorten only slightly, and may even lengthen, during anaphase. This causes some of the bridge kinetochores/chromosomes to lag behind in a position that is proximal to the cell/spindle equator and may cause the bridged chromosomes to be segregated into the same daughter nucleus or to form a micronucleus.

  19. Karyotypic abnormalities and clinical aspects of patients with multiple myeloma and related paraproteinemic disorders

    Energy Technology Data Exchange (ETDEWEB)

    Liang, W.; Hopper, J.E.; Rowley, J.D.

    1979-08-01

    Karyotypic abnormalities were detected in the malignant cells of 6 of 18 patients with multiple myeloma (MM). Six patients with benign monoclonal gammopathy, one with amyloidosis of immunoglobulin origin, and two with Waldenstroem's macroglobulinemia had normal karyotypes. All six MM patients with aneuploidy were in a group of 10 patients in an accelerated or relapse phase of their disease and four had high serum paraprotein levels when their abnormal karyotypes were detected. Five of the 6 MM patients with aneuploidy had received prior chemotherapy. Aneuploidy was not observed in 8 stable MM patients. Abnormalities of chromosome 14 were present in all 6 patients. A translocation between Nos. 11 and 14 was found in aneuploid cells of 2 patients who had plasma cell leukemia (PCL). A deletion of chromosome 6 was detected in 2 MM patients and a pericentric inversion of No. 6 was seen in the patient with PCL. Three of 4 MM patients had a nonrandom loss of one chromosome 8. Two other MM patients developed acute nonlymphocytic leukemia (ANLL) after the diagnosis of MM. Marrow cells of one patient showed a 5q- chromosome and a constitutional translocation involving Nos. 13 and 14 during the preleukemic stage; during the leukemic phase, the karyotype evolved to 50 chromosomes including extra chromosomes 1, 6, 8, 10, and 21 and a missing 7, in addition to the originally detected 5q- and the 13/14 translocation.The peripheral blood from the other patient was hypodiploid, with a missing chromosome 7 and a translocation between 3q and 9p. These patterns of chromosome change resemble those of ANLL rather than MM and are similar to the changes seen in ANLL after treated malignant lymphoma.

  20. Blastocyst Morphology Holds Clues Concerning The Chromosomal Status of The Embryo

    Directory of Open Access Journals (Sweden)

    Rita de Cassia Savio Figueira

    2015-07-01

    Full Text Available Background: Embryo morphology has been proposed as an alternative marker of chromosomal status. The objective of this retrospective cohort study was to investigate the association between the chromosomal status on day 3 of embryo development and blastocyst morphology. Materials and Methods: A total of 596 embryos obtained from 106 cycles of intracytoplasmic sperm injection (ICSI followed by preimplantation genetic aneuploidy screening (PGS were included in this retrospective study. We evaluated the relationship between blastocyst morphological features and embryonic chromosomal alteration. Results: Of the 564 embryos with fluorescent in situ hybridization (FISH results, 200 reached the blastocyst stage on day 5 of development. There was a significantly higher proportion of euploid embryos in those that achieved the blastocyst stage (59.0% compared to embryos that did not develop to blastocysts (41.2% on day 5 (P<0.001. Regarding blastocyst morphology, we observed that all embryos that had an abnormal inner cell mass (ICM were aneuploid. Embryos with morphologically normal ICM had a significantly higher euploidy rate (62.1%, P<0.001. As regards to the trophectoderm (TE morphology, an increased rate of euploidy was observed in embryos that had normal TE (65.8% compared to embryos with abnormal TE (37.5%, P<0.001. Finally, we observed a two-fold increase in the euploidy rate in high-quality blastocysts with both high-quality ICM and TE (70.4% compared to that found in low-quality blastocysts (31.0%, P<0.001. Conclusion: Chromosomal abnormalities do not impair embryo development as aneuploidy is frequently observed in embryos that reach the blastocyst stage. A high-quality blastocyst does not represent euploidy of chromosomes 13, 14, 15, 16, 18, 21, 22, X and Y. However, aneuploidy is associated with abnormalities in the ICM morphology. Further studies are necessary to confirm whether or not the transfer of blastocysts with low-quality ICM should be

  1. Genetic dissimilarity between primary colorectal carcinomas and their lymph node metastases: ploidy, p53, bcl-2, and c-myc expression--a pilot study.

    Science.gov (United States)

    Zalata, Khaled Refaat; Elshal, Mohamed Farouk; Foda, Abd AlRahman Mohammad; Shoma, Ashraf

    2015-08-01

    The current paradigm of metastasis proposes that rare cells within primary tumors acquire metastatic capability via sequential mutations, suggesting that metastases are genetically dissimilar from their primary tumors. This study investigated the changes in the level of expression of a well-defined panel of cell proliferation, differentiation, and apoptosis markers between the primary colorectal cancer (CRC) and the corresponding synchronous lymph node (LN) metastasis from the same patients. DNA flow cytometry and immunostaining of p53, bcl-2, and c-myc were carried out on 36 cases of CRC radical resection specimens with their corresponding LN metastases. There was very low probability that the histological patterns of primary tumors and LN metastases are independent (p < 0.001). Metastatic tumors were significantly more diffusely positive for p53 than the primary tumors (p < 0.001). Conversely, primary tumors were significantly more diffusely positive for c-myc than metastatic tumors (p = 0.011). No significant difference was found between the LNs and the primary tumors in bcl-2 positivity (p = 0.538) and DNA aneuploidy (p = 0.35), with a tendency towards negative bcl-2 and less aneuploidy in LN metastases than primary tumors. In conclusion, LN metastatic colorectal carcinomas have a tendency of being less differentiated, with a higher incidence of diffuse p53 staining, lower incidence of bcl-2 staining, and less aneuploidy in comparison to their primary counterparts suggesting a more aggressive biological behavior, which could indicate the necessity for more aggressive adjuvant therapy.

  2. Genotyping 1000 yeast strains by next-generation sequencing

    Directory of Open Access Journals (Sweden)

    Wilkening Stefan

    2013-02-01

    Full Text Available Abstract Background The throughput of next-generation sequencing machines has increased dramatically over the last few years; yet the cost and time for library preparation have not changed proportionally, thus representing the main bottleneck for sequencing large numbers of samples. Here we present an economical, high-throughput library preparation method for the Illumina platform, comprising a 96-well based method for DNA isolation for yeast cells, a low-cost DNA shearing alternative, and adapter ligation using heat inactivation of enzymes instead of bead cleanups. Results Up to 384 whole-genome libraries can be prepared from yeast cells in one week using this method, for less than 15 euros per sample. We demonstrate the robustness of this protocol by sequencing over 1000 yeast genomes at ~30x coverage. The sequence information from 768 yeast segregants derived from two divergent S. cerevisiae strains was used to generate a meiotic recombination map at unprecedented resolution. Comparisons to other datasets indicate a high conservation of recombination at a chromosome-wide scale, but differences at the local scale. Additionally, we detected a high degree of aneuploidy (3.6% by examining the sequencing coverage in these segregants. Differences in allele frequency allowed us to attribute instances of aneuploidy to gains of chromosomes during meiosis or mitosis, both of which showed a strong tendency to missegregate specific chromosomes. Conclusions Here we present a high throughput workflow to sequence genomes of large number of yeast strains at a low price. We have used this workflow to obtain recombination and aneuploidy data from hundreds of segregants, which can serve as a foundation for future studies of linkage, recombination, and chromosomal aberrations in yeast and higher eukaryotes.

  3. Sperm FISH and chromatin integrity in spermatozoa from a t(6;10;11) carrier.

    Science.gov (United States)

    Olszewska, Marta; Huleyuk, Nataliya; Fraczek, Monika; Zastavna, Danuta; Wiland, Ewa; Kurpisz, Maciej

    2014-05-01

    Complex chromosome rearrangements (CCRs) are structurally balanced or unbalanced aberrations involving more than two breakpoints on two or more chromosomes. CCRs can be a potential reason for genomic imbalance in gametes, which leads to a drastic reduction in fertility. In this study, the meiotic segregation pattern, aneuploidy of seven chromosomes uninvolved in the CCR and chromatin integrity were analysed in the ejaculated spermatozoa of a 46,XY,t(6;10;11)(q25.1;q24.3;q23.1)mat carrier with asthenozoospermia and a lack of conception. The frequency of genetically unbalanced spermatozoa was 78.8% with a prevalence of 4:2 segregants of 38.2%, while the prevalence of the adjacent 3:3 mode was 35.3%. Analysis of the aneuploidy of chromosomes 13, 15, 18, 21, 22, X and Y revealed an approximately fivefold increased level in comparison with that of the control group, indicating the presence of an interchromosomal effect. Sperm chromatin integrity status was evaluated using chromomycin A3 and aniline blue staining (deprotamination), acridine orange test and TUNEL assay (sperm DNA fragmentation). No differences were found when comparisons were made with a control group. We suggest that the accumulation of genetically unbalanced spermatozoa, significantly increased sperm aneuploidy level and decreased sperm motility (20%, progressive) were not responsible for the observed lack of reproductive success in the analysed infertile t(6;10;11) carrier. Interestingly, in the case described herein, a high level of sperm chromosomal imbalance appears not to be linked to sperm chromatin integrity status.

  4. Recent insights into the regulation of X-chromosome inactivation

    Directory of Open Access Journals (Sweden)

    Valencia K

    2015-05-01

    Full Text Available Karmele Valencia, Anton Wutz Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland Abstract: X-chromosome inactivation (XCI is the mechanism by which mammals compensate gene dosage differences between males and females. XCI is required for female development and has implications for human disease. As a result, a single X chromosome is transcriptionally active in both male and female cells. Functional hemizygosity of the X chromosomes greatly predisposes to phenotypic consequences of mutations. In females, X chromosomes are randomly chosen to become inactivated leading to a mosaic pattern of cells expressing genes from either chromosome. This facilitates the masking of phenotypic consequences of heterozygous X-linked mutations. Skewing of XCI in favor of one chromosome can result in increased severity of disease symptoms, if the X chromosome with a gene mutation remains preferentially active. In addition, phenotypic masking of X-linked mutations is not always observed. Rett syndrome represents a paradigm of this statement. Dosage compensation can also mask some aspects of sex chromosome aneuploidies. X-chromosome aneuploidies include Klinefelter, Turner, and X-trisomy syndromes. In all these cases, a single active X chromosome is present. However, in those cases with two or more X chromosomes, some genes from the inactivated X chromosome escape from XCI becoming active. Therefore, dose imbalances of escape genes cause pathologies. Defects in the structure and silencing of the inactive X chromosome are further observed in human pluripotent stem cells and in certain tumors. Taken together, these findings suggest that aspects of XCI are relevant for a large number of human diseases. Here we review basic and clinical research on XCI with the aim of illustrating connections and highlighting opportunities for future investigation. Keywords: XCI, X-linked diseases, sex chromosome

  5. Ploidy dynamics and evolvability in fungi

    Science.gov (United States)

    Stone, Neil

    2016-01-01

    Rapid responses to acute stresses are essential for stress survival and are critical to the ability of fungal pathogens to adapt to new environments or hosts. The rapid emergence of drug resistance is used as a model for how fungi adapt and survive stress conditions that inhibit the growth of progenitor cells. Aneuploidy and loss of heterozygosity (LOH), which are large-scale genome shifts involving whole chromosomes or chromosome arms, occur at higher frequency than point mutations and have the potential to mediate stress survival. Furthermore, the stress of exposure to an antifungal drug can induce elevated levels of LOH and can promote the formation of aneuploids. This occurs via mitotic defects that first produce tetraploid progeny with extra spindles, followed by chromosome mis-segregation. Thus, drug exposure induces elevated levels of aneuploidy, which can alter the copy number of genes that improve survival in a given stress or drug. Selection then acts to increase the proportion of adaptive aneuploids in the population. Because aneuploidy is a common property of many pathogenic fungi, including those posing emerging threats to plants, animals and humans, we propose that aneuploid formation and LOH often accompanying it contribute to the rapid generation of diversity that can facilitate the emergence of fungal pathogens to new environmental niches and/or new hosts, as well as promote antifungal drug resistance that makes emerging fungal infections ever more difficult to contain. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’. PMID:28080987

  6. Chromosome Bridges Maintain Kinetochore-Microtubule Attachment throughout Mitosis and Rarely Break during Anaphase.

    Science.gov (United States)

    Pampalona, Judit; Roscioli, Emanuele; Silkworth, William T; Bowden, Brent; Genescà, Anna; Tusell, Laura; Cimini, Daniela

    2016-01-01

    Accurate chromosome segregation during cell division is essential to maintain genome stability, and chromosome segregation errors are causally linked to genetic disorders and cancer. An anaphase chromosome bridge is a particular chromosome segregation error observed in cells that enter mitosis with fused chromosomes/sister chromatids. The widely accepted Breakage/Fusion/Bridge cycle model proposes that anaphase chromosome bridges break during mitosis to generate chromosome ends that will fuse during the following cell cycle, thus forming new bridges that will break, and so on. However, various studies have also shown a link between chromosome bridges and aneuploidy and/or polyploidy. In this study, we investigated the behavior and properties of chromosome bridges during mitosis, with the idea to gain insight into the potential mechanism underlying chromosome bridge-induced aneuploidy. We find that only a small number of chromosome bridges break during anaphase, whereas the rest persist through mitosis into the subsequent cell cycle. We also find that the microtubule bundles (k-fibers) bound to bridge kinetochores are not prone to breakage/detachment, thus supporting the conclusion that k-fiber detachment is not the cause of chromosome bridge-induced aneuploidy. Instead, our data suggest that while the microtubules bound to the kinetochores of normally segregating chromosomes shorten substantially during anaphase, the k-fibers bound to bridge kinetochores shorten only slightly, and may even lengthen, during anaphase. This causes some of the bridge kinetochores/chromosomes to lag behind in a position that is proximal to the cell/spindle equator and may cause the bridged chromosomes to be segregated into the same daughter nucleus or to form a micronucleus.

  7. An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population.

    Directory of Open Access Journals (Sweden)

    Peter Benn

    Full Text Available Analyze the economic value of replacing conventional fetal aneuploidy screening approaches with non-invasive prenatal testing (NIPT in the general pregnancy population.Using decision-analysis modeling, we compared conventional screening to NIPT with cell-free DNA (cfDNA analysis in the annual US pregnancy population. Sensitivity and specificity for fetal aneuploidies, trisomy 21, trisomy 18, trisomy 13, and monosomy X, were estimated using published data and modeling of both first- and second trimester screening. Costs were assigned for each prenatal test component and for an affected birth. The overall cost to the healthcare system considered screening costs, the number of aneuploid cases detected, invasive procedures performed, procedure-related euploid losses, and affected pregnancies averted. Sensitivity analyses evaluated the effect of variation in parameters. Costs were reported in 2014 US Dollars.Replacing conventional screening with NIPT would reduce healthcare costs if it can be provided for $744 or less in the general pregnancy population. The most influential variables were timing of screening entry, screening costs, and pregnancy termination rates. Of the 13,176 affected pregnancies undergoing screening, NIPT detected 96.5% (12,717/13,176 of cases, compared with 85.9% (11,314/13,176 by conventional approaches. NIPT reduced invasive procedures by 60.0%, with NIPT and conventional methods resulting in 24,596 and 61,430 invasive procedures, respectively. The number of procedure-related euploid fetal losses was reduced by 73.5% (194/264 in the general screening population.Based on our analysis, universal application of NIPT would increase fetal aneuploidy detection rates and can be economically justified. Offering this testing to all pregnant women is associated with substantial prenatal healthcare benefits.

  8. An infant with mos45,X/46,XY/47,XYY/48,XYYY: Genetic and clinical findings

    Energy Technology Data Exchange (ETDEWEB)

    Fox, J.; Blumenthal, D.; Brock, W. [Long Island Jewish Medical Center, New Hyde Park, NY (United States)] [and others

    1994-09-01

    We report on an infant with mos45,X/46,XY/47,XYY/48,XYYY who presented with ambiguous genitalia. The patient was the 2,637 gram product of a 38 week gestation and elective repeat C-section born to a 35 year old G3P2 mother. The pregnancy was complicated by placenta previa. There was no history of maternal health problems or drug or steroid use. At birth bilateral epicanthal folds and overfolded helices were noted without webbing of the neck or lymphedema. There was a phallic structure measuring 1.5 cm with dorsal hood and midline cleft with a normal female introitus, urethra, and vagina. Congenital adrenal hyperplaxia was excluded. Renal ultrasound was normal. Periperal blood chromosomes revealed a mos45,X(38%)/47,XYY(29%)/48,XYYY(33%) karyotype. Echocardiography revealed coarctation of the aorta and a bicuspid aortic valve. An additional cell line, 46,XY, was identified in aortic tissue obtained at the time of surgery. At age 15 months she was 25% in height and weight and had bilateral ptosis. Her development was within normal limits, but no words except {open_quotes}Mama{close_quotes} or {open_quotes}Dada{close_quotes} were spoken. A left intraabdominal testis with epididymis and dilated tubules and bilateral Fallopian tubes were removed at laparoscopy/reconstruction. Cell cultures were initiated from gonadal tissue, and karyotypes are pending. Patients with mosaic Y chromosome aneuploidy involving 2 Y chromosomes are rare. Eighteen patients with 45,X/47,XYY have been described; prenatally diagnosed cases appeared to be normal male whereas cases diagnosed postnally presented with ambiguous genitalia and/or other anomalies. The phenotype of Y chromosome aneuploidy with 3 Y chromosomes is even more unpredictable due to the paucity of reported cases. To our knowledge this is the first patient described with this unusual karyotype, thus adding to the limited information of patients with rare mosaic Y chromosome aneuploidy.

  9. Fetal cells in maternal blood: state of the art for non-invasive prenatal diagnosis.

    Science.gov (United States)

    Ho, S S; O'Donoghue, K; Choolani, M

    2003-09-01

    In Singapore, 1 in 5 pregnancies occur in mothers > 35 years old and genetic diseases, such as thalassaemia, are common. Current methods for the diagnosis of aneuploidy and monogenic disorders require invasive testing by amniocentesis, chorion villus biopsy or fetal blood sampling. These tests carry a procedure-related risk of miscarriage that is unacceptable to many couples. Development of non-invasive methods for obtaining intact fetal cells would allow accurate prenatal diagnosis for aneuploidy and single gene disorders, without the attendant risks associated with invasive testing, and would increase the uptake of prenatal diagnosis by women at risk. Isolation of fetal erythroblasts from maternal blood should allow accurate non-invasive prenatal diagnosis of both aneuploidies and monogenic disorders. Expression of gamma-globin in maternal erythroblasts and the inability to locate fetal erythroblasts reliably in all pregnancies have prevented its clinical application. In the absence of a highly specific fetal cell marker, enrichment, identification and diagnosis--the 3 components of non-invasive prenatal diagnosis--have clearly defined objectives. Since fetal cells are rare in maternal blood, the sole purpose of enrichment is yield--to recover as many fetal cells as possible--even if purity is compromised at this stage. In contrast, the primary goal of identification is specificity; absolute certainty of fetal origin is required at this stage if the ultimate objective of diagnosis, accuracy, is to be achieved. This review summarises the current state of the art of non-invasive prenatal diagnosis using fetal erythroblasts enriched from maternal blood.

  10. Flow cytometric DNA analysis of ducks accumulating 137Cs on a reactor reservoir.

    Science.gov (United States)

    George, L S; Dallas, C E; Brisbin, I L; Evans, D L

    1991-06-01

    The objective of this study was to detect red blood cell (rbc) DNA abnormalities in male, game-farm mallard ducks as they ranged freely and accumulated 137Cs (radiocesium) from an abandoned nuclear reactor cooling reservoir. Prior to release, the ducks were tamed to enable recapture at will. Flow cytometric measurements conducted at intervals during the first year of exposure yielded cell cycle percentages of DNA (G0/G1, S, G2 + M phases) of rbc, as well as coefficients of variation (CV) in the G0/G1 phase. DNA histograms of exposed ducks were compared with two sets of controls which were maintained 30 and 150 miles from the study site. 137Cs live wholebody burdens were also measured in these animals in a parallel kinetics study, and an approximate steady-state equilibrium was attained after about 8 months. DNA histograms from 2 of the 14 contaminated ducks revealed DNA aneuploid-like patterns after 9 months exposure. These two ducks were removed from the experiment at this time, and when sampled again 1 month later, one continued to exhibit DNA aneuploidy. None of the control DNA histograms demonstrated DNA aneuploid-like patterns. There were no significant differences in cell cycle percentages at any time point between control and exposed animals. A significant increase in CV was observed at 9 months exposure, but after removal of the two ducks with DNA aneuploidy, no significant difference was detected in the group monitored after 12 months exposure. An increased variation in the DNA and DNA aneuploidy could, therefore, be detected in duck rbc using flow cytometric analysis, with the onset of these effects being related to the attainment of maximal levels of 137Cs body burdens in the exposed animals.

  11. The combined QF-PCR and cytogenetic approach in prenatal diagnosis.

    Science.gov (United States)

    Tekcan, Akin; Tural, Sengul; Elbistan, Mehmet; Kara, Nurten; Guven, Davut; Kocak, Idris

    2014-11-01

    In this study, the importance of quantitative fluorescence polymerase chain reaction (QF-PCR) aneuploidy diagnosis test which provides earlier and easier results were discussed. The cell cultures and DNA isolations were performed on 100 amniotic fluids. DNA isolations were made from peripheral blood samples of mothers who had blood-stained amniotic fluid samples. The reasons of references of these pregnant women to our division were increased maternal age, positive double/triple screening test and fetal anomaly history. QF-PCR applied to 19 short tandem repeat markers in the chromosomes 13, 18, 21 and genes X and Y chromosomes. All electropherogram peaks were evaluated on ABI3130. Thirty two (32%) samples have high maternal age, seven (7%) have fetal anomaly and the others have double/triple screening test positivity. Ninety-nine (99%) of the 100 amniotic fluid samples were resulted, but one (1%) of them could not examined because of the culture failure. The maternal contamination rates were determined as 3%. Of 100 samples, 2 had trisomy 21 (2%), 1 had trisomy 13 (1%), 1 had structural abnormalities (1%) and the others (97%) have not any aneuploidy. The results of QF-PCR were in compatible with the results of cell culture and chromosome analysis. Although QF-PCR is an easier and an earlier test, it has a limitation of not to able to scan full genome. It is also sensitive for maternal contamination, so it should be tested together with maternal blood samples. QF-PCR aneuploidy test is the fastest diagnostic test for prenatal diagnosis and so it provides less stressful period for pregnant women.

  12. 32. Study the aneugenic effect of benzene on germ cell of animal and workers

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To study the aneupoidy effect of benzene on germ cells of animal and humans. Method: The NIH adult female mice were treated with varies doses of benzene (942, 1881 and 3762mg/kg respectively) by single gavage and (706, 1922 and 4864mg/m3 respectively) by inhalation (2h/d, 15d), the ovulated oocytes were collected for conventional cytogenetic analyses, and the frequencies of aneuploidy were detected. The frequencies of aneuploidy in sperm of benzene exposed workers were detected by two color fluorescence in situ hybridization with digoxingenin labeled 9 chromosome probe(D9Z1) and biotin labeled 18 chromosome probe (D18Z1). Result: The frequencies of aneuploidy in MII oocytes were significantly increased over the control in three groups treated by inhalation (7.06%,7.50% and 7.76% respectively control 1.30%, P<0.05 ), a dose-dependent response was present, But in gavage groups only the high dose group was increased over that of control. P<0.05. The timeweight average air concentration (TWA) of benzene in the workplace was 86.49mg/m3, it was two fold higher than the national maximum allowable concentration. The concentration of urinary trans, trans-muconic acid (ttMA) in exposed group was significantly higher than that of control group. A total of 136 401 sperm nuclei in 14 exposed workers and 156 955 sperm nuclei in 16 control workers were counted. The results showed that the frequencies of disomic sperm for chromosome 9 and 18, and diploidy sperm in exposed-workers (0.168%, 0.055%, 0.073%, respectively) were statistically increased over that (0.050%、 0. 033% and 0.040%, respectively) of controls. P<0.05. The frequencies of nullisomic sperm for chromosome 9,18 in the exposed group (0.206%,0.068%) were statistically increased also over that (0.067%,0.048% respectively) of control. The frequency of overall numerical chromosome aberrations (0.570%) in tbe exposed group was increased over that of control(0.218%)P<0.05.Conclusion:An increased aneuploidy

  13. Identification of submicroscopic chromosomal aberrations in fetuses with increased

    DEFF Research Database (Denmark)

    Leung, Tak Yeung; Vogel, Ida; Lau, Tze Kin;

    2011-01-01

    Objective: Fetal nuchal translucency (NT) is assessed by ultrasound as a screening tool for aneuploidy at 11-13+6 weeks’ gestation. Fetuses with increased NT but apparently normal karyotyping result are still at higher risk of structural abnormality and a range of genetic syndromes, which may...... found to have increased NT >3.5mm during first trimester screening. These samples were examined by microarray based comparative genomic hybridization (aCGH) using a 44K oligonucleotide array specifically constructed for prenatal screening. Variations in copy number (CNVs) were reported after excluding...

  14. Down syndrome child with 48,XXY,+21 karyotype

    Directory of Open Access Journals (Sweden)

    Cyrus Cyril

    2005-01-01

    Full Text Available Cytogenetic analysis in 60 clinically suspected cases of Down syndrome and their parents was carried out using conventional Giemsa-trypsin-banding technique. Fifty-five individuals (91% exhibited a free trisomy 21. Robertsonian translocations were seen in three cases and two cases exhibited a normal karyotype. A four-month-old child, the second-born of non-consanguineous parents, possessed an extra X chromosome in addition to trisomy 21. The proband′s parents and his brother showed a normal karyotype. The phenotypic characteristics of this child have been discussed in the light of the published reports on double aneuploidies of XXY and trisomy 21.

  15. Short QTc Interval in Males with Klinefelter Syndrome-Influence of CAG Repeat Length, Body Composition, and Testosterone Replacement Therapy

    DEFF Research Database (Denmark)

    Jørgensen, Inger Norlyk; Skakkebaek, Anne; Andersen, Niels Holmark;

    2015-01-01

    BackgroundKlinefelter syndrome (KS) is a sex chromosomal aneuploidy (47,XXY) affecting 1/660 males. Based on findings in Turner syndrome, we hypothesized that electrocardiogram (ECG) abnormalities would be present in males with KS. ObjectiveTo investigate ECGs in males with KS and compare...... syndrome was determined in participants with a QTc ... interval comparable to controls. No mutations in genes related to short QT syndrome were found. ConclusionWe found short QTc interval in males with KS, with further shortening of the QTc interval by T. These results suggest that genes on the X chromosome could be involved in regulation of the QTc interval...

  16. Chromosomal abnormalities associated with mental retardation in female subjects

    Directory of Open Access Journals (Sweden)

    Dutta Samikshan

    2009-01-01

    Full Text Available Chromosomal abnormalities are thought to be the most common cause of mental retardation (MR. However, apart from a few selected types with typical aneuploidy, like Downs syndrome, Klinefelter syndrome, Turner syndrome, etc., the frequency of detectable chromosomal abnormalities in association with idiopathic MR is very low. In this study, we have investigated chromosomal abnormalities in female MR subjects (n = 150 by high-resolution GTG banding. Of them, 30 cases were diagnosed as Downs syndrome. Among the remaining (n = 120, chromosomal abnormalities/marked polymorphisms were detectable in only three MR cases (0.025.

  17. A Sri Lankan child with 49,XXXXY syndrome

    Directory of Open Access Journals (Sweden)

    Dissanayake Vajira

    2010-01-01

    Full Text Available Pentasomy 49,XXXXY is a rare sex chromosome disorder usually presenting with ambigous genitalia, facial dysmorphism, mental retardation and a combination of cardiac, skeletal and other malformations. The incidence of the condition is estimated to be 1 in 85,000 male births. Previously, this condition was identified as a Klinefelter variant. The condition is suspected in a patient, by a combination of characteristic clinical findings, and the diagnosis is confirmed by chromosome culture and karyotyping. In the case we report here, the main presentation of ambiguous genitalia led to a suspicion of a sex chromosome aneuploidy which was subsequently confirmed by chromosomal analysis.

  18. Mitotically unstable polyploids in the yeast Pichia guilliermondii.

    Science.gov (United States)

    Klinner, U; Böttcher, F

    1992-01-01

    Attempts to obtain triploids or tetraploids of P. guilliermondii by sexual hybridization led to mitotically stable hybrids. However, their DNA content per cell was not higher than in diploids. The results of random spore analysis demonstrate that these hybrids were in fact aneuploids which obviously suffered drastic chromosome losses immediately after mating. This phenomenon could have been caused either by aneuploidy already present in the parental strains or it might have been due to a general inability of P. guilliermondii to maintain a polyploid genome.

  19. Inverted Pyramid of Care.

    Science.gov (United States)

    Sonek, Jiri D; Kagan, Karl Oliver; Nicolaides, Kypros H

    2016-06-01

    First-trimester pregnancy evaluation using fetal and maternal parameters not only allows for diagnoses to be made early in gestation but can also assess the risk of complications that become clinically evident later in pregnancy. This evaluation makes it possible for pregnancy care to be individualized. In select cases, treatment that reduces the risk of complications can be started early in pregnancy. Even though cell free DNA is a significant advance in diagnosing fetal aneuploidy, the combination of first-trimester ultrasound and maternal serum biochemistries casts a much wider diagnostic net; therefore, the 2 technologies are best used in combination.

  20. Decreased Expression of the Early Mitotic Gene, CHFR, Contributes to the Acquisition of Breast Cancer Phenotypes

    Science.gov (United States)

    2008-03-01

    aneuploidy [3]. Further analysis by spectral karyotyping (SKY) revealed two distinct cell populations - minimally aneuploid or near tetraploid (Figure 1A...der(9)t(3;9)(p14;p21)t(3; 5),der(11)t(8;11), t(15;18),+20. The consensus karyotype for the near tetraploid population was 81-95,XXXX,-1,t(1;2),der...decreased CHFR by shRNA were tetraploid (Figure 1A). In fact, 6% of transiently transfected MCF10:CHFR-siRNA cells were binucleated, suggesting tetraploidy

  1. Construction of a Sequencing Library from Circulating Cell-Free DNA.

    Science.gov (United States)

    Fang, Nan; Löffert, Dirk; Akinci-Tolun, Rumeysa; Heitz, Katja; Wolf, Alexander

    2016-04-01

    Circulating DNA is cell-free DNA (cfDNA) in serum or plasma that can be used for non-invasive prenatal testing, as well as cancer diagnosis, prognosis, and stratification. High-throughput sequence analysis of the cfDNA with next-generation sequencing technologies has proven to be a highly sensitive and specific method in detecting and characterizing mutations in cancer and other diseases, as well as aneuploidy during pregnancy. This unit describes detailed procedures to extract circulating cfDNA from human serum and plasma and generate sequencing libraries from a wide concentration range of circulating DNA.

  2. [Cytology is in pivotal role at screening and surveillance of PSC].

    Science.gov (United States)

    Boyd, Sonja; Arola, Johanna; Mäkisalo, Heikki; Färkkilä, Martti

    2014-01-01

    Primary sclerosing cholangitis (PSC) is an autoimmune disease leading to biliary strictures and inflammation. The lifetime risk for cholangiocarcinoma (CCA) among PSC patients is 7-13%, and biliary dysplasia is thought to be a precursor lesion for CCA. The diagnosis of PSC is based on endoscopic retrogradic cholangiography (ERC). During ERC brush cytology samples are routinely taken in our unit to detect possible biliary dysplasia. With repeated cytological dysplasia, liver transplantation is considered. Aneuploidy in DNA flow cytometry may support the suspicion of dysplasia. PSC is the most common indication for liver transplantation in Finland, and half of transplantations are prophylactic.

  3. Systematic Analysis of the Crosstalk between Mitosis and DNA Damage by a Live Cell siRNA Screen

    DEFF Research Database (Denmark)

    Pedersen, Ronni Sølvhøi

    Recent research has shown, that the biological processes of DNA replication, DNA damage, cell cycle and mitosis cannot be considered as isolated cellular functions but are mechanistically linked in many ways. For instance, when cells are exposed to replication stress and enter mitosis...... propose that this strong p53 response, which often occurs without detectable increase in DNA damage, is caused by the acute increase in chromosomal aneuploidy. Finally, our systematic approach to the DNA damage-mitosis crosstalk reveals widespread cell death in response to mitotic pertubations, showing...

  4. Chromosomal abnormalities associated with mental retardation in female subjects.

    Science.gov (United States)

    Dutta, Samikshan; Shaw, Jyothi; Sinha, Swagata; Mukhopadhyay, Kanchan

    2009-01-01

    Chromosomal abnormalities are thought to be the most common cause of mental retardation (MR). However, apart from a few selected types with typical aneuploidy, like Downs syndrome, Klinefelter syndrome, Turner syndrome, etc., the frequency of detectable chromosomal abnormalities in association with idiopathic MR is very low. In this study, we have investigated chromosomal abnormalities in female MR subjects (n = 150) by high-resolution GTG banding. Of them, 30 cases were diagnosed as Downs syndrome. Among the remaining (n = 120), chromosomal abnormalities/marked polymorphisms were detectable in only three MR cases (0.025).

  5. Down-regulation of replication factor C-40 (RFC40 causes chromosomal missegregation in neonatal and hypertrophic adult rat cardiac myocytes.

    Directory of Open Access Journals (Sweden)

    Hirotaka Ata

    Full Text Available BACKGROUND: Adult mammalian cardiac myocytes are generally assumed to be terminally differentiated; nonetheless, a small fraction of cardiac myocytes have been shown to replicate during ventricular remodeling. However, the expression of Replication Factor C (RFC; RFC140/40/38/37/36 and DNA polymerase δ (Pol δ proteins, which are required for DNA synthesis and cell proliferation, in the adult normal and hypertrophied hearts has been rarely studied. METHODS: We performed qRT-PCR and Western blot analysis to determine the levels of RFC and Pol δ message and proteins in the adult normal cardiac myocytes and cardiac fibroblasts, as well as in adult normal and pulmonary arterial hypertension induced right ventricular hypertrophied hearts. Immunohistochemical analyses were performed to determine the localization of the re-expressed DNA replication and cell cycle proteins in adult normal (control and hypertrophied right ventricle. We determined right ventricular cardiac myocyte polyploidy and chromosomal missegregation/aneuploidy using Fluorescent in situ hybridization (FISH for rat chromosome 12. RESULTS: RFC40-mRNA and protein was undetectable, whereas Pol δ message was detectable in the cardiac myocytes isolated from control adult hearts. Although RFC40 and Pol δ message and protein significantly increased in hypertrophied hearts as compared to the control hearts; however, this increase was marginal as compared to the fetal hearts. Immunohistochemical analyses revealed that in addition to RFC40, proliferative and mitotic markers such as cyclin A, phospho-Aurora A/B/C kinase and phospho-histone 3 were also re-expressed/up-regulated simultaneously in the cardiac myocytes. Interestingly, FISH analyses demonstrated cardiac myocytes polyploidy and chromosomal missegregation/aneuploidy in these hearts. Knock-down of endogenous RFC40 caused chromosomal missegregation/aneuploidy and decrease in the rat neonatal cardiac myocyte numbers. CONCLUSION: Our

  6. 高龄孕妇产前筛查与诊断分析%Prenatal diagnostic testing among women referred for advanced maternal age

    Institute of Scientific and Technical Information of China (English)

    李东明; 黄海锋; 陶春凤

    2016-01-01

    Objective:To investigate the incidence of aneuploidies of chromosomal in pregnant women with advanced maternal age (AMA) as indicator for invasive diagnostic testing.Methods:The results of prenatal diagnosis and clinical data were collected retrospectively,according to the indicator for invasive diagnostic testing.Results:Among the 8771 cases,188 cases (2.14%) of a fetal with aneuploidies of chromosomal were diagnosed,which are trisomy 21 (111 cases),trisomy 18 (27 cases),47,XXY (15 cases),45,X (13 cases),47,XXX (11 cases),trisomy 13 (10 cases),47,XYY (1 case).The detective rate of fetal with aneuploidies of chromosomal was higher in noninvasive prenatal testing (91.677%),followed by Abnormal serum screening and ultrasound findings group (7.01%),abnormal ultrasonic findings group (6.57%),Abnormal serum screening group (1.60%).Conclusion:The incidence of aneuploidies of chromosomal in pregnant women with AMA was high.The incidence was higher in pregnancy with multiple abnormal screening indexes.%目的 了解不同产前诊断指征高龄孕妇的胎儿染色体非整倍体检出情况.方法 回顾分析高龄孕妇产前诊断结果及其临床资料,分析不同指征孕妇胎儿非整倍体发生率.结果 8771例子高龄孕妇中,检出胎儿染色体非整倍体188例(2.14%),其中21三体最多为111例,依次为18三体27例,47,XXY 15例,45,X 13例,47,XXX 11例,13三体10例,47,XYY 1例.无创产前筛查阳性检出率最高为91.67%,其次为血清学筛查高风险+超声异常发现(7.10%)、超声异常发现(6.57%)和血清学筛查高风险(1.60%).结论 高龄妊娠胎儿染色体非整倍体发生率高于一般人群,妊娠合并多项筛查指标异常时,胎儿染色体非整倍体发生的风险增加.

  7. Genetics of mammalian meiosis: regulation, dynamics and impact on fertility.

    Science.gov (United States)

    Handel, Mary Ann; Schimenti, John C

    2010-02-01

    Meiosis is an essential stage in gamete formation in all sexually reproducing organisms. Studies of mutations in model organisms and of human haplotype patterns are leading to a clearer understanding of how meiosis has adapted from yeast to humans, the genes that control the dynamics of chromosomes during meiosis, and how meiosis is tied to gametic success. Genetic disruptions and meiotic errors have important roles in infertility and the aetiology of developmental defects, especially aneuploidy. An understanding of the regulation of meiosis, coupled with advances in genomics, may ultimately allow us to diagnose the causes of meiosis-based infertilities, more wisely apply assisted reproductive technologies, and derive functional germ cells.

  8. Acentrosomal spindle assembly and chromosome segregation during oocyte meiosis.

    Science.gov (United States)

    Dumont, Julien; Desai, Arshad

    2012-05-01

    The ability to reproduce relies in most eukaryotes on specialized cells called gametes. Gametes are formed by the process of meiosis in which, after a single round of replication, two successive cell divisions reduce the ploidy of the genome. Fusion of gametes at fertilization reconstitutes diploidy. In most animal species, chromosome segregation during female meiosis occurs on spindles assembled in the absence of the major microtubule-organizing center, the centrosome. In mammals, oocyte meiosis is error prone and underlies most birth aneuploidies. Here, we review recent work on acentrosomal spindle formation and chromosome alignment/separation during oocyte meiosis in different animal models.

  9. Evaluation of fluorescence in situ hybridization in prenatal diagnosis of uncultured amniotic fluid cells%荧光原位杂交技术在未培养羊水细胞产前诊断中的临床应用

    Institute of Scientific and Technical Information of China (English)

    吴莉; 钟进; 陈志华; 郭晓玲; 邓秀珍; 邓露莎

    2012-01-01

    目的 探讨荧光原位杂交(fluorescence in situ hybridization,FISH)技术在产前诊断中的优缺点及临床应用价值.方法 用FISH技术检测163例孕17 - 33周孕妇的未培养羊水细胞,每例均行常规染色体核型分析.结果 应用FISH法,所有样本均在24h内获得检测结果,除4例羊水培养失败外,其余样本均在3周内获得细胞遗传学诊断.两种方法均检测出3例非整倍体,FISH结果与核型分析结果一致.9例染色体结构异常,FISH法未能检出.结论 FISH技术应用于产前诊断染色体非整倍体,成功率高,准确可靠,较常规核型分析方法有效缩短报告时间.FISH不能完全替代常规染色体核型分析,疑有染色体结构异常者,必须行羊水细胞染色体核型分析.母血清唐氏征筛查异常孕妇产前诊断倾向选择FISH检测.%Objective: To evaluate clinical application value of fluorescence in situ hybridization. Methods: Amniotic fluid samples were taken from 163 women at 17 +4 ~ 33 +1 weeks of pregnancy; FISH was performed for diagnosing aneuploidies of five chromosomes (13, 18, 21, X and Y). The routine kaiyotypes analysis was performed at the same time. Results: The FISH diagnosis of all species was achieved in 24h, while 161 chromosome kaiyotypes diagnosis acquired in 3 weeks, since failed cell culture occurred in 2 amniotic fluid cases. 3 aneuploidies found by FISH and chromosome karyotypes. For the two methods, the diagnosis of aneuploidies matched perfectly. 9 Structural abnormalitic of chromosome were missed by FISH. Conclusion; FISH is a rapid and accurate method for prenatal diagnosis of chromosome aneuploidies, but it can't completely replace the conventional chromosome karyotype analysis. If structural abnormalities of chromosome was suspected to be, Amniotic fluid cell cultures and karyotype analysis must be performed. FISH could be choiced when biochemical data for Down's syndrome were positive.

  10. An unusual combination of Klinefelter syndrome and growth hormone deficiency in a prepubertal child.

    Science.gov (United States)

    Ramesh, Jayanthy; Nagasatyavani, Mudiganti; Venkateswarlu, Javvadii; Nagender, Jakka

    2014-09-01

    Klinefelter syndrome (KS) is the most common chromosomal aneuploidy in males. It is very difficult to diagnose this disorder in childhood due to absence of significant manifestations before puberty. These patients usually present with tall stature. We report a case of KS with short stature due to growth hormone deficiency. The boy's height was below the 3rd centile with significant delay in bone age. He responded well to growth hormone injections. In view of mental subnormality karyotyping was done, which revealed KS (47XXY).

  11. Detectable clonal mosaicism and its relationship to aging and cancer

    OpenAIRE

    Jacobs, Kevin B; Yeager, Meredith; Zhou, Weiyin; Wacholder, Sholom; Wang, Zhaoming; Rodriguez-Santiago, Benjamin; Hutchinson, Amy; Deng, Xiang; Liu, Chenwei; Horner, Marie-Josephe; Cullen, Michael; Epstein, Caroline G; Burdett, Laurie; Dean, Michael C.; Chatterjee, Nilanjan

    2012-01-01

    In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% u...

  12. Plasticity of the Leishmania genome leading to gene copy number variations and drug resistance [version 1; referees: 5 approved

    Directory of Open Access Journals (Sweden)

    Marie-Claude N. Laffitte

    2016-09-01

    Full Text Available Leishmania has a plastic genome, and drug pressure can select for gene copy number variation (CNV. CNVs can apply either to whole chromosomes, leading to aneuploidy, or to specific genomic regions. For the latter, the amplification of chromosomal regions occurs at the level of homologous direct or inverted repeated sequences leading to extrachromosomal circular or linear amplified DNAs. This ability of Leishmania to respond to drug pressure by CNVs has led to the development of genomic screens such as Cos-Seq, which has the potential of expediting the discovery of drug targets for novel promising drug candidates.

  13. Reversible phosphorylation and regulation of mammalian oocyte meiotic chromatin remodeling and segregation.

    Science.gov (United States)

    Swain, J E; Smith, G D

    2007-01-01

    The mammalian oocyte is notorious for high rates of chromosomal abnormalities. This results in subsequent embryonic aneuploidy, resulting in infertility and congenital defects. Therefore, understanding regulatory mechanisms involved in chromatin remodeling and chromosome segregation during oocyte meiotic maturation is imperative to fully understand the complex process and establish potential therapies. This review will focus on major events occurring during oocyte meiosis, critical to ensure proper cellular ploidy. Mechanistic and cellular events such as chromosome condensation, meiotic spindle formation, as well as cohesion of homologues and sister chromatids will be discussed, focusing on the role of reversible phosphorylation in control of these processes.

  14. An adolescent with 48,xxyy syndrome with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder and renal malformations

    Directory of Open Access Journals (Sweden)

    Prasad Katulanda

    2012-01-01

    Full Text Available 48,XXYY is a rare sex chromosome aneuploidy affecting 1 in 18,000 to 50,000 male births. They present with developmental delay, hypogonadism, gynecomastia, intention tremors, and a spectrum of neurodevelopmental and psychiatric disorders. At one time this condition was considered a variant of Klinefelter syndrome. In clinically suspected cases, 48,XXYY syndrome can be diagnosed by chromosome culture and karyotyping. This patient presented with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder, and renal malformatons. Klinefelter syndrome was clinically suspected. The karyotype confirmed the diagnosis of 48,XXYY syndrome. This is the first reported case of 48,XXYY syndrome from Sri Lanka.

  15. An adolescent with 48,XXYY syndrome with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder and renal malformations.

    Science.gov (United States)

    Katulanda, Prasad; Rajapakse, J Rasika D K; Kariyawasam, Jayani; Jayasekara, Rohan; Dissanayake, Vajira H W

    2012-09-01

    48,XXYY is a rare sex chromosome aneuploidy affecting 1 in 18,000 to 50,000 male births. They present with developmental delay, hypogonadism, gynecomastia, intention tremors, and a spectrum of neurodevelopmental and psychiatric disorders. At one time this condition was considered a variant of Klinefelter syndrome. In clinically suspected cases, 48,XXYY syndrome can be diagnosed by chromosome culture and karyotyping. This patient presented with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder, and renal malformatons. Klinefelter syndrome was clinically suspected. The karyotype confirmed the diagnosis of 48,XXYY syndrome. This is the first reported case of 48,XXYY syndrome from Sri Lanka.

  16. Microarray-Based Analysis of Methylation of 1st Trimester Trisomic Placentas from Down Syndrome, Edwards Syndrome and Patau Syndrome.

    Science.gov (United States)

    Hatt, Lotte; Aagaard, Mads M; Bach, Cathrine; Graakjaer, Jesper; Sommer, Steffen; Agerholm, Inge E; Kølvraa, Steen; Bojesen, Anders

    2016-01-01

    Methylation-based non-invasive prenatal testing of fetal aneuploidies is an alternative method that could possibly improve fetal aneuploidy diagnosis, especially for trisomy 13(T13) and trisomy 18(T18). Our aim was to study the methylation landscape in placenta DNA from trisomy 13, 18 and 21 pregnancies in an attempt to find trisomy-specific methylation differences better suited for non-invasive prenatal diagnosis. We have conducted high-resolution methylation specific bead chip microarray analyses assessing more than 450,000 CpGs analyzing placentas from 12 T21 pregnancies, 12 T18 pregnancies and 6 T13 pregnancies. We have compared the methylation landscape of the trisomic placentas to the methylation landscape from normal placental DNA and to maternal blood cell DNA. Comparing trisomic placentas to normal placentas we identified 217 and 219 differentially methylated CpGs for CVS T18 and CVS T13, respectively (delta β>0.2, FDR<0.05), but only three differentially methylated CpGs for T21. However, the methylation differences was only modest (delta β<0.4), making them less suitable as diagnostic markers. Gene ontology enrichment analysis revealed that the gene set connected to theT18 differentially methylated CpGs was highly enriched for GO terms related to"DNA binding" and "transcription factor binding" coupled to the RNA polymerase II transcription. In the gene set connected to the T13 differentially methylated CpGs we found no significant enrichments.

  17. Identification of genes that are essential to restrict genome duplication to once per cell division

    Science.gov (United States)

    Vassilev, Alex; Lee, Chrissie Y.; Vassilev, Boris; Zhu, Wenge; Ormanoglu, Pinar; Martin, Scott E.; DePamphilis, Melvin L.

    2016-01-01

    Nuclear genome duplication is normally restricted to once per cell division, but aberrant events that allow excess DNA replication (EDR) promote genomic instability and aneuploidy, both of which are characteristics of cancer development. Here we provide the first comprehensive identification of genes that are essential to restrict genome duplication to once per cell division. An siRNA library of 21,584 human genes was screened for those that prevent EDR in cancer cells with undetectable chromosomal instability. Candidates were validated by testing multiple siRNAs and chemical inhibitors on both TP53+ and TP53- cells to reveal the relevance of this ubiquitous tumor suppressor to preventing EDR, and in the presence of an apoptosis inhibitor to reveal the full extent of EDR. The results revealed 42 genes that prevented either DNA re-replication or unscheduled endoreplication. All of them participate in one or more of eight cell cycle events. Seventeen of them have not been identified previously in this capacity. Remarkably, 14 of the 42 genes have been shown to prevent aneuploidy in mice. Moreover, suppressing a gene that prevents EDR increased the ability of the chemotherapeutic drug Paclitaxel to induce EDR, suggesting new opportunities for synthetic lethalities in the treatment of human cancers. PMID:27144335

  18. Recent insights into spindle function in mammalian oocytes and early embryos.

    Science.gov (United States)

    Howe, Katie; FitzHarris, Greg

    2013-09-01

    Errors in chromosome segregation in oocytes and early embryos lead to embryo aneuploidy, which contributes to early pregnancy loss. At the heart of chromosome segregation is the spindle, a dynamic biomechanical machine fashioned from microtubules, which is tasked with gathering and sorting chromosomes and dispatching them to the daughter cells at the time of cell division. Understanding the causes of segregation error in the oocyte and early embryo will undoubtedly hinge on a thorough understanding of the mechanism of spindle assembly and function in these highly specialized cellular environments. The recent advent of live imaging approaches to observe chromosome segregation in real-time in oocytes and embryos, paired with gene-silencing techniques and specific inhibition for assessing the function of a protein of interest, has led to a substantial advance in our understanding of chromosome segregation in early mammalian development. These studies have uncovered numerous mechanistic differences between oocytes, embryos, and traditional model systems. In addition, a flurry of recent studies using naturally aged mice as the model for human aging have begun to shed light on the increased levels of aneuploidy seen in embryos from older mothers. Here we review these recent developments and consider what has been learned about the causes of chromosome missegregation in early development.

  19. Genome evolution during progression to breast cancer

    KAUST Repository

    Newburger, D. E.

    2013-04-08

    Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole-genome sequencing of early neoplasias, matched normal tissue, and carcinomas from six patients, for a total of 31 samples. By using somatic mutations as lineage markers we built trees that relate the tissue samples within each patient. On the basis of these lineage trees we inferred the order, timing, and rates of genomic events. In four out of six cases, an early neoplasia and the carcinoma share a mutated common ancestor with recurring aneuploidies, and in all six cases evolution accelerated in the carcinoma lineage. Transition spectra of somatic mutations are stable and consistent across cases, suggesting that accumulation of somatic mutations is a result of increased ancestral cell division rather than specific mutational mechanisms. In contrast to highly advanced tumors that are the focus of much of the current cancer genome sequencing, neither the early neoplasia genomes nor the carcinomas are enriched with potentially functional somatic point mutations. Aneuploidies that occur in common ancestors of neoplastic and tumor cells are the earliest events that affect a large number of genes and may predispose breast tissue to eventual development of invasive carcinoma.

  20. Biological characteristics of breast carcinomas with neuroendocrine cell differentiation

    Institute of Scientific and Technical Information of China (English)

    姚根有; 周吉林; 赵仲生; 阮俊

    2004-01-01

    Background The aim of this study was to investigate DNA content and expression of c-erbB-2, PS2, and prostate-specific antigen (PSA) proteins in breast carcinomas with neuroendocrine (NE) cell differentiation.Methods Chromogranin, c-erbB-2, PS2, and PSA in 131 samples of breast cancer were detected immunohistochemically. Classic Feulgen staining image analysis techniques were used to quantify DNA content in 81 of the breast cancer samples.Results The c-erbB-2 positive rate in breast carcinoma samples containing neuroendocrine cells was 37.5% and the rate of high expression of c-erbB-2 (++ or +++) was 33.3%, both significantly lower than that in breast carcinomas without neuroendocrine cells (62.6% and 68.7%, respectively, P 5c aneuploidy cells, and rate of aneuploidy among cells were all lower than that in NE (-) breast carcinomas (P<0.01). In NE (+) grade I or II breast carcinomas, these indices were also all lower than that in the NE (-) breast carcinoma samples (P<0.01).Conclusion Breast carcinomas with neuroendocrine differentiation have a lower rate of malignancy. Neuroendocrine differentiation could serve as a prognostic marker in clinical practice.

  1. Current Status of Comprehensive Chromosome Screening for Elective Single-Embryo Transfer

    Directory of Open Access Journals (Sweden)

    Ming-Yih Wu

    2014-01-01

    Full Text Available Most in vitro fertilization (IVF experts and infertility patients agree that the most ideal assisted reproductive technology (ART outcome is to have a healthy, full-term singleton born. To this end, the most reliable policy is the single-embryo transfer (SET. However, unsatisfactory results in IVF may result from plenty of factors, in which aneuploidy associated with advanced maternal age is a major hurdle. Throughout the past few years, we have got a big leap in advancement of the genetic screening of embryos on aneuploidy, translocation, or mutations. This facilitates a higher success rate in IVF accompanied by the policy of elective SET (eSET. As the cost is lowering while the scale of genome characterization continues to be up over the recent years, the contemporary technologies on trophectoderm biopsy and freezing-thaw, comprehensive chromosome screening (CCS with eSET appear to be getting more and more popular for modern IVF centers. Furthermore, evidence has showen that, by these avant-garde techniques (trophectoderm biopsy, vitrification, and CCS, older infertile women with the help of eSET may have an opportunity to increase the success of their live birth rates approaching those reported in younger infertility patients.

  2. The genomic landscape of hypodiploid acute lymphoblastic leukemia.

    Science.gov (United States)

    Holmfeldt, Linda; Wei, Lei; Diaz-Flores, Ernesto; Walsh, Michael; Zhang, Jinghui; Ding, Li; Payne-Turner, Debbie; Churchman, Michelle; Andersson, Anna; Chen, Shann-Ching; McCastlain, Kelly; Becksfort, Jared; Ma, Jing; Wu, Gang; Patel, Samir N; Heatley, Susan L; Phillips, Letha A; Song, Guangchun; Easton, John; Parker, Matthew; Chen, Xiang; Rusch, Michael; Boggs, Kristy; Vadodaria, Bhavin; Hedlund, Erin; Drenberg, Christina; Baker, Sharyn; Pei, Deqing; Cheng, Cheng; Huether, Robert; Lu, Charles; Fulton, Robert S; Fulton, Lucinda L; Tabib, Yashodhan; Dooling, David J; Ochoa, Kerri; Minden, Mark; Lewis, Ian D; To, L Bik; Marlton, Paula; Roberts, Andrew W; Raca, Gordana; Stock, Wendy; Neale, Geoffrey; Drexler, Hans G; Dickins, Ross A; Ellison, David W; Shurtleff, Sheila A; Pui, Ching-Hon; Ribeiro, Raul C; Devidas, Meenakshi; Carroll, Andrew J; Heerema, Nyla A; Wood, Brent; Borowitz, Michael J; Gastier-Foster, Julie M; Raimondi, Susana C; Mardis, Elaine R; Wilson, Richard K; Downing, James R; Hunger, Stephen P; Loh, Mignon L; Mullighan, Charles G

    2013-03-01

    The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

  3. Euploidy in somatic cells from R6/2 transgenic Huntington's disease mice

    Directory of Open Access Journals (Sweden)

    Stewénius Ylva

    2005-09-01

    Full Text Available Abstract Background Huntington's disease (HD is a hereditary neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. The huntingtin protein expressed from HD has an unknown function but is suggested to interact with proteins involved in the cell division machinery. The R6/2 transgenic mouse is the most widely used model to study HD. In R6/2 fibroblast cultures, a reduced mitotic index and high frequencies of multiple centrosomes and aneuploid cells have recently been reported. Aneuploidy is normally a feature closely connected to neoplastic disease. To further explore this unexpected aspect of HD, we studied cultures derived from 6- and 12-week-old R6/2 fibroblasts, skeletal muscle cells, and liver cells. Results Cytogenetic analyses revealed a high frequency of polyploid cells in cultures from both R6/2 and wild-type mice with the greatest proportions of polyploid cells in cultures derived from skeletal muscle cells of both genotypes. The presence of polyploid cells in skeletal muscle in vivo was confirmed by fluorescence in situ hybridisation with centromeric probes. Enlarged and supernumerary centrosomes were found in cultures from both R6/2 and wild-type mice. However, no aneuploid cells could be found in any of the tissues. Conclusion We conclude that polyploid cells are found in fibroblast and skeletal muscle cultures derived from both R6/2 and wild-type littermate mice and that aneuploidy is unlikely to be a hallmark of HD.

  4. MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13.

    Science.gov (United States)

    Sankaran, Vijay G; Menne, Tobias F; Šćepanović, Danilo; Vergilio, Jo-Anne; Ji, Peng; Kim, Jinkuk; Thiru, Prathapan; Orkin, Stuart H; Lander, Eric S; Lodish, Harvey F

    2011-01-25

    Many human aneuploidy syndromes have unique phenotypic consequences, but in most instances it is unclear whether these phenotypes are attributable to alterations in the dosage of specific genes. In human trisomy 13, there is delayed switching and persistence of fetal hemoglobin (HbF) and elevation of embryonic hemoglobin in newborns. Using partial trisomy cases, we mapped this trait to chromosomal band 13q14; by examining the genes in this region, two microRNAs, miR-15a and -16-1, appear as top candidates for the elevated HbF levels. Indeed, increased expression of these microRNAs in primary human erythroid progenitor cells results in elevated fetal and embryonic hemoglobin gene expression. Moreover, we show that a direct target of these microRNAs, MYB, plays an important role in silencing the fetal and embryonic hemoglobin genes. Thus we demonstrate how the developmental regulation of a clinically important human trait can be better understood through the genetic and functional study of aneuploidy syndromes and suggest that miR-15a, -16-1, and MYB may be important therapeutic targets to increase HbF levels in patients with sickle cell disease and β-thalassemia.

  5. Disruption of Mitotic Progression by Arsenic.

    Science.gov (United States)

    States, J Christopher

    2015-07-01

    Arsenic is an enigmatic xenobiotic that causes a multitude of chronic diseases including cancer and also is a therapeutic with promise in cancer treatment. Arsenic causes mitotic delay and induces aneuploidy in diploid human cells. In contrast, arsenic causes mitotic arrest followed by an apoptotic death in a multitude of virally transformed cells and cancer cells. We have explored the hypothesis that these differential effects of arsenic exposure are related by arsenic disruption of mitosis and are differentiated by the target cell's ability to regulate or modify cell cycle checkpoints. Functional p53/CDKN1A axis has been shown to mitigate the mitotic block and to be essential to induction of aneuploidy. More recent preliminary data suggest that microRNA modulation of chromatid cohesion also may play a role in escape from mitotic block and in generation of chromosomal instability. Other recent studies suggest that arsenic may be useful in treatment of solid tumors when used in combination with other cytotoxic agents such as cisplatin.

  6. Anatomy of trisomy 12.

    Science.gov (United States)

    Roberts, Wallisa; Zurada, Anna; Zurada-ZieliŃSka, Agnieszka; Gielecki, Jerzy; Loukas, Marios

    2016-07-01

    Trisomy 12 is a rare aneuploidy and fetuses with this defect tend to spontaneously abort. However, mosaicism allows this anomaly to manifest itself in live births. Due to the fact that mosaicism represents a common genetic abnormality, trisomy 12 is encountered more frequently than expected at a rate of 1 in 500 live births. Thus, it is imperative that medical practitioners are aware of this aneuploidy. Moreover, this genetic disorder may result from a complete or partial duplication of chromosome 12. A partial duplication may refer to a specific segment on the chromosome, or one of the arms. On the other hand, a complete duplication refers to duplication of both arms of chromosome 12. The combination of mosaicism and the variable duplication sites has led to variable phenotypes ranging from normal phenotype to Potter sequence to gross physical defects of the various organ systems. This article provides a review of the common anatomical variation of the different types of trisomy 12. This review revealed that further documentation is needed for trisomy 12q and complete trisomy 12 to clearly delineate the constellation of anomalies that characterize each genetic defect. Clin. Anat. 29:633-637, 2016. © 2016 Wiley Periodicals, Inc.

  7. Micro RNAs and DNA methylation are regulatory players in human cells with altered X chromosome to autosome balance

    Science.gov (United States)

    Rajpathak, Shriram N.; Deobagkar, Deepti D.

    2017-01-01

    The gene balance hypothesis predicts that an imbalance in the dosage sensitive genes affects the cascade of gene networks that may influence the fitness of individuals. The phenotypes associated with chromosomal aneuploidies demonstrate the importance of gene dosage balance. We have employed untransformed human fibroblast cells with different number of X chromosomes to assess the expression of miRNAs and autosomal genes in addition to the DNA methylation status. High throughput NGS analysis using illumina Next seq500 has detected several autosomal as well as X linked miRNAs as differentially expressed in X monosomy and trisomy cells. Two of these miRNAs (hsa-miR-125a-5p and 335-5p) are likely to be involved in regulation of the autosomal gene expression. Additionally, our data demonstrates altered expression and DNA methylation signatures of autosomal genes in X monosomy and trisomy cells. In addition to miRNAs, expression of DNMT1 which is an important epigenetic player involved in many processes including cancer, is seen to be altered. Overall, present study provides a proof for regulatory roles of micro RNAs and DNA methylation in human X aneuploidy cells opening up possible new ways for designing therapeutic strategies. PMID:28233878

  8. Mouse Lymphoblastic Leukemias Induced by Aberrant Prdm14 Expression Demonstrate Widespread Copy Number Alterations Also Found in Human ALL

    Directory of Open Access Journals (Sweden)

    Stephen J. Simko

    2012-10-01

    Full Text Available Aberrant expression and activation of oncogenes in somatic cells has been associated with cancer initiation. Required for reacquisition of pluripotency in the developing germ cell, PRDM14 initiates lymphoblastic leukemia when misexpressed in murine bone marrow. Activation of pluripotency in somatic cells can lead to aneuploidy and copy number alterations during iPS cell generation, and we hypothesized that PRDM14-induced lymphoblastic leukemias would demonstrate significant chromosomal damage. High-resolution oligo array comparative genomic hybridization demonstrated infrequent aneuploidy but frequent amplification and deletion, with amplifications occurring in a 5:1 ratio with deletions. Many deletions (i.e., Cdkn2a, Ebf1, Pax5, Ikzf1 involved B-cell development genes and tumor suppressor genes, recapitulating deletions occurring in human leukemia. Pathways opposing senescence were frequently deactivated via Cdkn2a deletion or Tbx2 amplification, with corollary gene expression. Additionally, gene expression studies of abnormal pre-leukemic B-precursors showed downregulation of genes involved in chromosomal stability (i.e., Xrcc6 and failure to upregulate DNA repair pathways. We propose a model of leukemogenesis, triggered by pluripotency genes like Prdm14, which involves ongoing DNA damage and failure to activate non-homologous end-joining secondary to aberrant gene expression.

  9. Correlation of DNA Ploidy with Progression of Cervical Cancer

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    M. Singh

    2008-01-01

    Full Text Available The majority of squamous cell carcinomas of cervix are preceded by visible changes in the cervix, most often detected by cervical smear. As cervical cancer is preceded by long precancerous stages, identification of the high-risk population through detection of DNA ploidy may be of importance in effective management of this disease. Here we attempted to correlate aneuploid DNA patterns and their influence on biological behavior of flow-cytometry analysis of DNA ploidy which was carried out in cytologically diagnosed cases of mild (79, moderate (36, and severe (12 dysplasia, as well as “atypical squamous cells of unknown significance (ASCUS” (57 along with controls (69, in order to understand its importance in malignant progression of disease. Cytologically diagnosed dysplasias, which were employed for DNA ploidy studies, 39 mild, 28 moderate, and 11 severe dysplasia cases were found to be aneuploid. Out of the 69 control subjects, 6 cases showed aneuploidy pattern and the rest 63 subjects were diploid. An aneuploidy pattern was observed in 8 out of 57 cases of cytologically evaluated ASCUS. The results of the followup studies showed that aberrant DNA content reliably predicts the occurrence of squamous cell carcinoma in cervical smear. Flow cytometric analysis of DNA ploidy may provide a strategic diagnostic tool for early detection of carcinoma cervix. Therefore, it is a concept of an HPV screening with reflex cytology in combination with DNA flow cytometry to detect progressive lesions with the greatest possible sensitivity and specificity.

  10. Cell-free fetal DNA and intact fetal cells in maternal blood circulation: implications for first and second trimester non-invasive prenatal diagnosis.

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    Bischoff, Farideh Z; Sinacori, Mina K; Dang, Dianne D; Marquez-Do, Deborah; Horne, Cassandra; Lewis, Dorothy E; Simpson, Joe Leigh

    2002-01-01

    Both intact fetal cells as well as cell-free fetal DNA are present in the maternal circulation and can be recovered for non-invasive prenatal genetic diagnosis. Although methods for enrichment and isolation of rare intact fetal cells have been challenging, diagnosis of fetal chromosomal aneuploidy including trisomy 21 in first- and second-trimester pregnancies has been achieved with a 50-75% detection rate. Similarly, cell-free fetal DNA can be reliably recovered from maternal plasma and assessed by quantitative PCR to detect fetal trisomy 21 and paternally derived single gene mutations. Real-time PCR assays are robust in detecting low-level fetal DNA concentrations, with sensitivity of approximately 95-100% and specificity near 100%. Comparing intact fetal cell versus cell-free fetal DNA methods for non-invasive prenatal screening for fetal chromosomal aneuploidy reveals that the latter is at least four times more sensitive. These preliminary results do not support a relationship between frequency of intact fetal cells and concentration of cell-free fetal DNA. The above results imply that the concentration of fetal DNA in maternal plasma may not be dependent on circulating intact fetal cells but rather be a product of growth and cellular turnover during embryonic or fetal development.

  11. The Spindle Assembly Checkpoint Safeguards Genomic Integrity of Skeletal Muscle Satellite Cells

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    Swapna Kollu

    2015-06-01

    Full Text Available To ensure accurate genomic segregation, cells evolved the spindle assembly checkpoint (SAC, whose role in adult stem cells remains unknown. Inducible perturbation of a SAC kinase, Mps1, and its downstream effector, Mad2, in skeletal muscle stem cells shows the SAC to be critical for normal muscle growth, repair, and self-renewal of the stem cell pool. SAC-deficient muscle stem cells arrest in G1 phase of the cell cycle with elevated aneuploidy, resisting differentiation even under inductive conditions. p21CIP1 is responsible for these SAC-deficient phenotypes. Despite aneuploidy’s correlation with aging, we find that aged proliferating muscle stem cells display robust SAC activity without elevated aneuploidy. Thus, muscle stem cells have a two-step mechanism to safeguard their genomic integrity. The SAC prevents chromosome missegregation and, if it fails, p21CIP1-dependent G1 arrest limits cellular propagation and tissue integration. These mechanisms ensure that muscle stem cells with compromised genomes do not contribute to tissue homeostasis.

  12. Transforming fusions of FGFR and TACC genes in human glioblastoma.

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    Singh, Devendra; Chan, Joseph Minhow; Zoppoli, Pietro; Niola, Francesco; Sullivan, Ryan; Castano, Angelica; Liu, Eric Minwei; Reichel, Jonathan; Porrati, Paola; Pellegatta, Serena; Qiu, Kunlong; Gao, Zhibo; Ceccarelli, Michele; Riccardi, Riccardo; Brat, Daniel J; Guha, Abhijit; Aldape, Ken; Golfinos, John G; Zagzag, David; Mikkelsen, Tom; Finocchiaro, Gaetano; Lasorella, Anna; Rabadan, Raul; Iavarone, Antonio

    2012-09-07

    The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.

  13. Cytogenetic studies of a male with sporadic intestinal lymphangiectasia: 45,X/46,XY mosaicism with pseudo- and hyperdiploid subpopulations in cultured tissues.

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    White, B J; Crandall, C; Flier, J S; Raveché, E S; Tjio, J H

    1979-01-01

    45,X/46,XY mosaicism was found in peripheral blood, bone marrow, and tissue cultures of an adult male with intestinal lymphangiectasia (IL). Turner phenotype was not present; his meiotic metaphase analysis was normak, and his dermatoglyphics resembled those of his family. Ten separate tissue culture lines from three biopsies of skin and thyroid gland contained 45,X cells (14.8 to 78.3%). Autosomal aneuploidy, resulting in pseudo- or hyperdiploidy, was also present in 4.3 to 41.6% of the cells. A hyperdiploid clone with a 47,X,+10,+18 karyotype was found in 22.6% of cells in one line. A second hyperdiploid clone with a 48,X,+2,+18,+18 karyotype occurred in 7.6% of cells from another line containing a total of 41.6% pseudo- and hyperdiploid cells. Such clonal abnormalities were not typical of tissue cultures from other patients done in our laboratory. Growth of our patient's tissue cultures was subnormal, and none proliferated beyond the fourth subculture. The significance of this observation remains to be determined. Our results do not allow us to conclude whether our patient's mosaicism of somatic tissues arose during embryogenesis, or whether it originated post-natally. The secondary immunodeficiency which occurs in IL may explain persistence of cells with unusual combinations of autosomal aneuploidy in our patient's tissues.

  14. Chromosomal abnormalities in patients with autism spectrum disorders from Taiwan.

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    Liao, Hsiao-Mei; Gau, Susan Shur-Fen; Tsai, Wen-Che; Fang, Jye-Siung; Su, Ying-Cheng; Chou, Miao-Chun; Liu, Shih-Kai; Chou, Wen-Jiun; Wu, Yu-Yu; Chen, Chia-Hsiang

    2013-10-01

    Autism spectrum disorders (ASD) are childhood-onset neurodevelopmental disorders characterized by verbal communication impairments, social reciprocity deficits, and the presence of restricted interests and stereotyped behaviors. Genetic factors contribute to the incidence of ASD evidently. However, the genetic spectrum of ASD is highly heterogeneous. Chromosomal abnormalities contribute significantly to the genetic deficits of syndromic and non-syndromic ASD. In this study, we conducted karyotyping analysis in a sample of 500 patients (447 males, 53 females) with ASD from Taiwan, the largest cohort in Asia, to the best of our knowledge. We found three patients having sex chromosome aneuploidy, including two cases of 47, XXY and one case of 47, XYY. In addition, we detected a novel reciprocal chromosomal translocation between long arms of chromosomes 4 and 14, designated t(4;14)(q31.3;q24.1), in a patient with Asperger's disorder. This translocation was inherited from his unaffected father, suggesting it might not be pathogenic or it needs further hits to become pathogenic. In line with other studies, our study revealed that subjects with sex chromosomal aneuploidy are liable to neurodevelopmental disorders, including ASD, and conventional karyotyping analysis is still a useful tool in detecting chromosomal translocation in patients with ASD, given that array-based comparative genomic hybridization technology can provide better resolution in detecting copy number variations of genomic DNA.

  15. A cytogenetic study of 47,XXY males of known origin and their parents.

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    Jacobs, P A; Bacino, C; Hassold, T; Morton, N E; Keston, M; Lee, M

    1988-10-01

    A number of patients with both sex chromosome aneuploidy and the fragile X syndrome have been reported and this has led to the hypothesis that females heterozygous for the fragile X mutation have an increased rate of meiotic nondisjunction. Furthermore the suggestion has frequently been made that a predisposition to meiotic nondisjunction is associated with an increase in mitotic nondisjunction. We have tested these two hypotheses by examining the chromosomes of a series of 47,XXY males and their parents. In the majority the parental origin of the additional sex chromosome was known. The cells were cultured under conditions suitable for demonstrating the fragile X and 100 cells were scored 'blind' from the patients and both parents. No fragile X individual was seen and there was no difference in the proportion of aneuploid cells between the parents in whom the nondisjunction event occurred and the control parents. Therefore, our results lend no support to the suggestions that the fragile X is associated with an increase in sex chromosome aneuploidy or that individuals in whom meiotic nondisjunction occurs have an increased level of mitotic nondisjunction.

  16. Genetic variations of 21 STR markers on chromosomes 13, 18, 21, X, and Y in the south Iranian population.

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    Saberzadeh, J; Miri, M R; Tabei, M B; Dianatpour, M; Fardaei, M

    2016-12-19

    Quantitative fluorescent polymerase chain reaction (QF-PCR), in recent years, has been accepted as a rapid, high throughput, and sensitive method for prenatal diagnosis of common chromosomal aneuploidies. Since short tandem repeats (STRs) are the cornerstone of QF-PCR technique, selection of the most polymorphic STR markers is an essential step for a successful QF-PCR assay. The genetic variation parameters of each STR marker differ among different populations. In this study, we investigated the size, frequency, heterozygosity, polymorphism information content, power of discrimination, and other genetic polymorphism data for 21 STR markers on chromosomes 13, 18, 21, X, and Y in 1000 amniotic fluid samples obtained from south Iranian women. Our results showed that all the 21 STR markers are highly polymorphic and informative in our population. The heterozygosity, polymorphism information content, and power of discrimination of the markers were 62-91.1%, 0.61-0.91, and 0.830-0.976, respectively. The locus D18S386 was the most polymorphic STR, while the locus DXYS218 was the least polymorphic STR among all the studied STRs. The present study has provided extensive data regarding the efficiency of the 21 STR markers for diagnosis of chromosomes 13, 18, 21, X, and Y aneuploidies in the south Iranian population.

  17. Biopsy of human morula-stage embryos: outcome of 215 IVF/ICSI cycles with PGS.

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    Elena E Zakharova

    Full Text Available Preimplantation genetic diagnosis (PGD is commonly performed on biopsies from 6-8-cell-stage embryos or blastocyst trophectoderm obtained on day 3 or 5, respectively. Day 4 human embryos at the morula stage were successfully biopsied. Biopsy was performed on 709 morulae from 215 ICSI cycles with preimplantation genetic screening (PGS, and 3-7 cells were obtained from each embryo. The most common vital aneuploidies (chromosomes X/Y, 21 were screened by fluorescence in situ hybridization (FISH. No aneuploidy was observed in 72.7% of embryos, 91% of those developed to blastocysts. Embryos were transferred on days 5-6. Clinical pregnancy was obtained in 32.8% of cases, and 60 babies were born. Patients who underwent ICSI/PGS treatment were compared with those who underwent standard ICSI treatment by examining the percentage of blastocysts, pregnancy rate, gestational length, birth height and weight. No significant differences in these parameters were observed between the groups. Day 4 biopsy procedure does not adversely affect embryo development in vitro or in vivo. The increased number of cells obtained by biopsy of morulae might facilitate diagnostic screening. There is enough time after biopsy to obtain PGD results for embryo transfer on day 5-6 in the current IVF cycle.

  18. High-resolution Whole-Genome Analysis of Skull Base Chordomas Implicates FHIT Loss in Chordoma Pathogenesis

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    Roberto Jose Diaz

    2012-09-01

    Full Text Available Chordoma is a rare tumor arising in the sacrum, clivus, or vertebrae. It is often not completely resectable and shows a high incidence of recurrence and progression with shortened patient survival and impaired quality of life. Chemotherapeutic options are limited to investigational therapies at present. Therefore, adjuvant therapy for control of tumor recurrence and progression is of great interest, especially in skull base lesions where complete tumor resection is often not possible because of the proximity of cranial nerves. To understand the extent of genetic instability and associated chromosomal and gene losses or gains in skull base chordoma, we undertook whole-genome single-nucleotide polymorphism microarray analysis of flash frozen surgical chordoma specimens, 21 from the clivus and 1 from C1 to C2 vertebrae. We confirm the presence of a deletion at 9p involving CDKN2A, CDKN2B, and MTAP but at a much lower rate (22% than previously reported for sacral chordoma. At a similar frequency (21%, we found aneuploidy of chromosome 3. Tissue microarray immunohistochemistry demonstrated absent or reduced fragile histidine triad (FHIT protein expression in 98% of sacral chordomas and 67%of skull base chordomas. Our data suggest that chromosome 3 aneuploidy and epigenetic regulation of FHIT contribute to loss of the FHIT tumor suppressor in chordoma. The finding that FHIT is lost in a majority of chordomas provides new insight into chordoma pathogenesis and points to a potential new therapeutic target for this challenging neoplasm.

  19. Chromosome mis-segregation and cytokinesis failure in trisomic human cells.

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    Nicholson, Joshua M; Macedo, Joana C; Mattingly, Aaron J; Wangsa, Darawalee; Camps, Jordi; Lima, Vera; Gomes, Ana M; Dória, Sofia; Ried, Thomas; Logarinho, Elsa; Cimini, Daniela

    2015-05-05

    Cancer cells display aneuploid karyotypes and typically mis-segregate chromosomes at high rates, a phenotype referred to as chromosomal instability (CIN). To test the effects of aneuploidy on chromosome segregation and other mitotic phenotypes we used the colorectal cancer cell line DLD1 (2n = 46) and two variants with trisomy 7 or 13 (DLD1+7 and DLD1+13), as well as euploid and trisomy 13 amniocytes (AF and AF+13). We found that trisomic cells displayed higher rates of chromosome mis-segregation compared to their euploid counterparts. Furthermore, cells with trisomy 13 displayed a distinctive cytokinesis failure phenotype. We showed that up-regulation of SPG20 expression, brought about by trisomy 13 in DLD1+13 and AF+13 cells, is sufficient for the cytokinesis failure phenotype. Overall, our study shows that aneuploidy can induce chromosome mis-segregation. Moreover, we identified a trisomy 13-specific mitotic phenotype that is driven by up-regulation of a gene encoded on the aneuploid chromosome.

  20. The Effect of Prolonged Culture of Chromosomally Abnormal Human Embryos on The Rate of Diploid Cells

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    Masood Bazrgar

    2016-12-01

    Full Text Available Background: A decrease in aneuploidy rate following a prolonged co-culture of human blastocysts has been reported. As co-culture is not routinely used in assisted reproductive technology, the present study aimed to evaluate the effect of the prolonged single culture on the rate of diploid cells in human embryos with aneuploidies. Materials and Methods: In this cohort study, we used fluorescence in situ hybridization (FISH to reanalyze surplus blastocysts undergoing preimplantation genetic diagnosis (PGD on day 3 postfertilization. They were randomly studied on days 6 or 7 following fertilization. Results: Of the 30 analyzed blastocysts, mosaicism was observed in 26(86.6%, while 2(6.7% were diploid, and 2(6.7% were triploid. Of those with mosaicism, 23(88.5% were determined to be diploid-aneuploid and 3(11.5% were aneuploid mosaic. The total frequency of embryos with more than 50% diploid cells was 33.3% that was lower on day 7 in comparison with the related value on day 6 (P<0.05; however, there were no differences when the embryos were classified according to maternal age, blastocyst developmental stage, total cell number on day 3, and embryo quality. Conclusion: Although mosaicism is frequently observed in blastocysts, the prolonged single culture of blastocysts does not seem to increase the rate of normal cells.