Hematological abnormalities and 22q11.2 deletion syndrome

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Rafael Fabiano Machado Rosa

2011-01-01

Full Text Available The 22q11.2 deletion syndrome (22q11DS is a common genetic disease characterized by broad phenotypic variability. Despite the small number of studies describing hematological alterations in individuals with 22q11DS, it appears that these abnormalities are more frequent than previously imagined. Thus, the objective of our study was to report on a patient with 22q11DS presenting thrombocytopenia and large platelets and to review the literature. The patient, a 13-year-old boy, was originally evaluated due to craniofacial dysmorphia and speech delay. He also had a history of behavioral changes, neuropsychomotor delay and recurrent otitis/sinusitis. The identification of a 22q11.2 microdeletion by fluorescent in situ hybridization diagnosed the syndrome. Despite his hematological alterations, he only had a history of epistaxis and bruising of the upper and lower limbs. Assessments of the prothrombin time, thrombin time, partial thromboplastin time, bleeding time, fibrinogen levels and platelet aggregation (including the ristocetin induced platelet aggregation test were all normal. Hematological alterations observed in 22q11DS are directly related to the genetic disorder itself (especially in respect to deletion of the GPIb gene and secondary to some clinical findings, such as immunodeficiency. Macrothrombocytopenia is increasingly being considered a feature of the broad spectrum of 22q11DS and may potentially be a clinical marker for the syndrome.

Novel ZEB2-BCL11B Fusion Gene Identified by RNA-Sequencing in Acute Myeloid Leukemia with t(2;14(q22;q32.

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Synne Torkildsen

Full Text Available RNA-sequencing of a case of acute myeloid leukemia with the bone marrow karyotype 46,XY,t(2;14(q22;q32[5]/47,XY,idem,+?4,del(6(q13q21[cp6]/46,XY[4] showed that the t(2;14 generated a ZEB2-BCL11B chimera in which exon 2 of ZEB2 (nucleotide 595 in the sequence with accession number NM_014795.3 was fused to exon 2 of BCL11B (nucleotide 554 in the sequence with accession number NM_022898.2. RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcript. All functional domains of BCL11B are retained in the chimeric protein. Abnormal expression of BCL11B coding regions subjected to control by the ZEB2 promoter seems to be the leukemogenic mechanism behind the translocation.

Developmental Course of Conversational Behaviour of Children with 22q11.2 Deletion Syndrome and Williams Syndrome

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Van Den Heuvel, Ellen; Botting, Nicola; Boudewijns, Inge; Manders, Eric; Swillen, Ann; Zink, Inge

2017-01-01

This study investigated three conversational subskills in children with 22q11.2 deletion syndrome (22q11.2DS, n = 8, ages 7-13) and Williams syndrome (WS, n = 8, ages 6-12). The researchers re-evaluated these subskills after 18 to 24 months and compared them to those of peers with idiopathic intellectual disability (IID) and IID and comorbid…

22q11.2 deletion syndrome

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McDonald-McGinn, Donna M.; Sullivan, Kathleen E.; Marino, Bruno; Philip, Nicole; Swillen, Ann; Vorstman, Jacob A. S.; Zackai, Elaine H.; Emanuel, Beverly S.; Vermeesch, Joris R.; Morrow, Bernice E.; Scambler, Peter J.; Bassett, Anne S.

2016-01-01

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population. PMID:27189754

Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry.

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Lin, Amy; Ching, Christopher R K; Vajdi, Ariana; Sun, Daqiang; Jonas, Rachel K; Jalbrzikowski, Maria; Kushan-Wells, Leila; Pacheco Hansen, Laura; Krikorian, Emma; Gutman, Boris; Dokoru, Deepika; Helleman, Gerhard; Thompson, Paul M; Bearden, Carrie E

2017-06-28

Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion control > duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development. SIGNIFICANCE STATEMENT Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly

Exclusion of 22q11 deletion in Noonan syndrome with Tetralogy of Fallot

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Digilio, M.C.; Marino, B.; Giannotti, A. [Bambino Gesu Hospital, Rome (Italy); Dallapiccola, B. [Univ. of Tor Vergata, Rome (Italy)]|[Casa Sollievo Sofferenza Hospital, San Giovanni Rotondo (Italy)

1996-04-24

We read with interest the report of Robin et al. [1995] published in recent issue of the Journal. The authors described 6 patients with Noonan syndrome (NS) who underwent molecular evaluation for submicroscopic deletion of chromosome band 22q11. None of those patients presented with conotruncal heart defects. Evidence for 22q11 hemizygosity was demonstrated in only one patient. This patient had NS-like manifestations without clinical manifestations of DiGeorge (DG) or velo-cardio-facial (VCF) syndromes. The molecular results obtained in the other 5 patients led the authors to conclude that classical NS is not due to del(22)(q11), even if some patients with del(22)(q11) may present NS-like manifestations. 12 refs., 1 tab.

Association of HLA Class I and Class II genes with bcr-abl transcripts in leukemia patients with t(9;22 (q34;q11

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Cano Pedro

2004-06-01

Full Text Available Abstract Background Based on the site of breakpoint in t(9;22 (q34;q11, bcr-abl fusion in leukemia patients is associated with different types of transcript proteins. In this study we have seen the association of HLA genes with different types of bcr-abl transcripts. The association could predict the bcr-abl peptide presentation by particular HLA molecules. Methods The study included a total of 189 patients of mixed ethnicity with chronic myelogenous leukemia and acute lymphocytic leukemia who were being considered for bone marrow transplantation. Typing of bcr-abl transcripts was done by reverse transcriptase PCR method. HLA typing was performed by molecular methods. The bcr-abl and HLA association was studied by calculating the relative risks and chi-square test. Results Significant negative associations (p Conclusions The negative associations of a particular bcr-abl transcript with specific HLA alleles suggests that these alleles play a critical role in presenting peptides derived from the chimeric proteins and eliciting a successful T-cell cytotoxic response. Knowledge of differential associations between HLA phenotypes and bcr-abl fusion transcript types would help in developing better strategies for immunization with the bcr-abl peptides against t(9;22 (q34;q11-positive leukemia.

Four novel Loci (19q13, 6q24, 12q24, and 5q14 influence the microcirculation in vivo.

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M Kamran Ikram

2010-10-01

Full Text Available There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652. All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP spread across five loci were significantly associated (p<5.0×10(-8 with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25, within the RASIP1 locus, rs225717 (6q24; p = 1.25×10(-16, adjacent to the VTA1 and NMBR loci, rs10774625 (12q24; p  =  2.15×10(-13, in the region of ATXN2,SH2B3 and PTPN11 loci, and rs17421627 (5q14; p = 7.32×10(-16, adjacent to the MEF2C locus. In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular

A rare balanced nonrobertsonian translocation involving acrocentric chromosomes: Chromosome abnormality of t(13;15(p11.2;q22.1

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Dalvi Rupa

2016-01-01

Full Text Available BACKGROUND: Balanced non-robertsonian translocation (RT, involving acrocentric chromosomes, is a rare event and only a few cases are reported. Most of the RTs are balanced involving acrocentric chromosomes with the breakpoints (q10;q10. MATERIALS AND METHODS: Chromosome analysis was performed as per standard procedure – Giemsa-trypsin banding with 500 band resolution was analyzed for chromosome identification. RESULTS: In the present study, we report a rare balanced non-RTs involving chromosomes 13 and 15 with cytogenetic finding of 46, XX, t(13;15(p11.2;q22.1. CONCLUSION: To the best of our knowledge, this is the first such report of an unusual non-RT of t(13:15 with (p11.2;q22.1 break points.

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements.

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Demaerel, Wolfram; Hestand, Matthew S; Vergaelen, Elfi; Swillen, Ann; López-Sánchez, Marcos; Pérez-Jurado, Luis A; McDonald-McGinn, Donna M; Zackai, Elaine; Emanuel, Beverly S; Morrow, Bernice E; Breckpot, Jeroen; Devriendt, Koenraad; Vermeesch, Joris R

2017-10-05

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A-D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A-B 22q11.2 deletion carry inversions of LCR22B-D or LCR22C-D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders. Copyright © 2017. Published by Elsevier Inc.

Translocation t(11;14 (q13;q32 and genomic imbalances in multi-ethnic multiple myeloma patients: a Malaysian study

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Ivyna Bong Pau Ni

2012-09-01

Full Text Available More than 50% of myeloma cases have normal karyotypes under conventional cytogenetic analysis due to low mitotic activity and content of plasma cells in the bone marrow. We used a polymerase chain reaction (PCR-based translocation detection assay to detect BCL1/JH t(11;14 (q13;q32 in 105 myeloma patients, and randomly selected 8 translocation positive samples for array comparative genomic hybridization (aCGH analysis. Our findings revealed 14.3% of myeloma samples were positive for BCL1/JH t(11;14 (q13;q32 translocation (n=15 of 105. We found no significant correlation between this translocation with age (P=0.420, gender (P=0.317, ethnicity (P=0.066 or new/relapsed status of multiple myeloma (P=0.412 at 95% confidence interval level by x2 test. In addition, aCGH results showed genomic imbalances in all samples analyzed. Frequent chromosomal gains were identified at regions 1q, 2q, 3p, 3q, 4p, 4q, 5q, 7q, 9q, 11q, 13q, 15q, 21q, 22q and Xq, while chromosomal losses were detected at 4q and 14q. Copy number variations at genetic loci that contain NAMPT, IVNS1ABP and STK17B genes are new findings that have not previously been reported in myeloma patients. Besides fluorescence in situ hybridization, PCR is another rapid, sensitive and simple technique that can be used for detecting BCL1/JH t(11;14(q13;q32 translocation in multiple myeloma patients. Genes located in the chromosomal aberration regions in our study, such as NAMPT, IVNS1ABP, IRF2BP2, PICALM, STAT1, STK17B, FBXL5, ACSL1, LAMP2, SAMSN1 and ATP8B4 might be potential prognostic markers and therapeutic targets in the treatment and management of multiple myeloma patients positive for BCL1/JH t(11;14 (q13;q32 translocation.

A Rare Interstitial Duplication of 8q22.1–8q24.3 Associated with Syndromic Bilateral Cleft Lip/Palate

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Regina Ferreira Rezek

2014-01-01

Full Text Available We present a rare case of 8q interstitial duplication derived from maternal balanced translocations in a patient with bilateral cleft lip and palate in syndromic form associated with other congenital malformations. G-banding cytogenetic analysis revealed a chromosomal abnormality in the form of the karyotype 46,XX der(22t(8;22(q22.1;p11.1mat. Chromosome microarray analysis evidenced a 49 Mb duplicated segment of chromosome 8q with no pathogenic imbalances on chromosome 22. Two siblings also carry the balanced translocation. We have compared this case with other “pure” trisomies of 8q patients reported in the literature and with genome wide association studies recently published. This work highlights the involvement of chromosome 8q in orofacial clefts.

A patient with de-novo partial deletion of Xp (p11.4-pter) and partial duplication of 22q (q11.2-qter).

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Armour, Christine M; McGowan-Jordan, Jean; Lawrence, Sarah E; Bouchard, Amélie; Basik, Mark; Allanson, Judith E

2008-01-01

We report on a girl with partial deletion of Xp and partial duplication of 22q. Family studies demonstrate that both the patient's mother and her nonidentical twin sister carry the corresponding balanced translocation; 46,X,t(X;22)(p11.4;q11.2). This girl has developmental delay, microcephaly, mild dysmorphisms and hearing loss but otherwise shows few of the features described in individuals with duplications of the long arm of chromosome 22. She does manifest characteristics, such as short stature and biochemical evidence of ovarian failure, which are seen in partial or complete Xp deletions and Turner's syndrome.

Constitutional chromosomal events at 22q11 and 15q26 in a child with a pilocytic astrocytoma of the spinal cord.

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Mascelli, Samantha; Severino, Mariasavina; Raso, Alessandro; Nozza, Paolo; Tassano, Elisa; Morana, Giovanni; De Marco, Patrizia; Merello, Elisa; Milanaccio, Claudia; Pavanello, Marco; Rossi, Andrea; Cama, Armando; Garrè, Maria Luisa; Capra, Valeria

2014-01-01

We report on a 9-years-old patient with mild intellectual disability, facial dimorphisms, bilateral semicircular canal dysplasia, periventricular nodular heterotopias, bilateral hippocampal malrotation and abnormal cerebellar foliation, who developed mild motor impairment and gait disorder due to a pilocytic astrocytoma of the spinal cord. Array-CGH analysis revealed two paternal inherited chromosomal events: a 484.3 Kb duplication on chromosome 15q26.3 and a 247 Kb deletion on 22q11.23. Further, a second de novo 1.5 Mb deletion on 22q11.21 occurred. Chromosome 22 at q11.2 and chromosome 15 at q24q26 are considered unstable regions subjected to copy number variations, i.e. structural alterations of genome, mediated by low copy repeat sequences or segmental duplications. The link between some structural CNVs, which compromise fundamental processes controlling DNA stability, and genomic disorders suggest a plausible scenario for cancer predisposition. Evaluation of the genes at the breakpoints cannot account simultaneously for the phenotype and tumour development in this patient. The two paternal inherited CNVs arguably are not pathogenic and do not contribute to the clinical manifestations. Similarly, although the de novo large deletion at 22q11.21 overlaps with the Di George (DGS) critical region and results in haploinsufficiency of genes compromising critical processes for DNA stability, this case lacks several hallmarks of DGS.

Psychopathology and cognition in children with 22q11.2 deletion syndrome

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Niarchou, Maria; Zammit, Stanley; van Goozen, Stephanie H. M.; Thapar, Anita; Tierling, Hayley M.; Owen, Michael J.; van den Bree, Marianne B. M.

2014-01-01

Background Children with 22q11.2 deletion syndrome (22q11.2DS) have been reported to have high rates of cognitive and psychiatric problems. Aims To establish the nature and prevalence of psychiatric disorder and neurocognitive impairment in children with 22q11.2DS and test whether risk of psychopathology is mediated by the children’s intellectual impairment. Method Neurocognition and psychopathology were assessed in 80 children with 22q11.2DS (mean age 10.2 years, s.d. = 2.1) and 39 sibling controls (mean age 10.9 years, s.d. = 2.0). Results More than half (54%) of children with 22q11.2DS met diagnostic criteria for one or more DSM-IV-TR psychiatric disorder. These children had lower IQ (mean 76.8, s.d. = 13.0) than controls (mean 108.6, s.d. = 15.2) (Ppsychopathology was not mediated by intellectual impairment. Conclusions 22q11.2DS is not related to a specific psychiatric phenotype in children. Moreover, the deletion has largely independent effects on IQ and risk of psychopathology, indicating that psychopathology in 22q11.2DS is not a non-specific consequence of generalised cognitive impairment. PMID:24115343

The dimensional structure of psychopathology in 22q11.2 Deletion Syndrome.

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Niarchou, Maria; Moore, Tyler M; Tang, Sunny X; Calkins, Monica E; McDonald-McGuinn, Donna M; Zackai, Elaine H; Emanuel, Beverly S; Gur, Ruben C; Gur, Raquel E

2017-09-01

22q11.2 Deletion Syndrome (22q11.2DS) is one of the strongest known genetic risk factors for developing schizophrenia. Individuals with 22q11.2DS have high rates of neurodevelopmental disorders in childhood, while in adulthood ∼25% develop schizophrenia. Similar to the general population, high rates of comorbidity are common in 22q11.2DS. Employing a dimensional approach where psychopathology is examined at the symptom-level as complementary to diagnostic categories in a population at such high genetic risk for schizophrenia can help gain a better understanding of how psychopathology is structured as well as its genetic underpinnings. This is the first study to examine the dimensional structure of a wide spectrum of psychopathology in the context of a homogeneous genetic etiology like 22q11.2DS. We evaluated 331 individuals with 22q11.2DS, mean age (SD) = 16.9(8.7); 51% males, who underwent prospective comprehensive phenotyping. We sought to replicate previous findings by examining a bi-factor model that derives a general factor of psychopathology in addition to more specific dimensions of psychopathology (i.e., internalizing, externalizing and thought disorder). Psychopathology in 22q11.2DS was divided into one 'general psychopathology' factor and four specific dimensions (i.e., 'anxiety', 'mood', 'ADHD' and 'psychosis'). The 'psychosis' symptoms loaded strongly on the 'general psychopathology' factor. The similarity of the symptom structure of psychopathology between 22q11.2DS and community and clinical populations without the deletion indicate that 22q11.2DS can provide a model to explore alternative approaches to our current nosology. Our findings add to a growing literature indicating the need to reorganize current diagnostic classification systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

[22q11.2DS Syndrome as a Genetic Subtype of Schizophrenia].

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Huertas-Rodríguez, Cindy Katherin; Payán-Gómez, César; Forero-Castro, Ruth Maribel

2015-01-01

The 22q11.2 deletion syndrome (22q11.2DS) is associated with the microdeletion of this chromosomal region, and represents the second most common genetic syndrome after Down's syndrome. In patients with schizophrenia, 22q11.2DS has a prevalence of 2%, and in selected groups can be increased to between 32-53%. To describe the generalities of 22q11.2DS syndrome as a genetic subtype of schizophrenia, its clinical characteristics, molecular genetic aspects, and frequency in different populations. A review was performed from 1967 to 2013 in scientific databases, compiling articles about 22q11.2DS syndrome and its association with schizophrenia. The 22q11.2 DS syndrome has a variable phenotype associated with other genetic syndromes, birth defects in many tissues and organs, and a high rate of psychiatric disorders, particularly schizophrenia. Likewise, it has been identified in clinical populations with schizophrenia selected by the presence of common syndromic characteristics. FISH, qPCR and MLPA techniques, and recently, aCGH and NGS technologies, are being used to diagnose this microdeletion. It is important in clinical practice to remember that people suffering the 22q11.2DS have a high genetic risk for developing schizophrenia, and it is considered that the simultaneous presence of this disease and 22q11.2DS represents a genetic subtype of schizophrenia. There are clear phenotypic criteria, molecular and cytogenetic methods to diagnose this group of patients, and to optimize a multidisciplinary approach in their monitoring. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Neurocognitive profile in psychotic versus nonpsychotic individuals with 22q11.2 deletion syndrome.

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Weinberger, Ronnie; Yi, James; Calkins, Monica; Guri, Yael; McDonald-McGinn, Donna M; Emanuel, Beverly S; Zackai, Elaine H; Ruparel, Kosha; Carmel, Miri; Michaelovsky, Elena; Weizman, Abraham; Gur, Ruben C; Gur, Raquel E; Gothelf, Doron

2016-10-01

The 22q11.2 deletion syndrome (22q11DS) is associated with increased rates of psychotic disorders and cognitive deficits, but large scale studies are needed to elucidate their interaction. The objective of this two-center study was to identify the neurocognitive phenotype of individuals with 22q11DS and psychotic disorders. We hypothesized that psychotic 22q11DS individuals compared to nonpsychotic deleted individuals would have more severe neurocognitive deficits, especially in executive function and social cognition. These deficits would be present when compared to IQ- matched individuals with Williams Syndrome (WS). Three groups were ascertained from the Tel Aviv and Philadelphia centers: 22q11DS individuals with a psychotic disorder (n=31), nonpsychotic 22q11DS (n=86) and typically-developing controls (TD, n=828). In Tel Aviv a group of individuals with WS (n=18) matched in IQ to the 22q11DS psychotic group was also included. The Penn Computerized Neurocognitive Battery (CNB) was used to assess a wide-range of cognitive functions and all patients underwent structured psychiatric evaluations. 22q11DS individuals performed poorly on all CNB domains compared to TD. Participants with 22q11DS and psychosis, compared to nonpsychotic 22q11DS, had more severe deficits in global neurocognitive performance (GNP), executive function, social cognition and episodic memory domains. The primary deficits were also significant when comparing the Tel Aviv 22q11DS psychotic group to IQ-matched individuals with WS. In conclusion, 22q11DS individuals with a psychotic disorder have specific neurocognitive deficits that are reliably identified cross nationality using the CNB. These cognitive dysfunctions should be further studied as potential endophenotypes of psychosis in 22q11DS and as targets for intervention. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Constitutional 11q14-q22 chromosome deletion syndrome in a child with neuroblastoma MYCN single copy.

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Passariello, Annalisa; De Brasi, Daniele; Defferrari, Raffaella; Genesio, Rita; Tufano, Maria; Mazzocco, Katia; Capasso, Maria; Migliorati, Roberta; Martinsson, Tommy; Siani, Paolo; Nitsch, Lucio; Tonini, Gian Paolo

2013-11-01

Constitutional 11q deletion is a chromosome imbalance possibly found in MCA/MR patients analyzed for chromosomal anomalies. Its role in determining the phenotype depends on extension and position of deleted region. Loss of heterozygosity of 11q (region 11q23) is also associated with neuroblastoma, the most frequent extra cranial cancer in children. It represents one of the most frequent cytogenetic abnormalities observed in the tumor of patients with high-risk disease even if germline deletion of 11q in neuroblastoma is rare. Hereby, we describe a 18 months old girl presenting with trigonocephaly and dysmorphic facial features, including hypotelorism, broad depressed nasal bridge, micrognathia, synophrys, epicanthal folds, and with a stage 4 neuroblastoma without MYCN amplification, carrying a germline 11q deletion (11q14.1-q22.3), outside from Jacobsen syndrome and from neuroblastoma 11q critical regions. The role of 11q deletion in determining the clinical phenotype and its association with neuroblastoma development in the patient are discussed. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Chromosome 12q24.31-q24.33 deletion causes multiple dysmorphic features and developmental delay: First mosaic patient and overview of the phenotype related to 12q24qter defects

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Sakati Nadia

2011-04-01

Full Text Available Abstract Background Genomic imbalances of the 12q telomere are rare; only a few patients having 12q24.31-q24.33 deletions were reported. Interestingly none of these were mosaic. Although some attempts have been made to establish phenotype/genotype interaction for the deletions in this region, no clear relationship has been established to date. Results We have clinically screened more than 100 patients with dysmorphic features, mental retardation and normal karyotype using high density oligo array-CGH (aCGH and identified a ~9.2 Mb hemizygous interstitial deletion at the 12q telomere (Chromosome 12: 46,XY,del(12(q24.31q24.33 in a severely developmentally retarded patient having dysmorphic features such as low set ears, microcephaly, undescended testicles, bent elbow, kyphoscoliosis, and micropenis. Parents were found to be not carriers. MLPA experiments confirmed the aCGH result. Interphase FISH revealed mosaicism in cultured peripheral blood lymphocytes. Conclusions Since conventional G-Banding technique missed the abnormality; this work re-confirms that any child with unexplained developmental delay and systemic involvement should be studied by aCGH techniques. The FISH technique, however, would still be useful to further delineate the research work and identify such rare mosaicism. Among the 52 deleted genes, P2RX2, ULK1, FZD10, RAN, NCOR2 STX2, TESC, FBXW8, and TBX3 are noteworthy since they may have a role in observed phenotype.

The cognitive development of children with the 22q11.2 deletion syndrome

NARCIS (Netherlands)

Duijff, S.N.

2012-01-01

Background: The 22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with palatal abnormalities, cardiac defects and characteristic facial features. On a behavioural/ psychiatric level, children with 22q11DS are at an increased risk for various psychiatric problems, including Autism

Neural correlates of reward processing in adults with 22q11 deletion syndrome

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van Duin, Esther D. A.; Goossens, Liesbet; Hernaus, Dennis; da Silva Alves, Fabiana; Schmitz, Nicole; Schruers, Koen; van Amelsvoort, Therese

2016-01-01

Background: 22q11.2 deletion syndrome (22q11DS) is caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk to develop psychosis. The gene coding for catechol-O-methyl-transferase (COMT) is located at the deleted region, resulting in disrupted dopaminergic

Referential communication abilities in children with 22q11.2 deletion syndrome.

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Van Den Heuvel, Ellen; ReuterskiöLd, Christina; Solot, Cynthia; Manders, Eric; Swillen, Ann; Zink, Inge

2017-10-01

This study describes the performance on a perspective- and role-taking task in 27 children, ages 6-13 years, with 22q11.2 deletion syndrome (22q11.2DS). A cross-cultural design comparing Dutch- and English-speaking children with 22q11.2DS explored the possibility of cultural differences. Chronologically age-matched and younger typically developing (TD) children matched for receptive vocabulary served as control groups to identify challenges in referential communication. The utterances of children with 22q11.2DS were characterised as short and simple in lexical and grammatical terms. However, from a language use perspective, their utterances were verbose, ambiguous and irrelevant given the pictured scenes. They tended to elaborate on visual details and conveyed off-topic, extraneous information when participating in a barrier-game procedure. Both types of aberrant utterances forced a listener to consistently infer the intended message. Moreover, children with 22q11.2DS demonstrated difficulty selecting correct speech acts in accordance with contextual cues during a role-taking task. Both English- and Dutch-speaking children with 22q11.2DS showed impoverished information transfer and an increased number of elaborations, suggesting a cross-cultural syndrome-specific feature.

HELICOBACTER PYLORI AND t(11;18(q21;q21 TRANSLOCATION IN GASTRIC MALT LYMPHOMA

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Karine Sampaio LIMA

2014-04-01

Full Text Available Context Gastric mucosa-associated lymphoid tissue (MALT lymphoma is clearly associated with Helicobacter pylori gastritis and can be cured with anti- H pylori therapy alone. The presence of t(11;18(q21;q21 translocation is thought to predict a lower response rate to anti- H pylori treatment. Objectives To study the presence of t(11;18(q21;q21 genetic translocation and its clinical impact in low-grade gastric MALT lymphoma Brazilian patients. Methods A consecutive series of eight patients with gastric MALT lymphoma were submitted to gastroscopy, endoscopic ultrasound, histopathological examination, H pylori search and RT-PCR-based methodology. All patients received anti-H pylori treatment. Eradicated patients were followed-up every 3-6 months for 2 years. Results Eight patients were studied. All patients had tumor involvement restricted to the mucosa or submucosa and seven patients had low-grade gastric MALT lymphoma. All infected patients achieved H pylori eradication. Histological tumor regression was observed in 5/7 (71% of the low-grade gastric MALT lymphoma patients. The presence of t(11;18(q21;q21 translocation was found in 4 (57% of these patients; among them only two had histological tumor regression following H pylori eradication. Conclusions RT-PCR is a feasible and efficient method to detect t(11;18(q21;q21 translocation, being carried out in routine molecular biology laboratories. The early detection of such translocation can be very helpful for better targeting the therapy to be applied to gastric MALT lymphoma patients.

Heart defects and other features of the 22q11 distal deletion syndrome

DEFF Research Database (Denmark)

Fagerberg, Christina Ringmann; Graakjaer, Jesper; Heinl, Ulrike D

2013-01-01

patients with 22q11 distal deletions, of whom two have complex congenital heart malformation, thus broadening the phenotypic spectrum. We compare cardiac malformations reported in 22q11 distal deletion to those reported in the common 22q11 deletion syndrome. We also review the literature for patients...... with 22q11 distal deletions, and discuss the possible roles of haploinsufficiency of the MAPK1 gene. We find the most frequent features in 22q11 distal deletion to be developmental delay or learning disability, short stature, microcephalus, premature birth with low birth weight, and congenital heart...... malformation ranging from minor anomalies to complex malformations. Behavioral problems are also seen in a substantial portion of patients. The following dysmorphic features are relatively common: smooth philtrum, abnormally structured ears, cleft palate/bifid uvula, micro-/retrognathia, upslanting palpebral...

Tetralogy of Fallot associated with deletion in the DiGeorge region of chromosome 22 (22q11)

Energy Technology Data Exchange (ETDEWEB)

D`Angelo, J.A.; Pillers, D.M.; Jett, P.L. [Oregon Health Sciences Univ. Portland, OR (United States)] [and others

1994-09-01

Cardiac conotruncal defects, such as Tetralogy of Fallot (TOF), are associated with DiGeorge syndrome which has been mapped to the q11 region of chromosome 22 and includes abnormalities of neural crest and branchial arch development. Patients with conotruncal defects and velo-cardio-facial syndrome may have defects in the 22q11 region but not show the complete DiGeorge phenotype consisting of cardiac, thymus, and parathyroid abnormalities. We report two neonates with TOF and small deletions in the DiGeorge region of chromosome 22 (46,XX,del(22)(q11.21q11.23) and 46,XY,del(22)(q11.2q11.2)) using both high-resolution cytogenetics and fluorescence in situ hybridization (FISH). The first patient is a female with TOF and a family history of congenital heart disease. The mother has pulmonic stenosis and a right-sided aortic arch, one brother has TOF, and a second brother has a large VSD. The patient had intrauterine growth retardation and had thrombocytopenia due to maternal IgG platelet-directed autoantibody. Lymphocyte populations, both T and B cells, were reduced in number but responded normally to stimulation. The findings were not attributed to a DiGeorge phenotype. Although she had transient neonatal hypocalcemia, her parathyroid hormone level was normal. The patient was not dysmorphic in the newborn period but her mother had features consistent with velo-cardio-facial syndrome. The second patient was a male with TOF who was not dysmorphic and had no other significant clinical findings and no family history of heart disease. Lymphocyte testing did not reveal a specific immunodeficiency. No significant postnatal hypocalcemia was noted. These cases illustrate that there is a wide spectrum of clinical features associated with defects of the 22q11 region. We recommend karyotype analysis, including FISH probes specific to the DiGeorge region, in any patient with conotruncal cardiac defects.

[Grave's disease in children with 22q11 deletion. Report of three cases].

Science.gov (United States)

Gosselin, J; Lebon-Labich, B; Lucron, H; Marçon, F; Leheup, B

2004-12-01

Hypothyroidism is a well recognized complication of 22q11.2 deletion syndrome. Auto-immune hyperthyroidism is less common. We report three patients with a 22q11.2 deletion and Graves' disease diagnosed at age 17, 14 and 11 years, respectively. The clinical and biological presentation was typical for auto-immune hyperthyroidism. Graves' disease should be periodically sought during the follow-up program of patients with 22q11.2 deletion syndrome.

The Danish 22q11 research initiative

DEFF Research Database (Denmark)

Schmock, Henriette; Vangkilde, Anders; Larsen, Kit Melissa

2015-01-01

mechanisms may come from studies of subjects with homogenous etiologies. Breakthroughs in psychiatric genetics have shown that several genetic anomalies predispose for neurodevelopmental brain disorders. We have established a Danish research initiative to study the common microdeletion at chromosome 22q11...

Altered auditory processing and effective connectivity in 22q11.2 deletion syndrome.

Science.gov (United States)

Larsen, Kit Melissa; Mørup, Morten; Birknow, Michelle Rosgaard; Fischer, Elvira; Hulme, Oliver; Vangkilde, Anders; Schmock, Henriette; Baaré, William Frans Christiaan; Didriksen, Michael; Olsen, Line; Werge, Thomas; Siebner, Hartwig R; Garrido, Marta I

2018-01-30

22q11.2 deletion syndrome (22q11.2DS) is one of the most common copy number variants and confers a markedly increased risk for schizophrenia. As such, 22q11.2DS is a homogeneous genetic liability model which enables studies to delineate functional abnormalities that may precede disease onset. Mismatch negativity (MMN), a brain marker of change detection, is reduced in people with schizophrenia compared to healthy controls. Using dynamic causal modelling (DCM), previous studies showed that top-down effective connectivity linking the frontal and temporal cortex is reduced in schizophrenia relative to healthy controls in MMN tasks. In the search for early risk-markers for schizophrenia we investigated the neural basis of change detection in a group with 22q11.2DS. We recorded high-density EEG from 19 young non-psychotic 22q11.2 deletion carriers, as well as from 27 healthy non-carriers with comparable age distribution and sex ratio, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Despite finding no significant reduction in the MMN responses, whole-scalp spatiotemporal analysis of responses to the tones revealed a greater fronto-temporal N1 component in the 22q11.2 deletion carriers. DCM showed reduced intrinsic connection within right primary auditory cortex as well as in the top-down, connection from the right inferior frontal gyrus to right superior temporal gyrus for 22q11.2 deletion carriers although not surviving correction for multiple comparison. We discuss these findings in terms of reduced adaptation and a general increased sensitivity to tones in 22q11.2DS. Copyright © 2018. Published by Elsevier B.V.

Behavioral phenotype in children with 22q11Ds : Agreement between parents and teachers

NARCIS (Netherlands)

Klaassen, Petra W J; Duijff, Sasja N.; Sinnema, Gerben; Beemer, Frits A.; Swanenburg de Veye, Henriëtte F N; Vorstman, Jacob A S

2015-01-01

Patients with the 22q11-deletion syndrome (22q11DS) are at an increased risk of developing schizophrenia. Besides the effects of genetic variation, environmental factors could also be important in modifying the risk of schizophrenia in 22q11DS patients. In particular, previous studies have shown the

A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population.

Science.gov (United States)

Entesarian, Miriam; Carlsson, Birgit; Mansouri, Mahmoud Reza; Stattin, Eva-Lena; Holmberg, Eva; Golovleva, Irina; Stefansson, Hreinn; Klar, Joakim; Dahl, Niklas

2009-03-01

We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four non-related Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden. 2009 Wiley-Liss, Inc.

Association of HLA Class I and Class II genes with bcr-abl transcripts in leukemia patients with t(9;22) (q34;q11)

International Nuclear Information System (INIS)

Mundhada, Shailendra; Luthra, Rajyalakshmi; Cano, Pedro

2004-01-01

Based on the site of breakpoint in t(9;22) (q34;q11), bcr-abl fusion in leukemia patients is associated with different types of transcript proteins. In this study we have seen the association of HLA genes with different types of bcr-abl transcripts. The association could predict the bcr-abl peptide presentation by particular HLA molecules. The study included a total of 189 patients of mixed ethnicity with chronic myelogenous leukemia and acute lymphocytic leukemia who were being considered for bone marrow transplantation. Typing of bcr-abl transcripts was done by reverse transcriptase PCR method. HLA typing was performed by molecular methods. The bcr-abl and HLA association was studied by calculating the relative risks and chi-square test. Significant negative associations (p < 0.05) were observed with HLA-A*02 (b2a2, e1a2), -A*68 (b2a2, b3a2, e1a2), -B*14 (b2a2, b3a2, e1a2), -B*15 (b2a2, b3a2), -B*40 (b2a2), -DQB1*0303 (b2a2, b3a2), -DQB1*0603 (b2a2), -DRB1*0401 (e1a2), -DRB1*0701 (b3a2), and -DRB1*1101 (b2a2). The negative associations of a particular bcr-abl transcript with specific HLA alleles suggests that these alleles play a critical role in presenting peptides derived from the chimeric proteins and eliciting a successful T-cell cytotoxic response. Knowledge of differential associations between HLA phenotypes and bcr-abl fusion transcript types would help in developing better strategies for immunization with the bcr-abl peptides against t(9;22) (q34;q11)-positive leukemia

Chromosome 15q24 microdeletion syndrome

Directory of Open Access Journals (Sweden)

Magoulas Pilar L

2012-01-01

Full Text Available Abstract Chromosome 15q24 microdeletion syndrome is a recently described rare microdeletion syndrome that has been reported in 19 individuals. It is characterized by growth retardation, intellectual disability, and distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems. Other less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity. Congenital malformations, while rare, can be severe and include structural brain anomalies, cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele. Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH. The deletions range in size from 1.7-6.1 Mb and usually result from nonallelic homologous recombination (NAHR between paralogous low-copy repeats (LCRs. The majority of 15q24 deletions have breakpoints that localize to one of five LCR clusters labeled LCR15q24A, -B, -C, -D, and -E. The smallest region of overlap (SRO spans a 1.2 Mb region between LCR15q24B to LCR15q24C. There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome. The deletion occurred as a de novo event in all of the individuals when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling and guidance regarding prognosis, recurrence risk, and reproductive options. Management

Characterization of a recurrent t(1;2)(p36;p24) in human uterine leiomyoma.

NARCIS (Netherlands)

Rijk, A. van; Sweers, M.A.; Huys, E.; Kersten, M.; Merkx, G.F.M.; Geurts van Kessel, A.H.M.; Debiec-Rychter, M.; Schoenmakers, E.F.P.M.

2009-01-01

Uterine leiomyomas are the most common neoplasms in women of reproductive age. Approximately 40% of these neoplasms show recurring structural cytogenetic anomalies, including del(7)(q22), t(12;14)(q15;q24), t(1;2)(p36;p24), and anomalies affecting 6p21 or 10q22. Using positional cloning strategies,

Chromosomal amplifications, 3q gain and deletions of 2q33-q37 are the frequent genetic changes in cervical carcinoma

International Nuclear Information System (INIS)

Rao, Pulivarthi H; Murty, Vundavalli VVS; Arias-Pulido, Hugo; Lu, Xin-Yan; Harris, Charles P; Vargas, Hernan; Zhang, Fang F; Narayan, Gopeshwar; Schneider, Achim; Terry, Mary Beth

2004-01-01

Carcinoma of uterine cervix is the second most common cancers among women worldwide. Combined radiation and chemotherapy is the choice of treatment for advanced stages of the disease. The prognosis is poor, with a five-year survival rate ranging from about 20–65%, depending on stage of the disease. Therefore, genetic characterization is essential for understanding the biology and clinical heterogeneity in cervical cancer (CC). We used a genome-wide screening method – comparative genomic hybridization (CGH) to identify DNA copy number changes in 77 patients with cervical cancer. We applied categorical and survival analyses to analyze whether chromosomal changes were related to clinico-pathologic characteristics and patients survival. The CGH analysis revealed a loss of 2q33-q37 (57.1%), gain of 3q (54.5%) and chromosomal amplifications (20.77%) as frequent genetic changes. A total of 15 amplified chromosomal sites were detected in 16 cases that include 1p31, 2q32, 7q22, 8q21.2-q24, 9p22, 10q21, 10q24, 11q13, 11q21, 12q15, 14q12, 17p11.2, 17q22, 18p11.2, and 19q13.1. Recurrent amplified sites were noted at 11q13, 11q21, and 19q13.1. The genomic alterations were further evaluated for prognostic significance in CC patients, and we did not find any correlation with a number of clinical or histological parameters. The tumors harboring HPV18 exhibited higher genomic instability compared to tumors with HPV 16. This study demonstrated that 2q33-q37 deletions, 3q gains and chromosomal amplifications as characteristic changes in invasive CC. These genetic alterations will aid in the identification of novel tumor suppressor gene(s) at 2q33-q37 and oncogenes at amplified chromosomal sites. Molecular characterization of these chromosomal changes utilizing the current genomic technologies will provide new insights into the biology and clinical behavior of CC

Attention Deficit Hyperactivity Disorder Symptoms and Psychosis in 22q11.2 Deletion Syndrome.

Science.gov (United States)

Niarchou, Maria; Calkins, Monica E; Moore, Tyler M; Tang, Sunny X; McDonald-McGinn, Donna M; Zackai, Elaine H; Emanuel, Beverly S; Gur, Ruben C; Gur, Raquel E

2017-10-10

22q11.2 Deletion Syndrome (22q11.2DS) is associated with increased risk for schizophrenia in adulthood while Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent diagnosis in childhood. Inattention symptoms are pronounced in 22q11.2DS and given that attentional impairment is a core feature of schizophrenia, inattention symptoms may reflect underlying ADHD, psychosis, or both. We investigate whether inattention is associated with psychosis in 22q11.2DS and in other groups at risk for psychosis but without the deletion (ND) (idiopathic clinical risk and first degree family members of individuals with schizophrenia). One hundred thirty-seven individuals with 22q11.2DS (mean age: 14.0), 84 ND individuals with subthreshold psychosis (mean age: 16.9) and 31 ND individuals with family history of psychosis (mean age: 17.0) were included in the study. Psychopathology was assessed using research diagnostic assessments. ADHD total symptoms were associated with overall levels of subthreshold psychosis symptoms in 22q11.2DS (β = .8, P = .04). Inattention symptoms were specifically associated with positive (β = .5, P = .004), negative (β = .5, P = .03), and disorganized (β = .5, P hyperactivity-impulsivity symptoms were associated with disorganized symptoms (β = .5, P = .01). The prevalence of ADHD inattention symptoms was higher in 22q11.2DS with subthreshold psychosis compared to ND individuals with subthreshold psychosis (P < .001), even when adjusting for cognitive impairment and overall psychopathology. The pattern was similar when comparing individuals with 22q11.2DS and ND individuals with family history of psychosis. This is the first study to examine the associations between ADHD symptoms and psychosis in 22q11.2DS. Our findings support a potentially important role of ADHD inattention symptoms in psychosis in 22q11.2DS. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights

Children with Chromosome 22q11.2 Deletion Syndrome Exhibit Impaired Spatial Working Memory

Science.gov (United States)

Wong, Ling M.; Riggins, Tracy; Harvey, Danielle; Cabaral, Margarita; Simon, Tony J.

2014-01-01

Individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) have been shown to have impairments in processing spatiotemporal information. The authors examined whether children with 22q11.2DS exhibit impairments in spatial working memory performance due to these weaknesses, even when controlling for maintenance of attention. Children with…

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

NARCIS (Netherlands)

Demaerel, Wolfram; Hestand, Matthew S.; Vergaelen, Elfi; Swillen, Ann; López-Sánchez, Marcos; Pérez-Jurado, Luis A.; McDonald-Mcginn, Donna M.; Zackai, Elaine; Emanuel, Beverly S.; Morrow, Bernice E.; Breckpot, Jeroen; Devriendt, Koenraad; Vermeesch, Joris R.; Antshel, Kevin M.; Arango, Celso; Armando, Marco; Bassett, Anne S.; Bearden, Carrie E.; Boot, Erik; Bravo-Sanchez, Marta; Breetvelt, Elemi; Busa, Tiffany; Butcher, Nancy J.; Campbell, Linda E.; Carmel, Miri; Chow, Eva W C; Crowley, T. Blaine; Cubells, Joseph; Cutler, David; Demaerel, Wolfram; Digilio, Maria Cristina; Duijff, Sasja; Eliez, Stephan; Emanuel, Beverly S.; Epstein, Michael P.; Evers, Rens; Fernandez Garcia-Moya, Luis; Fiksinski, Ania; Fraguas, David; Fremont, Wanda; Fritsch, Rosemarie; Garcia-Minaur, Sixto; Golden, Aaron; Gothelf, Doron; Guo, Tingwei; Gur, Ruben C.; Gur, Raquel E.; Heine-Suner, Damian; Hestand, Matthew; Hooper, Stephen R.; Kates, Wendy R.; Kushan, Leila; Laorden-Nieto, Alejandra; Maeder, Johanna; Marino, Bruno; Marshall, Christian R.; McCabe, Kathryn; McDonald-Mcginn, Donna M.; Michaelovosky, Elena; Morrow, Bernice E.; Moss, Edward; Mulle, Jennifer; Murphy, Declan; Murphy, Kieran C.; Murphy, Clodagh M.; Niarchou, Maria; Ornstein, Claudia; Owen, Michael J; Philip, Nicole; Repetto, Gabriela M.; Schneider, Maude; Shashi, Vandana; Simon, Tony J.; Swillen, Ann; Tassone, Flora; Unolt, Marta; Van Amelsvoort, Therese; van den Bree, Marianne B M; Van Duin, Esther; Vergaelen, Elfi; Vermeesch, Joris R.; Vicari, Stefano; Vingerhoets, Claudia; Vorstman, Jacob; Warren, Steve; Weinberger, Ronnie; Weisman, Omri; Weizman, Abraham; Zackai, Elaine; Zhang, Zhengdong; Zwick, Michael

2017-01-01

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have

Examining the Overlap between Autism Spectrum Disorder and 22q11.2 Deletion Syndrome.

Science.gov (United States)

Ousley, Opal; Evans, A Nichole; Fernandez-Carriba, Samuel; Smearman, Erica L; Rockers, Kimberly; Morrier, Michael J; Evans, David W; Coleman, Karlene; Cubells, Joseph

2017-05-18

22q11.2 deletion syndrome (22q11.2DS) is a genomic disorder reported to associate with autism spectrum disorders (ASDs) in 15-50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD diagnoses. Such wide variability in findings may arise in part due to methodological differences across studies. Our study sought to determine whether individuals with 22q11.2DS meet strict ASD diagnostic criteria using research-based guidelines from the Collaborative Programs of Excellence in Autism (CPEA), which required a gathering of information from three sources: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observational Schedule (ADOS), and a clinician's best-estimate diagnosis. Our study examined a cohort of children, adolescents, and young adults ( n = 56) with 22q11.2DS, who were ascertained irrespective of parents' behavioral or developmental concerns, and found that 17.9% ( n = 10) of the participants met CPEA criteria for an ASD diagnosis, and that a majority showed some level of social-communication impairment or the presence of repetitive behaviors. We conclude that strictly defined ASDs occur in a substantial proportion of individuals with 22q11.2DS, and recommend that all individuals with 22q11.2DS be screened for ASDs during early childhood.

Early onset intellectual disability in chromosome 22q11.2 deletion syndrome.

Science.gov (United States)

Cascella, Marco; Muzio, Maria Rosaria

2015-01-01

Chromosome 22q11.2 deletion syndrome, or DiGeorge syndrome, or velocardiofacial syndrome, is one of the most common multiple anomaly syndromes in humans. This syndrome is commonly caused by a microdelection from chromosome 22 at band q11.2. Although this genetic disorder may reflect several clinical abnormalities and different degrees of organ commitment, the clinical features that have driven the greatest amount of attention are behavioral and developmental features, because individuals with 22q11.2 deletion syndrome have a 30-fold risk of developing schizophrenia. There are differing opinions about the cognitive development, and commonly a cognitive decline rather than an early onset intellectual disability has been observed. We report a case of 22q11.2 deletion syndrome with both early assessment of mild intellectual disabilities and tetralogy of Fallot as the only physic manifestation. Copyright © 2015 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Ocular Findings in Children With 22q11.2 Deletion Syndrome.

Science.gov (United States)

Gokturk, Bahar; Topcu-Yilmaz, Pinar; Bozkurt, Banu; Yildirim, Mahmut Selman; Guner, Sukru Nail; Sayar, Esra Hazar; Reisli, Ismail

2016-07-01

To identify the ocular features of children diagnosed as having 22q11.2 deletion syndrome in a Turkish population, which is the most common microdeletion syndrome with a wide range of facial and ocular abnormalities. Sixteen children aged between 4 months and 18 years with a microdeletion in chromosome 22q11.2 underwent a detailed ophthalmological examination including uncorrected and best corrected visual acuity testing, stereoscopic vision examination, biomicroscopic and indirect fundus examination, and ocular motility testing. All patients had at least one ocular abnormality. The major abnormalities were eyelid abnormalities (eye hooding, narrow palpebral fissure, telecanthus, hypertelorism, sparse and thin eyebrows and eyelashes, blepharitis, and distichiasis), posterior embryotoxon, and tortuous retinal vessels in at least half of the patients. Other ophthalmological disorders were refractive errors, iris remnants, and strabismus. The chromosome 22q11.2 deletion syndrome is associated with a wide range of ocular disorders, which necessitates a comprehensive eye examination for appropriate treatment and follow-up. Ocular findings sometimes can provide a clue to the diagnosis of 22q11.2 deletion. [J Pediatr Ophthalmol Strabismus. 2016;53(4):218-222]. Copyright 2016, SLACK Incorporated.

Transformation of an Unclassified Myeloproliferative Neoplasm with a Rare BCR-JAK2 Fusion Transcript Resulting from the Translocation (9;22)(p24;q11)

OpenAIRE

A. N. Chamseddine; P. Etancelin; D. Penther; F. Parmentier; C. Kuadjovi; V. Camus; N. Contentin; P. Lenain; C. Bastard; H. Tilly; F. Jardin

2015-01-01

BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most...

Platybasia in 22q11.2 Deletion Syndrome Is Not Correlated with Speech Resonance

Directory of Open Access Journals (Sweden)

Nicole E Spruijt

2014-07-01

Full Text Available Background An abnormally obtuse cranial base angle, also known as platybasia, is a common finding in patients with 22q11.2 deletion syndrome (22q11DS. Platybasia increases the depth of the velopharynx and is therefore postulated to contribute to velopharyngeal dysfunction. Our objective was to determine the clinical significance of platybasia in 22q11DS by exploring the relationship between cranial base angles and speech resonance. Methods In this retrospective chart review at a tertiary hospital, 24 children (age, 4.0-13.1 years with 22q11.2DS underwent speech assessments and lateral cephalograms, which allowed for the measurement of the cranial base angles. Results One patient (4% had hyponasal resonance, 8 (33% had normal resonance, 10 (42% had hypernasal resonance on vowels only, and 5 (21% had hypernasal resonance on both vowels and consonants. The mean cranial base angle was 136.5° (standard deviation, 5.3°; range, 122.3-144.8°. The Kruskal-Wallis test showed no significant relationship between the resonance ratings and cranial base angles (P=0.242. Cranial base angles and speech ratings were not correlated (Spearman correlation=0.321, P=0.126. The group with hypernasal resonance had a significantly more obtuse mean cranial base angle (138° vs. 134°, P=0.049 but did not have a greater prevalence of platybasia (73% vs. 56%, P=0.412. Conclusions In this retrospective chart review of patients with 22q11DS, cranial base angles were not correlated with speech resonance. The clinical significance of platybasia remains unknown.

Detection of chromosomal abnormalities and the 22q11 microdeletion in fetuses with congenital heart defects.

Science.gov (United States)

Lv, Wei; Wang, Shuyu

2014-11-01

Chromosomal abnormalities and the 22q11 microdeletion are implicated in congenital heart defects (CHDs). This study was designed to detect these abnormalities in fetuses and determine the effect of genetic factors on CHD etiology. Between January 2010 and December 2011, 113 fetuses with CHD treated at the Beijing Obstetrics and Gynecology Hospital were investigated, using chromosome karyotyping of either amniotic fluid cell or umbilical cord blood cell samples. Fetuses with a normal result were then investigated for the 22q11 microdeletion by fluorescence in situ hybridization. Of the 113 patients, 12 (10.6%) exhibited chromosomal abnormalities, while 6 (5.3%) of the remaining 101 cases presented with a 22q11 microdeletion. The incidence of chromosomal abnormalities was significantly higher in the group of fetuses presenting with extracardiac malformations in addition to CHD (Pheart defects should also be considered for 22q11 microdeletion detection to evaluate fetal prognosis, particularly prior to surgery.

Visual processing deficits in 22q11.2 Deletion Syndrome

Directory of Open Access Journals (Sweden)

Marjan Biria

2018-01-01

The reduced activity of ventral and dorsal visual areas during early stages points to an impairment in visual processing seen both in schizophrenia and 22q11.2DS. During intervals related to perceptual closure, the inverse correlation of high amplitudes with positive symptoms suggests that participants with 22q11.2DS who show an increased brain response to illusory contours during the relevant window for contour processing have less psychotic symptoms and might thus be at a reduced prodromal risk for schizophrenia.

Examining the Overlap between Autism Spectrum Disorder and 22q11.2 Deletion Syndrome

Directory of Open Access Journals (Sweden)

Opal Ousley

2017-05-01

Full Text Available 22q11.2 deletion syndrome (22q11.2DS is a genomic disorder reported to associate with autism spectrum disorders (ASDs in 15–50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD diagnoses. Such wide variability in findings may arise in part due to methodological differences across studies. Our study sought to determine whether individuals with 22q11.2DS meet strict ASD diagnostic criteria using research-based guidelines from the Collaborative Programs of Excellence in Autism (CPEA, which required a gathering of information from three sources: the Autism Diagnostic Interview-Revised (ADI-R, the Autism Diagnostic Observational Schedule (ADOS, and a clinician’s best-estimate diagnosis. Our study examined a cohort of children, adolescents, and young adults (n = 56 with 22q11.2DS, who were ascertained irrespective of parents’ behavioral or developmental concerns, and found that 17.9% (n = 10 of the participants met CPEA criteria for an ASD diagnosis, and that a majority showed some level of social-communication impairment or the presence of repetitive behaviors. We conclude that strictly defined ASDs occur in a substantial proportion of individuals with 22q11.2DS, and recommend that all individuals with 22q11.2DS be screened for ASDs during early childhood.

Association between prematurity and the evolution of psychotic disorders in 22q11.2 deletion syndrome.

Science.gov (United States)

Midbari Kufert, Yael; Nachmani, Ariela; Nativ, Einat; Weizman, Abraham; Gothelf, Doron

2016-12-01

In this study, we report the developmental, physical and psychiatric manifestations of 22q11.2 deletion syndrome (22q11.2DS) in a large Israeli cohort, and search for a possible association between preterm birth and the risk for psychotic disorders. The study population consisted of 128 individuals with 22q11.2DS (77 male, 51 female), aged 1-55 years (mean ± SD 12.9 ± 11.0). All subjects underwent a comprehensive medical evaluation. All subjects older than 5 years (n = 104) were also evaluated psychiatrically. Overall, we found rates of physical manifestations similar to those previously reported in the literature. Psychiatric disorders were very common among our study population, with psychotic disorders occurring in 16.3 % of the psychiatrically evaluated population. We found an association between the presence of psychotic disorders and preterm birth. Our results replicate and extend the findings of a previous work and suggest that the evolution of psychosis in 22q11.2DS is a neurodevelopmental process with early obstetric and medical precursors.

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.

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Bassett, Anne S; Lowther, Chelsea; Merico, Daniele; Costain, Gregory; Chow, Eva W C; van Amelsvoort, Therese; McDonald-McGinn, Donna; Gur, Raquel E; Swillen, Ann; Van den Bree, Marianne; Murphy, Kieran; Gothelf, Doron; Bearden, Carrie E; Eliez, Stephan; Kates, Wendy; Philip, Nicole; Sashi, Vandana; Campbell, Linda; Vorstman, Jacob; Cubells, Joseph; Repetto, Gabriela M; Simon, Tony; Boot, Erik; Heung, Tracy; Evers, Rens; Vingerhoets, Claudia; van Duin, Esther; Zackai, Elaine; Vergaelen, Elfi; Devriendt, Koen; Vermeesch, Joris R; Owen, Michael; Murphy, Clodagh; Michaelovosky, Elena; Kushan, Leila; Schneider, Maude; Fremont, Wanda; Busa, Tiffany; Hooper, Stephen; McCabe, Kathryn; Duijff, Sasja; Isaev, Karin; Pellecchia, Giovanna; Wei, John; Gazzellone, Matthew J; Scherer, Stephen W; Emanuel, Beverly S; Guo, Tingwei; Morrow, Bernice E; Marshall, Christian R

2017-11-01

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

Movement Disorders and Other Motor Abnormalities in Adults With 22q11.2 Deletion Syndrome

Science.gov (United States)

Boot, Erik; Butcher, Nancy J; van Amelsvoort, Thérèse AMJ; Lang, Anthony E; Marras, Connie; Pondal, Margarita; Andrade, Danielle M; Fung, Wai Lun Alan; Bassett, Anne S

2015-01-01

Movement abnormalities are frequently reported in children with 22q11.2 deletion syndrome (22q11.2DS), but knowledge in this area is scarce in the increasing adult population. We report on five individuals illustrative of movement disorders and other motor abnormalities in adults with 22q11.2DS. In addition to an increased susceptibility to neuropsychiatric disorders, seizures, and early-onset Parkinson disease, the underlying brain dysfunction associated with 22q11.2DS may give rise to an increased vulnerability to multiple movement abnormalities, including those influenced by medications. Movement abnormalities may also be secondary to treatable endocrine diseases and congenital musculoskeletal abnormalities. We propose that movement abnormalities may be common in adults with 22q11.2DS and discuss the implications and challenges important to clinical practice. PMID:25684639

Periventricular nodular heterotopia and bilateral intraventricular xanthogranulomas in 22q11.2 deletion syndrome

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Moogeh Baharnoori

2017-09-01

Full Text Available 22q11.2 deletion syndrome (22q11DS is the most common pathogenic copy number variant in humans. Neuropsychiatric phenotypes, including schizophrenia, are prominent. Imaging studies of individuals with this syndrome show a variety of abnormalities that may indicate abnormal neuronal migration. Here we present the neuroimaging and neuropathologic features of a 22q11DS patient with bilateral periventricular nodular heterotopias (PNH and intraventricular xanthogranulomas that were identified by post-mortem examination.

An interictal schizophrenia-like psychosis in an adult patient with 22q11.2 deletion syndrome

OpenAIRE

Yasutaka Tastuzawa; Kanako Sekinaka; Tetsufumi Suda; Hiroshi Matsumoto; Hiroyuki Otabe; Shigeaki Nonoyama; Aihide Yoshino

2015-01-01

In addition to causing polymalformative syndrome, 22q11.2 deletion can lead to various neuropsychiatric disorders including mental retardation, psychosis, and epilepsy. However, few reports regarding epilepsy-related psychosis in 22q11.2 deletion syndrome (22q11.2DS) exist. We describe the clinical characteristics and course of 22q11.2DS in a Japanese patient with comorbid mild mental retardation, childhood-onset localization-related epilepsy, and adult-onset, interictal schizophrenia-like ps...

Multitasking Abilities in Adolescents With 22q11.2 Deletion Syndrome: Results From an Experimental Ecological Paradigm.

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Schneider, Maude; Eliez, Stephan; Birr, Julie; Menghetti, Sarah; Debbané, Martin; Van der Linden, Martial

2016-03-01

The 22q11.2 deletion syndrome (22q11.2DS) is associated with cognitive and functional impairments and increased risk for schizophrenia. We characterized multitasking abilities of adolescents with 22q11.2DS using an experimental naturalistic setting and examined whether multitasking impairments were associated with real-world functioning and negative symptoms. Thirty-nine adolescents (19 with 22q11.2DS and 20 controls) underwent the Multitasking Evaluation for Adolescents. Real-world functioning and clinical symptoms were assessed in participants with 22q11.2DS. Adolescents with 22q11.2DS performed poorly in the multitasking evaluation. Our data also suggest that multitasking abilities are related to adaptive functioning in the practical domain and negative symptoms. This study shows that adolescents with 22q11.2DS are characterized by multitasking impairments, which may be relevant for several aspects of the clinical phenotype.

Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants.

Science.gov (United States)

Swansbury, G J; Slater, R; Bain, B J; Moorman, A V; Secker-Walker, L M

1998-05-01

This paper reports clinical and cytogenetic data from 125 cases with t(9;11)(p21-22;q32) which were accepted for a European Union Concerted Action Workshop on 11q23. This chromosome abnormality is known to occur predominantly in acute myeloid leukemia (AML) FAB type M5a and less often in AML M4; in this series it was also found to occur, uncommonly, in other AML FAB types, in childhood acute lymphoblastic leukemia (ALL) (nine cases), in relatively young patients with myelodysplastic syndrome (MDS) (five cases), acute biphenotypic leukemia (two cases), and acute undifferentiated leukemia (one case). All age groups were represented but 50% of the patients were aged less than 15 years. The t(9;11) was the sole abnormality in 57 cases with AML; trisomy 8 was the most common additional abnormality (23 cases, including seven with further abnormalities), and 28 cases had other additional abnormalities. Among the t(9;11)+ve patients with AML, the white cell count (WBC) and age group were significant predictors of event-free survival; central nervous system (CNS) involvement or karyotype class (sole, with trisomy 8, or with other), also contributed to prognosis although our data could not show these to be independent factors. The best outcome was for patients aged 1-9 years, with low WBC, and with absence of CNS disease or presence of trisomy 8. For patients aged less than 15 years, the event-free survival for ALL patients was not significantly worse than that of AML patients.

Sequence analysis of the MYC oncogene involved in the t(8;14)(q24;q11) chromosome translocation in a human leukemia T-cell line indicates that putative regulatory regions are not altered

International Nuclear Information System (INIS)

Finver, S.N.; Nishikura, K.; Finger, L.R.; Haluska, F.G.; Finan, J.; Nowell, P.C.; Croce, C.M.

1988-01-01

The authors cloned the translocation-associated and homologous normal MYC alleles from SKW-3, a leukemia T-cell line with the t(8; 14)(q24; q11) translocation, and determined the sequence of the MYC oncogene first exon and flanking 5' putative regulatory regions. S1 nuclease protection experiments utilizing a MYC first exon probe demonstrated transcriptional deregulation of the MYC gene associated with the T-cell receptor α locus on the 8q + chromosome of SKW-3 cells. Nucleotide sequence analysis of the translocation-associated (8q +) MYC allele identified a single base substitution within the upstream flanking region; the homologous nontranslocated allele contained an additional substitution and a two-base deletion. None of the deletions or substitutions localized to putative 5' regulatory regions. The MYC first exon sequence was germ line in both alleles. These results demonstrate that alterations within the putative 5' MYC regulatory regions are not necessarily involved in MYC deregulation in T-cell leukemias, and they show that juxtaposition of the T-cell receptor α locus to a germ-line MYC oncogene results in MYC deregulation

22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy.

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Wither, Robert G; Borlot, Felippe; MacDonald, Alex; Butcher, Nancy J; Chow, Eva W C; Bassett, Anne S; Andrade, Danielle M

2017-06-01

Previous studies examining seizures in patients with 22q11.2 deletion syndrome (22q11.2DS) have focused primarily on children and adolescents. In this study we investigated the prevalence and characteristics of seizures and epilepsy in an adult 22q11.2DS population. The medical records of 202 adult patients with 22q11.2DS were retrospectively reviewed for documentation of seizures, electroencephalography (EEG) reports, and magnetic resonance imaging (MRI) findings. Epilepsy status was assigned in accordance with 2010 International League Against Epilepsy Classification. Of 202 patients, 32 (15.8%) had a documented history of seizure. Of these 32, 23 (71.8%) had acute symptomatic seizures, usually associated with hypocalcemia and/or antipsychotic or antidepressant use. Nine patients (9/32, 28%; 9/202, 4%) met diagnostic criteria for epilepsy. Two patients had genetic generalized epilepsy; two patients had focal seizures of unknown etiology; two had epilepsy due to malformations of cortical development; in two the epilepsy was due to acquired structural changes; and in one patient the epilepsy could not be further classified. Similarly to children, the prevalence of epilepsy and acute symptomatic seizures in adults with 22q11.2DS is higher than in the general population. Hypocalcemia continues to be a risk factor for adults, but differently from kids, the main cause of seizures in adults with 22q11.2DS is exposure to antipsychotics and antidepressants. Further prospective studies are warranted to investigate how 22q11.2 microdeletion leads to an overall decreased seizure threshold. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Development of a 22q11DS psycho-educational programme: exploration of the views, concerns and educational needs of parents caring for children or adolescents with 22q11DS in relation to mental health issues.

Science.gov (United States)

Alugo, T; Malone, H; Sheehan, A; Coyne, I; Lawlor, A; McNicholas, F

2017-07-01

22q11.2 deletion syndrome (22q11DS) is a multisystem genetic condition with a broad phenotype. It is associated with a high prevalence of depression and anxiety during childhood and increased risk of schizophrenia in adulthood. Despite this, studies report that families may receive inadequate information of mental health (MH) risks at diagnosis. Therefore, this study investigated parents' experiences of caring for a child with 22q11DS, investigated their knowledge regarding the risk of MH problems and assessed the need for a psycho-educational programme. A qualitative design and purposeful sampling was utilized. Parents registered with the '22q11 Ireland' support group, and parents listed on the cleft palate database in a children's hospital in Ireland were invited to participate. Focus groups were held with 22 parents. Data were thematically analysed using Burnard's method of analysis. Most parents had some knowledge of the relationship between 22q11DS and an increased risk of MH issues. Parents reported that MH information relating to 22q11DS was mainly obtained from 22q11DS conferences, the '22q11 Ireland' support group and the Internet. Parents expressed a need for information to prevent or cope with their child's MH issues. Parents suggested that the following topics would be quite useful in a psycho-educational programme. These included information on the early warning signs of MH issues and guidance on when and how to tell the child about the condition and how to manage the child or young person's anxiety, obsessive behaviour or hearing voices. The findings indicated parental support for a psycho-educational programme that would provide relevant, accurate and timely information on how to effectively care for a child with 22q11DS MH needs. © 2017 John Wiley & Sons Ltd.

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

DEFF Research Database (Denmark)

Delio, Maria; Guo, Tingwei; McDonald-McGinn, Donna M

2013-01-01

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplication...

A novel del(8)(q23.2q24.11) contributing to disease progression in a case of JAK2/TET2 double mutated chronic myelomonocytic leukemia

DEFF Research Database (Denmark)

Toft-Petersen, Marie; Kjeldsen, Eigil; Nederby, Line

2014-01-01

We have identified a novel 7.7 Mb del(8)(q23.2q24.11) in a patient progressing to acute myeloid leukemia (AML) following a 12-year stable phase of chronic myelomonocytic leukemia (CMML). A surprisingly high JAK2+ allelic burden of 92% at the time of AML led us to delineate the molecular aberrations...... relevant for leukemogenesis. While a frameshift mutation in the TET2 gene was stably present throughout the course of disease the JAK2 mutation was acquired after initial diagnosis of CMML. At progression aCGH revealed del(8q)(q23.2q24.11) encompassing various cancer relevant genes of which RAD21 and CSMD3...

Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome

NARCIS (Netherlands)

Vorstman, Jacob A S; Breetvelt, Elemi J.; Duijff, Sasja N.; Eliez, Stephan; Schneider, Maude; Jalbrzikowski, Maria; Armando, Marco; Vicari, Stefano; Shashi, Vandana; Hooper, Stephen R.; Chow, Eva W C; Fung, Wai Lun Alan; Butcher, Nancy J.; Young, Donald A.; McDonald-McGinn, Donna M.; Vogels, Annick; Van Amelsvoort, Therese; Gothelf, Doron; Weinberger, Ronnie; Weizman, Abraham; Klaassen, Petra W J; Koops, Sanne; Kates, Wendy R.; Antshel, Kevin M.; Simon, Tony J.; Ousley, Opal Y.; Swillen, Ann; Gur, Raquel E.; Bearden, Carrie E.; Kahn, René S.; Bassett, Anne S.; Emanuel, Beverly S.; Zackai, Elaine H.; Kushan, Leila; Fremont, Wanda; Schoch, Kelly; Stoddard, Joel; Cubells, Joseph; Fu, Fiona; Campbell, Linda E.; Fritsch, Rosemarie; Vergaelen, Elfi; Neeleman, Marjolein; Boot, Erik; Debbané, Martin; Philip, Nicole; Green, Tamar; Van DenBree, Marianne B M; Murphy, Declan; Canyelles, Jaume Morey; Arango, Celso; Murphy, Kieran C.; Pontillo, Maria

2015-01-01

Importance: Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age.Objective: To determine whether

The interaction between neurocognitive functioning, subthreshold psychotic symptoms and pharmacotherapy in 22q11.2 deletion syndrome: A longitudinal comparative study.

Science.gov (United States)

Weinberger, R; Weisman, O; Guri, Y; Harel, T; Weizman, A; Gothelf, D

2018-02-01

The 22q11.2 deletion syndrome (22q11DS) is the most common genetic syndrome associated with schizophrenia. The goal of this study was to evaluate longitudinally the interaction between neurocognitive functioning, the presence of subthreshold psychotic symptoms (SPS) and conversion to psychosis in individuals with 22q11DS. In addition, we attempted to identify the specific neurocognitive domains that predict the longitudinal evolution of positive and negative SPS, as well as the effect of psychiatric medications on 22q11DS psychiatric and cognitive developmental trajectories. Forty-four participants with 22q11DS, 19 with Williams syndrome (WS) and 30 typically developing (TD) controls, age range 12-35years, were assessed at two time points (15.2±2.1months apart). Evaluation included the Structured Interview for Prodromal Symptoms (SIPS), structured psychiatric evaluation and the Penn Computerized Neurocognitive Battery (CNB). 22q11DS individuals with SPS had a yearly conversion rate to psychotic disorders of 8.8%, compared to none in both WS and TD controls. Baseline levels of negative SPS were associated with global neurocognitive performance (GNP), executive function and social cognition deficits, in individuals with 22q11DS, but not in WS. Deficits in GNP predicted negative SPS in 22q11DS and the emergence or persistence of negative SPS. 22q11DS individuals treated with psychiatric medications showed significant improvement in GNP score between baseline and follow-up assessments, an improvement that was not seen in untreated 22q11DS. Our results highlight the time-dependent interplay among positive and negative SPS symptoms, neurocognition and pharmacotherapy in the prediction of the evolution of psychosis in 22q11DS. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The Development of Cognitive Control in Children with Chromosome 22q11.2 Deletion Syndrome

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Heather M Shapiro

2014-06-01

Full Text Available Chromosome 22q11.2 Deletion Syndrome (22q11.2DS is caused by the most common human microdeletion, and it is associated with cognitive impairments across many domains. While impairments in cognitive control have been described in children with 22q11.2DS, the nature and development of these impairments are not clear. Children with 22q11.2DS and typically developing children (TD were tested on four well-validated tasks aimed at measuring specific foundational components of cognitive control: response inhibition, cognitive flexibility, and working memory. Molecular assays were also conducted in order to examine genotype of catechol-O-methyltransferase (COMT, a gene located within the deleted region in 22q11.2DS and hypothesized to play a role in cognitive control. Mixed model regression analyses were used to examine group differences, as well as age-related effects on cognitive control component processes in a cross-sectional analysis. Regression models with COMT genotype were also conducted in order to examine potential effects of the different variants of the gene. Response inhibition, cognitive flexibility, and working memory were impaired in children with 22q11.2DS relative to TD children, even after accounting for global intellectual functioning (as measured by full-scale IQ. When compared with TD individuals, children with 22q11.2DS demonstrated atypical age-related patterns of response inhibition and cognitive flexibility. Both groups demonstrated typical age-related associations with working memory. The results of this cross-sectional analysis suggest a specific aberration in the development of systems mediating response inhibition in a sub-set of children with 22q11.2DS. It will be important to follow up with longitudinal analyses to directly examine these developmental trajectories, and correlate neurocognitive variables with clinical and adaptive outcome measures.

Frontal dysconnectivity in 22q11.2 deletion syndrome: an atlas-based functional connectivity analysis.

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Mattiaccio, Leah M; Coman, Ioana L; Thompson, Carlie A; Fremont, Wanda P; Antshel, Kevin M; Kates, Wendy R

2018-01-20

22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental syndrome associated with deficits in cognitive and emotional processing. This syndrome represents one of the highest risk factors for the development of schizophrenia. Previous studies of functional connectivity (FC) in 22q11DS report aberrant connectivity patterns in large-scale networks that are associated with the development of psychotic symptoms. In this study, we performed a functional connectivity analysis using the CONN toolbox to test for differential connectivity patterns between 54 individuals with 22q11DS and 30 healthy controls, between the ages of 17-25 years old. We mapped resting-state fMRI data onto 68 atlas-based regions of interest (ROIs) generated by the Desikan-Killany atlas in FreeSurfer, resulting in 2278 ROI-to-ROI connections for which we determined total linear temporal associations between each. Within the group with 22q11DS only, we further tested the association between prodromal symptoms of psychosis and FC. We observed that relative to controls, individuals with 22q11DS displayed increased FC in lobar networks involving the frontal-frontal, frontal-parietal, and frontal-occipital ROIs. In contrast, FC between ROIs in the parietal-temporal and occipital lobes was reduced in the 22q11DS group relative to healthy controls. Moreover, positive psychotic symptoms were positively associated with increased functional connections between the left precuneus and right superior frontal gyrus, as well as reduced functional connectivity between the bilateral pericalcarine. Positive symptoms were negatively associated with increased functional connectivity between the right pericalcarine and right postcentral gyrus. Our results suggest that functional organization may be altered in 22q11DS, leading to disruption in connectivity between frontal and other lobar substructures, and potentially increasing risk for prodromal psychosis.

Prevalence of 22q11.2 deletions in 311 Dutch patients with schizophrenia

NARCIS (Netherlands)

Hoogendoorn, Mechteld L C; Vorstman, Jacob A S; Jalali, Gholam R; Selten, Jean-Paul; Sinke, Richard J; Emanuel, Beverly S; Kahn, René S

UNLABELLED: The objectives of this study were 1) to examine whether the prevalence of 22q11.2 deletion syndrome (22q11DS) in schizophrenia patients with the Deficit syndrome is higher than the reported approximately 2% for the population of schizophrenia patients as a whole, and 2) to estimate the

Graves disease and IgA deficiency as manifestations of 22q11.2 deletion syndrome:

OpenAIRE

Silva, João Miguel de Almeida; Silva, Cecília Pereira; Melo, Flavio Fernando Nogueira de; Silva, Luis Alberto A.; Utagawa, Claudia Yamada

2010-01-01

A síndrome de deleção 22q11.2 (SD22q11.2) está associada à alta variabilidade fenotípica, abrangendo o espectro velocardiofacial/síndrome de DiGeorge. Manifestações autoimunes, endocrinológicas e de imunodeficiência vêm sendo relatadas associadas à síndrome. O objetivo deste estudo foi relatar um caso de SD22q11.2 associado à deficiência de IgA e à doença de Graves e rever a literatura visando verificar a frequência dessas alterações na SD22q11.2. Os distúrbios autoimunes, cada vez mais relac...

Subthreshold social cognitive deficits may be a key to distinguish 22q11.2DS from schizophrenia.

Science.gov (United States)

Peyroux, Elodie; Rigard, Caroline; Saucourt, Guillaume; Poisson, Alice; Plasse, Julien; Franck, Nicolas; Demily, Caroline

2018-03-25

Social cognitive impairments are core features in 22q11.2 deletion syndrome (22q11.2DS) and schizophrenia (SCZ). Indeed, adults with 22q.11.2 DS often have poorer social competence as well as poorer performance on measures of social cognitive skills (emotion recognition and theory of mind, ToM) compared with typically developing people. However, studies comparing specific social cognitive components in 22q11.2DS and SCZ have not yet been widely conducted. In this study we compared performances of 22q11.2DS and SCZ on both facial emotion recognition and ToM. Patients with 22q11.2DS (n = 18) and matched SCZ patients were recruited. After neuropsychological testing, the facial emotion recognition test assessed the patients' ability to recognize six basic, universal emotions (joy, anger, sadness, fear, disgust, and contempt). The Versailles-situational intentional reading evaluated ToM with six scenes from movies showing characters in complex interactions (involving hints, lies, and indirect speech). We show that 22q11.2DS exhibited significantly lower performance in emotion recognition than SCZ patients did, especially for disgust, contempt, and fear. This impairment seems to be a core cognitive phenotype in 22q11.2DS, regardless of the presence of SCZ symptoms. Concerning ToM, our results may highlight the same impairment level in 22q11.2DS and SCZ but require to be replicated in a larger cohort. Our results document the existence of threshold social cognitive deficits distinguishing 22q11.2DS from SCZ. © 2018 John Wiley & Sons Australia, Ltd.

Speech and language abilities of children with the familial form of 22q11.2 deletion syndrome

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Rakonjac Marijana

2016-01-01

Full Text Available The 22q11.2 Deletion Syndrome (22q11.2DS, which encompasses Shprintzen syndrome, DiGeorge and velocardiofacial syndrome, is the most common microdeletion syndrome in humans with an estimated incidence of approximately 1/4000 per live births. After Down syndrome, it is the second most common genetic syndrome associated with congenital heart malformations. The mode of inheritance of the 22q11.2DS is autosomal dominant. In approximately 72 - 94% of the cases the deletion has occurred de novo, while in 6 to 28% of patients deletion was inherited from a parent. As a part of a multidisciplinary study we examined the speech and language abilities of members of two families with inherited form of 22q11.2DS. The presence of 22q11.2 microdeletion was revealed by fluorescence in situ hybridization (FISH and/or multiplex ligation-dependent probe amplification (MLPA. In one family we detected 1.5 Mb 22q11.2 microdeletion, while in the other family we found 3Mb microdeletion. Patients from both families showed delays in cognitive, socio-emotional, speech and language development. Furthermore, we found considerable variability in the phenotypic characteristics of 22q11.2DS and the degree of speech-language pathology not only between different families with 22q11.2 deletion, but also among members of the same family. In addition, we detected no correlation between the phenotype and the size of 22q11.2 microdeletion.

An interictal schizophrenia-like psychosis in an adult patient with 22q11.2 deletion syndrome

Directory of Open Access Journals (Sweden)

Yasutaka Tastuzawa

2015-01-01

Full Text Available In addition to causing polymalformative syndrome, 22q11.2 deletion can lead to various neuropsychiatric disorders including mental retardation, psychosis, and epilepsy. However, few reports regarding epilepsy-related psychosis in 22q11.2 deletion syndrome (22q11.2DS exist. We describe the clinical characteristics and course of 22q11.2DS in a Japanese patient with comorbid mild mental retardation, childhood-onset localization-related epilepsy, and adult-onset, interictal schizophrenia-like psychosis. From a diagnostic viewpoint, early detection of impaired intellectual functioning and hyperprolinemia in patients with epilepsy with 22q11.2DS may be helpful in predicting the developmental timing of interictal psychosis. From a therapeutic viewpoint, special attention needs to be paid to phenytoin-induced hypocalcemia in this syndrome.

22q11.2 deletion carriers and schizophrenia-associated novel variants.

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Balan, S; Iwayama, Y; Toyota, T; Toyoshima, M; Maekawa, M; Yoshikawa, T

2014-01-01

The penetrance of schizophrenia risk in carriers of the 22q11.2 deletion is high but incomplete, suggesting the possibility of additional genetic defects. We performed whole exome sequencing on two individuals with 22q11.2 deletion, one with schizophrenia and the other who was psychosis-free. The results revealed novel genetic variants related to neuronal function exclusively in the person with schizophrenia (frameshift: KAT8, APOH and SNX31; nonsense: EFCAB11 and CLVS2). This study paves the way towards a more complete understanding of variant dose and genetic architecture in schizophrenia.

Replication the association of 2q32.2-q32.3 and 14q32.11 with hepatocellular carcinoma.

Science.gov (United States)

Chen, Wei; Wang, Mingquan; Zhang, Zhen; Tang, Huayang; Zuo, Xianbo; Meng, Xiangling; Xiong, Maoming; Zhou, Fusheng; Liang, Bo; Dai, Fen; Fang, Jun; Gao, Jinping; Zhu, Jun; Zhu, Yong; Wan, Hong; Wang, Miaofeng; Chan, Shixin; Sun, Liangdan

2015-04-25

Hepatocellular carcinoma (HCC) is a malignant tumor. The morbidity and mortality of HCC tend to ascend and become a serious threat to the population health. Genetic studies of HCC have identified several susceptibility loci of HCC. In this study, we aim to replicate the association of these loci in our samples from Chinese population and further investigate the genetic interaction. We selected 16 SNPs within 1p36.22, 2q32.2-q32.3, 3p21.33, 8p12, 14q32.11 and 21q21.3 and genotyped in 507 HCC patients and 3014 controls by using Sequenom MassARRAY system. Association analyses were performed by using PLINK 1.07. We observed that the STAT4 (2q32.2-q32.3) at rs7574865 (P=1.17×10(-3), OR=0.79) and EFCAB11 (14q32.11) at rs8013403 (P=1.54×10(-3), OR=0.80) were significantly associated with HCC in this study. In 3p21.33, genetic variant rs6795737 within GLB1 was also observed with suggestive evidence (P=9.98×10(-3), OR=0.84). In the interaction analysis, the pair of associated SNPs (rs7574865 within STAT4, rs8013403 within EFCAB11) generated evidence for interaction (P=4.10×10(-3)). In summary, our work first reported the association of 14q32.11 (EFCAB11) with HCC in Chinese Han population and revealed the genetic interaction between STAT4 (2q32.2-q32.3) and EFCAB11 (14q32.11) in HCC. Copyright © 2015 Elsevier B.V. All rights reserved.

MicroRNA Dysregulation, Gene Networks, and Risk for Schizophrenia in 22q11.2 Deletion Syndrome

Science.gov (United States)

Merico, Daniele; Costain, Gregory; Butcher, Nancy J.; Warnica, William; Ogura, Lucas; Alfred, Simon E.; Brzustowicz, Linda M.; Bassett, Anne S.

2014-01-01

The role of microRNAs (miRNAs) in the etiology of schizophrenia is increasingly recognized. Microdeletions at chromosome 22q11.2 are recurrent structural variants that impart a high risk for schizophrenia and are found in up to 1% of all patients with schizophrenia. The 22q11.2 deletion region overlaps gene DGCR8, encoding a subunit of the miRNA microprocessor complex. We identified miRNAs overlapped by the 22q11.2 microdeletion and for the first time investigated their predicted target genes, and those implicated by DGCR8, to identify targets that may be involved in the risk for schizophrenia. The 22q11.2 region encompasses seven validated or putative miRNA genes. Employing two standard prediction tools, we generated sets of predicted target genes. Functional enrichment profiles of the 22q11.2 region miRNA target genes suggested a role in neuronal processes and broader developmental pathways. We then constructed a protein interaction network of schizophrenia candidate genes and interaction partners relevant to brain function, independent of the 22q11.2 region miRNA mechanisms. We found that the predicted gene targets of the 22q11.2 deletion miRNAs, and targets of the genome-wide miRNAs predicted to be dysregulated by DGCR8 hemizygosity, were significantly represented in this schizophrenia network. The findings provide new insights into the pathway from 22q11.2 deletion to expression of schizophrenia, and suggest that hemizygosity of the 22q11.2 region may have downstream effects implicating genes elsewhere in the genome that are relevant to the general schizophrenia population. These data also provide further support for the notion that robust genetic findings in schizophrenia may converge on a reasonable number of final pathways. PMID:25484875

Hearing loss in a mouse model of 22q11.2 Deletion Syndrome.

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Jennifer C Fuchs

Full Text Available 22q11.2 Deletion Syndrome (22q11DS arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear, including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM.

Differentiated psychopharmacological treatment in three genetic subtypes of 22q11.2 deletion syndrome

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Verhoeven, W.M.A.; Egger, J.I.M.; Leeuw, N. de

2017-01-01

Introduction: The 22q11.2 deletion syndrome (22q11DS), mostly caused by the common deletion including the TBX- and COMT-genes (LCR22A-D), is highly associated with somatic anomalies. The distal deletion (distal of LCR22D) comprises the MAPK1-gene and is associated with specific heart defects. The

Eye Gaze During Face Processing in Children and Adolescents with 22q11.2 Deletion Syndrome

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Glaser, Bronwyn; Debbane, Martin; Ottet, Marie-Christine; Vuilleumier, Patrik; Zesiger, Pascal; Antonarakis, Stylianos E.; Eliez, Stephan

2010-01-01

Objective: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic syndrome with high risk for the development of psychiatric disorder. There is interest in identifying reliable markers for measuring and monitoring socio-emotional impairments in 22q11DS during development. The current study investigated eye gaze as a potential marker during a…

22q11.2 deletion status and disease burden in children and adolescents with tetralogy of Fallot.

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Mercer-Rosa, Laura; Paridon, Stephen M; Fogel, Mark A; Rychik, Jack; Tanel, Ronn E; Zhao, Huaqing; Zhang, Xuemei; Yang, Wei; Shults, Justine; Goldmuntz, Elizabeth

2015-02-01

Patients with repaired tetralogy of Fallot experience variable outcomes for reasons that are incompletely understood. We hypothesize that genetic variants contribute to this variability. We sought to investigate the association of 22q11.2 deletion status with clinical outcome in patients with repaired tetralogy of Fallot. We performed a cross-sectional study of tetralogy of Fallot subjects who were tested for 22q11.2 deletion, and underwent cardiac magnetic resonance, exercise stress test, and review of medical history. We studied 165 subjects (12.3±3.1 years), of which 30 (18%) had 22q11.2 deletion syndrome (22q11.2DS). Overall, by cardiac magnetic resonance the right ventricular ejection fraction was 60±8%, pulmonary regurgitant fraction was 34±17%, and right ventricular end-diastolic volume was 114±39 cc/m(2). On exercise stress test, maximum oxygen consumption was 76±16% predicted. Despite comparable right ventricular function and pulmonary regurgitant fraction, on exercise stress test the 22q11.2DS had significantly lower percent predicted: forced vital capacity (61.5±16 versus 80.5±14; Ptetralogy of Fallot. These findings may provide avenues for intervention to improve outcomes, and should be re-evaluated longitudinally because these associations may become more pronounced with time. © 2015 American Heart Association, Inc.

Abordaje inmunológico del síndrome por deleción 22q11

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Estefanía Vásquez-Echeverri

Full Text Available El síndrome por deleción 22q11 (SD22q11 es el síndrome por deleción cromosómica más frecuente en humanos y se caracteriza por la tríada clínica que incluye cardiopatía congénita, hipocalcemia e inmunodeficiencia primaria. El 85-90% de los pacientes tienen microdeleciones en el cromosoma 22q11.2. Tomando como punto cardinal la cardiopatía congénita, se diseñó una estrategia para tamización y diagnóstico de SD22q11 con énfasis en la evaluación inmune. Es imprescindible realizar una historia clínica detallada y, posteriormente, un análisis cuantitativo y funcional de las subpoblaciones de linfocitos en sangre periférica para clasificarlo en SD22q11 completo (<1% o parcial (95-99% e instaurar las pautas de tratamiento en aspectos como: aislamiento del paciente, vacunación, profilaxis contra microorganismos oportunistas, uso de productos sanguíneos irradiados y reconstitución inmunológica. Sin embargo, el abordaje del paciente debe ser multidisciplinario para detectar y prevenir complicaciones a largo plazo que pueden ser graves, especialmente en los pacientes con SD22q11 completo.

Risk of Psychiatric Disorders Among Individuals With the 22q11.2 Deletion or Duplication

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Hoeffding, Louise K; Trabjerg, Betina B; Olsen, Line

2017-01-01

) age at diagnosis of any psychiatric disorder was 12.5 (8.3) years for individuals with deletions and 6.1 (0.9) years for duplication carriers. A parental diagnosis of schizophrenia-but not of other psychiatric diagnoses-was associated with a 22q11.2 deletion, and parental psychiatric diagnoses other.......2 deletion or duplicationwas performed. A total of 3 768 943 individuals born in Denmark from 1955 to 2012 were followed up during the study period (total follow-up, 57.1 million person-years). Indicators of 22q11.2 deletion or duplication and cumulative incidenceswere estimated using a nested case...

Prevalence and Nature of Hearing Loss in 22q11.2 Deletion Syndrome

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Van Eynde, Charlotte; Swillen, Ann; Lambeens, Elien; Verhaert, Nicolas; Desloovere, Christian; Luts, Heleen; Vander Poorten, Vincent; Devriendt, Koenraad; Hens, Greet

2016-01-01

Purpose: The purpose of this study was to clarify the prevalence, type, severity, and age-dependency of hearing loss in 22q11.2 deletion syndrome. Method: Extensive audiological measurements were conducted in 40 persons with proven 22q11.2 deletion (aged 6-36 years). Besides air and bone conduction thresholds in the frequency range between 0.125…

Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects.

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Carmel, Miri; Zarchi, Omer; Michaelovsky, Elena; Frisch, Amos; Patya, Miriam; Green, Tamar; Gothelf, Doron; Weizman, Abraham

2014-09-01

The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals. Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of 22q11.2 deletion in Cleft Palate patients

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Prabodha, L. B. Lahiru; Dias, Dayanath Kumara; Nanayakkara, B. Ganananda; de Silva, Deepthi C.; Chandrasekharan, N. Vishvanath; Ileyperuma, Isurani

2012-01-01

Background: Cleft palate is the commonest multifactorial epigenetic disorder with a prevalence of 0.43-2.45 per 1000. The objectives of this study were to evaluate the clinical features and identify the 22q11.2 deletion in patients with cleft palate in Sri Lanka. Materials and Methods: Cleft patients attending a Teaching Hospital in Sri Lanka were recruited for this study. The relevant data were obtained from review of case notes, interviews, and examination of patients according to a standard evaluation sheet. Quantitative multiplex polymerase chain reaction (PCR) was performed to identify the 22q11.2 deletion. A gel documentation system (Bio-Doc) was used to quantify the PCR product following electrophoresis on 0.8% agarose gel. Results and Conclusion: There were 162 cleft palate patients of whom 59% were females. A total of 92 cleft palate subjects (56.2%) had other associated clinical features. Dysmorphic features (25.27%) and developmental delays (25.27%) were the commonest medical problems encountered. The cleft was limited to the soft palate in 125 patients, while in 25 patients it involved both the hard and the soft palate. There were seven subjects with bifid uvula and five subjects with submucous cleft palate. None of the patients had 22q11.2 deletion in this study population. A multicentered large population-based study is needed to confirm the results of this study and to develop guidelines on the appropriate use of 22q11.2 deletion testing, which are valid for cleft palate patients in Sri Lanka. PMID:23483617

Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene

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brasch-andersen, c; Tan, Q; Børglum, A D

2006-01-01

-wide scan in one set of families followed by (2) fine scale mapping in an independent set of families in candidate regions with a maximum likelihood score (MLS) of > or =1.5 in the genome-wide scan. Polymorphisms in a candidate gene in the region on 12q24.33 were tested for association with asthma...... 12q, and suggests a candidate region distal to most previously reported regions. Three single nucleotide polymorphisms in splicing factor, arginine/serine-rich 8 (SFRS8) had an association with asthma (p ..., a protein which, through alternative splice variants, has an essential role in activating T cells. T cells are involved in the pathogenesis of atopic diseases such as asthma, so SFRS8 is a very interesting candidate gene in the region. CONCLUSIONS: Linkage and simulation studies show that the very distal...

Fluency aspects of oral narrative task in del22q11.2 syndrome.

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Santos, Amanda Oliveira; Rossi, Natalia Freitas; Tandel, Maria da Conceição Faria Freitas; Richieri-Costa, Antonio; Giacheti, Célia Maria

2016-01-01

To investigate the fluency aspects of the oral narrative task in individuals with del22q11.2 syndrome and compare them with those of individuals with typical language development. Fifteen individuals diagnosed with del22q11.2 syndrome, both genders, aged 7-17 years participated in this study. They were compared with 15 individuals with typical language development, with similar gender and chronological age profiles. The oral narrative was elicited using the book "Frog, Where Are You?", and the fluency aspects were analyzed according to speech rate and type and frequency of disfluency (typical and stuttering). The number and duration of pauses were also investigated. The data were statistically analyzed. The group with del22q11.2 syndrome showed a higher average when compared with the group without the syndrome for the percentage of typical disfluencies, mainly hesitation and revision. The group presenting the syndrome also showed a higher average for stuttering disfluencies, with pause as the most frequent disfluency. With respect to speech rate, the group with the syndrome presented a lower average for the number of words and syllables per minute. Individuals with del22q11.2 syndrome showed greater difficulties of narration than their peers. The fluency aspects of the oral narrative task in subjects with del22q11.2 syndrome were similar to those of individuals with typical language development regarding the presence of hesitation, revision, and pause, but they were different with respect to frequency of disfluency, which was higher in individuals with the syndrome.

Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome

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Maria eJalbrzikowski

2014-11-01

Full Text Available 22q11.2 Microdeletion Syndrome (22q11DS is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: 1 differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI measures within white matter tracts; 2 whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and 3 relationships between DTI measures, social cognition task performance and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls. We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA, axial (AD and radial diffusivity (RD, using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the inferior fronto-occipital fasciculus in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to

Subtypes in 22q11.2 Deletion Syndrome Associated with Behaviour and Neurofacial Morphology

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Sinderberry, Brooke; Brown, Scott; Hammond, Peter; Stevens, Angela F.; Schall, Ulrich; Murphy, Declan G. M.; Murphy, Kieran C.; Campbell, Linda E.

2013-01-01

22q11.2 deletion syndrome (22q11DS) has a complex phenotype with more than 180 characteristics, including cardiac anomalies, cleft palate, intellectual disabilities, a typical facial morphology, and mental health problems. However, the variable phenotype makes it difficult to predict clinical outcome, such as the high prevalence of psychosis among…

Mathematical Learning Disabilities in Children with 22q11.2 Deletion Syndrome: A Review

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De Smedt, Bert; Swillen, Ann; Verschaffel, Lieven; Ghesquiere, Pol

2009-01-01

Mathematical learning disabilities (MLD) occur frequently in children with specific genetic disorders, like Turner syndrome, fragile X syndrome and neurofibromatosis. This review focuses on MLD in children with chromosome 22q11.2 deletion syndrome (22q11DS). This syndrome is the most common known microdeletion syndrome with a prevalence of at…

Gene fusions AHRR-NCOA2, NCOA2-ETV4, ETV4-AHRR, P4HA2-TBCK, and TBCK-P4HA2 resulting from the translocations t(5;8;17)(p15;q13;q21) and t(4;5)(q24;q31) in a soft tissue angiofibroma.

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Panagopoulos, Ioannis; Gorunova, Ludmila; Viset, Trond; Heim, Sverre

2016-11-01

We present an angiofibroma of soft tissue with the karyotype 46,XY,t(4;5)(q24;q31),t(5;8;17)(p15;q13;q21)[8]/46,XY,t(1;14)(p31;q32)[2]/46,XY[3]. RNA‑sequencing showed that the t(4;5)(q24;q31) resulted in recombination of the genes TBCK on 4q24 and P4HA2 on 5q31.1 with generation of an in‑frame TBCK‑P4HA2 and the reciprocal but out‑of‑frame P4HA2‑TBCK fusion transcripts. The putative TBCK‑P4HA2 protein would contain the kinase, the rhodanese‑like domain, and the Tre‑2/Bub2/Cdc16 (TBC) domains of TBCK together with the P4HA2 protein which is a component of the prolyl 4‑hydroxylase. The t(5;8;17)(p15;q13;q21) three‑way chromosomal translocation targeted AHRR (on 5p15), NCOA2 (on 8q13), and ETV4 (on 17q21) generating the in‑frame fusions AHRR‑NCOA2 and NCOA2‑ETV4 as well as an out‑of‑frame ETV4‑AHRR transcript. In the AHRR‑NCOA2 protein, the C‑terminal part of AHRR is replaced by the C‑terminal part of NCOA2 which contains two activation domains. The NCOA2‑ETV4 protein would contain the helix‑loop‑helix, PAS_9 and PAS_11, CITED domains, the SRC‑1 domain of NCOA2 and the ETS DNA‑binding domain of ETV4. No fusion gene corresponding to t(1;14)(p31;q32) was found. Our findings indicate that, in spite of the recurrence of AHRR‑NCOA2 in angiofibroma of soft tissue, additional genetic events (or fusion genes) might be required for the development of this tumor.

Cognitive behavioral therapy in 22q11.2 microdeletion with psychotic symptoms: What do we learn from schizophrenia?

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Demily, Caroline; Franck, Nicolas

2016-11-01

The 22q11.2 deletion syndrome (22q11.2DS) is one of the most common microdeletion syndromes, with a widely underestimated prevalence between 1 per 2000 and 1 per 6000. Since childhood, patients with 22q11.2DS are described as having difficulties to initiate and maintain peer relationships. This lack of social skills has been linked to attention deficits/hyperactivity disorder, anxiety and depression. A high incidence of psychosis and positive symptoms is observed in patients with 22q11.2DS and remains correlated with poor social functioning, anxiety and depressive symptoms. Because 22q11.2DS and schizophrenia share several major clinical features, 22q11.2DS is sometimes considered as a genetic model for schizophrenia. Surprisingly, almost no study suggests the use of cognitive and behavioral therapy (CBT) in this indication. We reviewed what should be learned from schizophrenia to develop specific intervention for 22q11.2DS. In our opinion, the first step of CBT approach in 22q11.2DS with psychotic symptoms is to identify precisely which tools can be used among the already available ones. Cognitive behavioral therapy (CBT) targets integrated disorders, i.e. reasoning biases and behavior disorders. In 22q11.2DS, CBT-targeted behavior disorders may take the form of social avoidance and withdrawal or, in the contrary, a more unusual disinhibition and aggressiveness. In our experience, other negative symptoms observed in 22q11.2DS, such as motivation deficit or anhedonia, may also be reduced by CBT. Controlled trials have been studying the benefits of CBT in schizophrenia and several meta-analyses proved its effectiveness. Therefore, it is legitimate to propose this tool in 22q11.2DS, considering symptoms similarities. Overall, CBT is the most effective psychosocial intervention on psychotic symptoms and remains a relevant complement to pharmacological treatments such as antipsychotics. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

An affected core drives network integration deficits of the structural connectome in 22q11.2 deletion syndrome

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František Váša

2016-01-01

Full Text Available Chromosome 22q11.2 deletion syndrome (22q11DS is a genetic disease known to lead to cerebral structural alterations, which we study using the framework of the macroscopic white-matter connectome. We create weighted connectomes of 44 patients with 22q11DS and 44 healthy controls using diffusion tensor magnetic resonance imaging, and perform a weighted graph theoretical analysis. After confirming global network integration deficits in 22q11DS (previously identified using binary connectomes, we identify the spatial distribution of regions responsible for global deficits. Next, we further characterize the dysconnectivity of the deficient regions in terms of sub-network properties, and investigate their relevance with respect to clinical profiles. We define the subset of regions with decreased nodal integration (evaluated using the closeness centrality measure as the affected core (A-core of the 22q11DS structural connectome. A-core regions are broadly bilaterally symmetric and consist of numerous network hubs — chiefly parietal and frontal cortical, as well as subcortical regions. Using a simulated lesion approach, we demonstrate that these core regions and their connections are particularly important to efficient network communication. Moreover, these regions are generally densely connected, but less so in 22q11DS. These specific disturbances are associated to a rerouting of shortest network paths that circumvent the A-core in 22q11DS, “de-centralizing” the network. Finally, the efficiency and mean connectivity strength of an orbito-frontal/cingulate circuit, included in the affected regions, correlate negatively with the extent of negative symptoms in 22q11DS patients, revealing the clinical relevance of present findings. The identified A-core overlaps numerous regions previously identified as affected in 22q11DS as well as in schizophrenia, which approximately 30–40% of 22q11DS patients develop.

The tumor suppressor gene TRC8/RNF139 is disrupted by a constitutional balanced translocation t(8;22(q24.13;q11.21 in a young girl with dysgerminoma

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Fiorio Patrizia

2009-07-01

Full Text Available Abstract Background RNF139/TRC8 is a potential tumor suppressor gene with similarity to PTCH, a tumor suppressor implicated in basal cell carcinomas and glioblastomas. TRC8 has the potential to act in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control and has been identified in families with hereditary renal (RCC and thyroid cancers. Haploinsufficiency of TRC8 may facilitate development of clear cell-RCC in association with VHL mutations, and may increase risk for other tumor types. We report a paternally inherited balanced translocation t(8;22 in a proposita with dysgerminoma. Methods The translocation was characterized by FISH and the breakpoints cloned, sequenced, and compared. DNA isolated from normal and tumor cells was checked for abnormalities by array-CGH. Expression of genes TRC8 and TSN was tested both on dysgerminoma and in the proposita and her father. Results The breakpoints of the translocation are located within the LCR-B low copy repeat on chromosome 22q11.21, containing the palindromic AT-rich repeat (PATRR involved in recurrent and non-recurrent translocations, and in an AT-rich sequence inside intron 1 of the TRC8 tumor-suppressor gene at 8q24.13. TRC8 was strongly underexpressed in the dysgerminoma. Translin is underexpressed in the dysgerminoma compared to normal ovary. TRC8 is a target of Translin (TSN, a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells. Conclusion A role for TRC8 in dysgerminoma may relate to its interaction with Translin. We propose a model in which one copy of TRC8 is disrupted by a palindrome-mediated translocation followed by complete loss of expression through suppression, possibly mediated by miRNA.

22q11.2 Deletion Syndrome Is Associated With Impaired Auditory Steady-State Gamma Response

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Larsen, Kit Melissa; Pellegrino, Giovanni; Birknow, Michelle Rosgaard

2017-01-01

The 22q11.2 deletion syndrome confers a markedly increased risk for schizophrenia. 22q11.2 deletion carriers without manifest psychotic disorder offer the possibility to identify functional abnormalities that precede clinical onset. Since schizophrenia is associated with a reduced cortical gamma...

Neonatal hypocalcemia, neonatal seizures, and intellectual disability in 22q11.2 deletion syndrome

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Cheung, Evelyn Ning Man; George, Susan R.; Andrade, Danielle M.; Chow, Eva W. C.; Silversides, Candice K.; Bassett, Anne S.

2015-01-01

Purpose Hypocalcemia is a common endocrinological condition in 22q11.2 deletion syndrome. Neonatal hypocalcemia may affect neurodevelopment. We hypothesized that neonatal hypocalcemia would be associated with rare, more severe forms of intellectual disability in 22q11.2 deletion syndrome. Methods We used a logistic regression model to investigate potential predictors of intellectual disability severity, including neonatal hypocalcemia, neonatal seizures, and complex congenital heart disease, e.g., interrupted aortic arch, in 149 adults with 22q11.2 deletion syndrome. Ten subjects had moderate-to-severe intellectual disability. Results The model was highly significant (P < 0.0001), showing neonatal seizures (P = 0.0018) and neonatal hypocalcemia (P = 0.047) to be significant predictors of a more severe level of intellectual disability. Neonatal seizures were significantly associated with neonatal hypocalcemia in the entire sample (P < 0.0001), regardless of intellectual level. There was no evidence for the association of moderate- to-severe intellectual disability with other factors such as major structural brain malformations in this sample. Conclusion The results suggest that neonatal seizures may increase the risk for more severe intellectual deficits in 22q11.2 deletion syndrome, likely mediated by neonatal hypocalcemia. Neonatal hypocalcemia often remains unrecognized until the postseizure period, when damage to neurons may already have occurred. These findings support the importance of early recognition and treatment of neonatal hypocalcemia and potentially neonatal screening for 22q11.2 deletions. PMID:23765047

Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype?

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Angkustsiri, Kathleen; Goodlin-Jones, Beth; Deprey, Lesley; Brahmbhatt, Khyati; Harris, Susan; Simon, Tony J.

2014-01-01

High prevalence of autism spectrum disorders (ASD) has been reported in 22q11.2DS, although this has been based solely on parent report measures. This study describes the presence of ASD using a procedure more similar to that used in clinical practice by incorporating history (Social Communication Questionnaire) AND a standardized observation…

MicroRNA Dysregulation, Gene Networks, and Risk for Schizophrenia in 22q11.2 Deletion Syndrome

OpenAIRE

Merico, Daniele; Costain, Gregory; Butcher, Nancy J.; Warnica, William; Ogura, Lucas; Alfred, Simon E.; Brzustowicz, Linda M.; Bassett, Anne S.

2014-01-01

The role of microRNAs (miRNAs) in the etiology of schizophrenia is increasingly recognized. Microdeletions at chromosome 22q11.2 are recurrent structural variants that impart a high risk for schizophrenia and are found in up to 1% of all patients with schizophrenia. The 22q11.2 deletion region overlaps gene DGCR8, encoding a subunit of the miRNA microprocessor complex. We identified miRNAs overlapped by the 22q11.2 microdeletion and for the first time investigated their predicted target genes...

The clinical presentation of attention deficit-hyperactivity disorder (ADHD) in children with 22q11.2 deletion syndrome.

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Niarchou, Maria; Martin, Joanna; Thapar, Anita; Owen, Michael J; van den Bree, Marianne B M

2015-12-01

Although attention deficit-hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2DS, it remains unclear whether its clinical presentation is similar to that in children with idiopathic ADHD. The aim of this study is to compare the ADHD phenotype in children with and without 22q11.2DS by examining ADHD symptom scores, patterns of psychiatric comorbidity, IQ and gender distribution. Forty-four children with 22q11.2DS and ADHD (mean age = 9.6), 600 clinic children (mean age = 10.8) and 77 children with ADHD from a population cohort (mean age = 10.8) participated in the study. Psychopathology was assessed using parent-report research diagnostic instruments. There was a higher proportion of females in the 22q11.2DS ADHD sample in relation to the clinical sample (χ(2)  = 18.2, P ADHD inattentive subtype (χ(2)  = 114.76, P hyperactive-impulsive symptoms compared to the clinical group (z = 8.43, P ADHD group parents reported fewer oppositional defiant disorder/conduct disorder symptoms (z = 6.33, P disorder (χ(2)  = 4.56, P = 0.03) in relation to the clinical group. Two percent of the 22q11.2 DS ADHD sample had received ADHD treatment. The results were similar when the 22q11.2 ADHD group was compared to the population cohort ADHD group. The clinical presentation of ADHD and patterns of co-morbidity in 22q11.2DS is different from that in idiopathic ADHD. This could lead to clinical under-recognition of ADHD in this group. Examining psychopathology in 22q11.2DS can provide insights into the genetic origins of psychiatric problems with implications beyond the 22q11.2DS population. © 2015 Wiley Periodicals, Inc.

Identification of a Cryptic Insertion ins(11;X)(q23;q28q12) Resulting in a KMT2A-FLNA Fusion in a 13-Month-Old Child with Acute Myelomonocytic Leukemia.

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Lentes, Jana; Thomay, Kathrin; Schneider, Dominik T; Bernbeck, Benedikt; Reinhardt, Dirk; Marschalek, Rolf; Meyer, Claus; Schlegelberger, Brigitte; Göhring, Gudrun

2016-01-01

In pediatric acute myeloid leukemia (AML), chromosomal abnormalities leading to a disruption of the lysine methyltransferase 2A (KMT2A) gene in 11q23 are the most frequent rearrangements. Here, we report on the identification of a novel cryptic insertion, ins(11;X)(q23;q28q12), resulting in a translocation of the KMT2A gene in 11q23, leading to a KMT2A-FLNA fusion in a 13-month-old boy with de novo acute myelomonocytic leukemia, who died 38 days after diagnosis. The patient presented a complex karyotype 48∼49,Y,del(X)(q12),+del(X)(q12),+8,ins(11;X)(q23; q28q12),+19. The identified fusion gene was predicted to be out-of-frame (fusion of portions of KMT2A exon 11 with FLNA exon 11). However, RT-PCR experiments demonstrated that a potentially functional transcript was generated by alternative splicing where KMT2A exon 10 was spliced in-frame to the truncated FLNA exon 11. This case report helps to better understand the rare but potentially severe impact of KMT2A- FLNA fusions in infants with AML to improve prognostic stratification of therapy and clinical management. © 2017 S. Karger AG, Basel.

Identification of a novel percent mammographic density locus at 12q24.

Science.gov (United States)

Stevens, Kristen N; Lindstrom, Sara; Scott, Christopher G; Thompson, Deborah; Sellers, Thomas A; Wang, Xianshu; Wang, Alice; Atkinson, Elizabeth; Rider, David N; Eckel-Passow, Jeanette E; Varghese, Jajini S; Audley, Tina; Brown, Judith; Leyland, Jean; Luben, Robert N; Warren, Ruth M L; Loos, Ruth J F; Wareham, Nicholas J; Li, Jingmei; Hall, Per; Liu, Jianjun; Eriksson, Louise; Czene, Kamila; Olson, Janet E; Pankratz, V Shane; Fredericksen, Zachary; Diasio, Robert B; Lee, Adam M; Heit, John A; DeAndrade, Mariza; Goode, Ellen L; Vierkant, Robert A; Cunningham, Julie M; Armasu, Sebastian M; Weinshilboum, Richard; Fridley, Brooke L; Batzler, Anthony; Ingle, James N; Boyd, Norman F; Paterson, Andrew D; Rommens, Johanna; Martin, Lisa J; Hopper, John L; Southey, Melissa C; Stone, Jennifer; Apicella, Carmel; Kraft, Peter; Hankinson, Susan E; Hazra, Aditi; Hunter, David J; Easton, Douglas F; Couch, Fergus J; Tamimi, Rulla M; Vachon, Celine M

2012-07-15

Percent mammographic density adjusted for age and body mass index (BMI) is one of the strongest risk factors for breast cancer and has a heritable component that remains largely unidentified. We performed a three-stage genome-wide association study (GWAS) of percent mammographic density to identify novel genetic loci associated with this trait. In stage 1, we combined three GWASs of percent density comprised of 1241 women from studies at the Mayo Clinic and identified the top 48 loci (99 single nucleotide polymorphisms). We attempted replication of these loci in 7018 women from seven additional studies (stage 2). The meta-analysis of stage 1 and 2 data identified a novel locus, rs1265507 on 12q24, associated with percent density, adjusting for age and BMI (P = 4.43 × 10(-8)). We refined the 12q24 locus with 459 additional variants (stage 3) in a combined analysis of all three stages (n = 10 377) and confirmed that rs1265507 has the strongest association in the 12q24 region (P = 1.03 × 10(-8)). Rs1265507 is located between the genes TBX5 and TBX3, which are members of the phylogenetically conserved T-box gene family and encode transcription factors involved in developmental regulation. Understanding the mechanism underlying this association will provide insight into the genetics of breast tissue composition.

An Fgf8 Mouse Mutant Phenocopies Human 22q11 Deletion Syndrome

OpenAIRE

Frank, Deborah U.; Fotheringham, Lori K.; Brewer, Judson A.; Muglia, Louis J.; Tristani-Firouzi, Martin; Capecchi, Mario R.; Moon, Anne M.

2002-01-01

Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array of birth defects. Although 90% of affected individuals share the same three megabase deletion, their phenotype is highly variable and includes craniofacial and cardiovascular anomalies, hypoplasia or aplasia of the thymus with associated deficiency of T cells, hypocalcemia with hypoplasia or aplasia of the parathyroids, and a variety of central nervous system abnormaliti...

Development of Structural Covariance From Childhood to Adolescence: A Longitudinal Study in 22q11.2DS

Directory of Open Access Journals (Sweden)

Corrado Sandini

2018-05-01

Full Text Available Background: Schizophrenia is currently considered a neurodevelopmental disorder of connectivity. Still few studies have investigated how brain networks develop in children and adolescents who are at risk for developing psychosis. 22q11.2 Deletion Syndrome (22q11DS offers a unique opportunity to investigate the pathogenesis of schizophrenia from a neurodevelopmental perspective. Structural covariance (SC is a powerful approach to explore morphometric relations between brain regions that can furthermore detect biomarkers of psychosis, both in 22q11DS and in the general population.Methods: Here we implement a state-of-the-art sliding-window approach to characterize maturation of SC network architecture in a large longitudinal cohort of patients with 22q11DS (110 with 221 visits and healthy controls (117 with 211 visits. We furthermore propose a new clustering-based approach to group regions according to trajectories of structural connectivity maturation. We correlate measures of SC with development of working memory, a core executive function that is highly affected in both idiopathic psychosis and 22q11DS. Finally, in 22q11DS we explore correlations between SC dysconnectivity and severity of internalizing psychopathology.Results: In HCs network architecture underwent a quadratic developmental trajectory maturing up to mid-adolescence. Late-childhood maturation was particularly evident for fronto-parietal cortices, while Default-Mode-Network-related regions showed a more protracted linear development. Working memory performance was positively correlated with network segregation and fronto-parietal connectivity. In 22q11DS, we demonstrate aberrant maturation of SC with disturbed architecture selectively emerging during adolescence and correlating more severe internalizing psychopathology. Patients also presented a lack of typical network development during late-childhood, that was particularly prominent for frontal connectivity.Conclusions: Our

Chromosome 22q11 in a Xhosa schizophrenia population | Koen ...

African Journals Online (AJOL)

Chromosome 22q11 aberrations substantially increase the risk for developing schizophrenia. Although micro-deletions in this region have been extensively investigated in different populations across the world, little is known of their prevalence in African subjects with schizophrenia. We screened 110 African ...

Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome

DEFF Research Database (Denmark)

Starnawska, A; Hansen, C S; Sparsø, T

2017-01-01

Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous...... with mental disorder later in life. DNA methylation was measured genome-wide from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 individuals diagnosed with a psychiatric disorder. Among several CpG sites with P-value...-98), in NOSIP (P-value=5.12 × 10-8) with disorders of psychological development (F80-89) and in SEMA4B (P-value=4.02 × 10-7) with schizophrenia spectrum disorders (F20-29). In conclusion, our study suggests an association of DNA methylation differences at birth with development of mental disorder later in life...

Comparing the broad socio-cognitive profile of youth with Williams syndrome and 22q11.2 deletion syndrome.

Science.gov (United States)

Weisman, O; Feldman, R; Burg-Malki, M; Keren, M; Geva, R; Diesendruck, G; Gothelf, D

2017-12-01

Numerous studies have assessed the socio-cognitive profile in Williams syndrome (WS) and, independently, in 22q11.2 deletion syndrome (22q11.2DS). Yet, a cross-syndrome comparison of these abilities between individuals with these two syndromes with known social deficits has not been conducted. Eighty-two children participated in four study groups: WS (n = 18), 22q112.DS (n = 24), age-matched individuals with idiopathic developmental disability (IDD; n = 20) and typically developing (TD) controls (n = 20). Participants completed four socio-cognitive tests: facial emotion recognition, mental state attribution, differentiating real from apparent emotions and trait inference based on motives and actions-outcomes. The current findings demonstrate that children with WS were better in labelling happy faces compared with children with 22q11.2DS, partially reflecting their exaggerated social drive. In the false belief task, however, the WS and IDD groups performed poorly compared with the 22q11.2DS group, possibly due to their difficulty to interpret subtle social cues. When asked to identify the gap between real-negative vs. apparent-positive emotions, the 22q11.2DS group performed similarly to TD children but better than the WS group, possibly due to their anxious personality and their innate bias towards negatively valence cues. Finally, individuals with WS were more willing to become friends with a story character even when the character's motives were negative, reflecting their difficulty to avoid potentially harmful real-life situations. Overall, our multi-facet socio-cognitive battery uncovered strengths and weaknesses in social cognition that are syndrome-specific, shared among the genetic syndromes, or common to the three clinical groups compared with healthy controls. Our findings underscore the need to devise age-specific and condition-specific assessment tools and intervention programs towards improving these children's socio-cognitive deficits. © 2017

Negative subthreshold psychotic symptoms distinguish 22q11.2 deletion syndrome from other neurodevelopmental disorders: A two-site study.

Science.gov (United States)

Mekori-Domachevsky, Ehud; Guri, Yael; Yi, James; Weisman, Omri; Calkins, Monica E; Tang, Sunny X; Gross, Raz; McDonald-McGinn, Donna M; Emanuel, Beverly S; Zackai, Elaine H; Zalsman, Gil; Weizman, Abraham; Gur, Ruben C; Gur, Raquel E; Gothelf, Doron

2017-10-01

About one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia. Notably, a full-blown psychotic disorder is usually preceded by subthreshold symptoms. Therefore, it is important to identify early signs of psychosis in this population, a task that is complicated by the intellectual disabilities typically seen in 22q11.2DS. We aimed to identify subthreshold psychotic symptoms that distinguish 22q11.2DS from other neurodevelopmental disorders. The study included two independent cohorts from Tel Aviv and Philadelphia. 22q11.2DS (N=171) and typically developing (TD; N=832) individuals were enrolled at both sites and further compared to two groups with intellectual disabilities: Williams syndrome (WS; N=21) in the Tel Aviv cohort and idiopathic developmental disabilities (IDD; N=129) in the Philadelphia cohort. Participants and their primary caregivers were interviewed with the Structured Interview for Prodromal Symptoms (SIPS) and psychopathologies were assessed using standardized tools; general cognitive abilities were assessed with the Computerized Neurocognitive Battery. Negative/disorganized subthreshold syndrome was significantly more common in the 22q11.2DS group than in the WS (OR=3.90, 95% CI=1.34-11.34) or IDD (OR=5.05, 95% CI=3.01-10.08) groups. The 22q11.2DS group had higher scores than the two intellectual disabilities groups on several SIPS negative items, including avolition and decreased expression of emotion. Overall, there were few significant correlations between level of cognitive deficits and severity of negative symptoms in 22q11.2DS and only in the Tel Aviv cohort. Our findings suggest that 22q11.2DS individuals at the age of risk for developing psychosis should be closely monitored for negative symptoms. Copyright © 2016 Elsevier B.V. All rights reserved.

Partial monosomy 8q and partial trisomy 9q due to the maternal translocation t(8;9(q24.3;q34.1)

DEFF Research Database (Denmark)

Tos, T; Alp, M Y; Eker, H K

2014-01-01

Partial trisomy 9q34-qter and partial monosomy 8q24.3-qter are very rare chromosomal abnormalities. Characteristic features of partial trisomy 9q34-qter are hypotonia, developmental delay, mild intellectual disability, dolichocephaly, distinct facial phenotype, long and thin fingers, and cardiac...

Performance on a computerized neurocognitive battery in 22q11.2 deletion syndrome: A comparison between US and Israeli cohorts.

Science.gov (United States)

Yi, James J; Weinberger, Ronnie; Moore, Tyler M; Calkins, Monica E; Guri, Yael; McDonald-McGinn, Donna M; Zackai, Elaine H; Emanuel, Beverly S; Gur, Raquel E; Gothelf, Doron; Gur, Ruben C

2016-07-01

Increasingly, the effects of copy number variation (CNV) in the genome on brain function and behaviors are recognized as means to elucidate pathophysiology of psychiatric disorders. Such studies require large samples and we characterized the neurocognitive profile of two cohorts of individuals with 22q11.2 deletion syndrome (22q11DS), the most common CNV associated with schizophrenia, in an effort to harmonize phenotyping in multi-site global collaborations. The Penn Computerized Neurocognitive Battery (PCNB) was administered to individuals with 22q11DS in Philadelphia (PHL; n=155, aged 12-40) and Tel Aviv (TLV; n=59, aged 12-36). We examined effect sizes of performance differences between the cohorts and confirmed the factor structure of PCNB performance efficiency in the combined sample based on data from a large comparison community sample. The cohorts performed comparably with notable deficits in executive function, episodic memory and social cognition domains that were previously associated with abnormal neuroimaging findings in 22q11DS. In mixed model analysis, while there was a main effect for site for accuracy (number of correct response) and speed (time to correct response) independently, there were no main site effects for standardized efficiency (average of accuracy and speed). The fit of a structural model was excellent indicating that PCNB tests were related to the targeted cognitive domains. Thus, our results provide preliminary support for the use of the PCNB as an efficient tool for neurocognitive assessment in international 22q11DS collaborations. Copyright © 2016 Elsevier Inc. All rights reserved.

Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study

NARCIS (Netherlands)

Campbell, Linda E.; Daly, Eileen; Toal, Fiona; Stevens, Angela; Azuma, Rayna; Catani, Marco; Ng, Virginia; van Amelsvoort, Therese; Chitnis, Xavier; Cutter, William; Murphy, Declan G. M.; Murphy, Kieran C.

2006-01-01

In people with velo-cardio-facial syndrome [or 22q11.2 deletion syndrome (22qDS)], a single interstitial deletion of chromosome 22q11.2 causes a wide spectrum of cognitive deficits ranging from global learning difficulties to specific cognitive deficits. People with 22qDS are also at high risk of

Transcriptome Profiling of Peripheral Blood in 22q11.2 Deletion Syndrome Reveals Functional Pathways Related to Psychosis and Autism Spectrum Disorder.

Directory of Open Access Journals (Sweden)

Maria Jalbrzikowski

Full Text Available 22q11.2 Deletion Syndrome (22q11DS represents one of the greatest known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes.We used a high-resolution aCGH array to precisely characterize deletion breakpoints. Using peripheral blood, we examined differential expression (DE and networks of co-expressed genes related to phenotypic variation within 22q11DS patients. Whole-genome transcriptional profiling was performed using Illumina Human HT-12 microarrays. Data mining techniques were used to validate our results against independent samples of both peripheral blood and brain tissue from idiopathic psychosis and ASD cases.Eighty-five percent of 22q11DS individuals (N = 39 carried the typical 3 Mb deletion, with significant variability in deletion characteristics in the remainder of the sample (N = 7. DE analysis and weighted gene co-expression network analysis (WGCNA identified expression changes related to psychotic symptoms in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. This module was enriched for brain-expressed genes, was not related to antipsychotic medication use, and significantly overlapped with transcriptional changes in idiopathic schizophrenia. In 22q11DS-ASD, both DE and WGCNA analyses implicated dysregulation of immune response pathways. The ASD-associated module showed significant overlap with genes previously associated with idiopathic ASD.These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD.

The clinical presentation of attention deficit‐hyperactivity disorder (ADHD) in children with 22q11.2 deletion syndrome

Science.gov (United States)

Martin, Joanna; Thapar, Anita; Owen, Michael J.

2015-01-01

Background: Although attention deficit‐hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2DS, it remains unclear whether its clinical presentation is similar to that in children with idiopathic ADHD. The aim of this study is to compare the ADHD phenotype in children with and without 22q11.2DS by examining ADHD symptom scores, patterns of psychiatric comorbidity, IQ and gender distribution. Methods: Forty‐four children with 22q11.2DS and ADHD (mean age = 9.6), 600 clinic children (mean age = 10.8) and 77 children with ADHD from a population cohort (mean age = 10.8) participated in the study. Psychopathology was assessed using parent‐report research diagnostic instruments. Results: There was a higher proportion of females in the 22q11.2DS ADHD sample in relation to the clinical sample (χ2 = 18.2, P ADHD inattentive subtype (χ2 = 114.76, P ADHD group parents reported fewer oppositional defiant disorder/conduct disorder symptoms (z = 6.33, P ADHD sample had received ADHD treatment. The results were similar when the 22q11.2 ADHD group was compared to the population cohort ADHD group. Conclusions: The clinical presentation of ADHD and patterns of co‐morbidity in 22q11.2DS is different from that in idiopathic ADHD. This could lead to clinical under‐recognition of ADHD in this group. Examining psychopathology in 22q11.2DS can provide insights into the genetic origins of psychiatric problems with implications beyond the 22q11.2DS population. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID:26400629

Inconspicuous insertion 22;12 in myxoid/round cell liposarcoma accompanied by the secondary structural abnormality der(16)t(1;16).

Science.gov (United States)

Birch, Nathan C; Antonescu, Cristina R; Nelson, Marilu; Sarran, Lisa; Neff, James R; Seemayer, Thomas; Bridge, Julia A

2003-08-01

In myxoid/round cell liposarcoma, the t(12;16)(q13;p11) and its associated fusion transcript, FUS-CHOP, characterize greater than 95% of cases. The variant translocation t(12;22)(q13;q12) and associated EWS-CHOP fusion transcript are rare. A second non-random aberration observed in roughly 20% of Ewing's sarcomas, and to a lesser extent other select sarcomas, is the unbalanced 1;16 translocation. Recognition of this secondary aberration in the absence of an obvious primary karyotypic abnormality strongly suggests that the use of other genetic approaches will be informative in uncovering a clinically suspected primary anomaly. The following case illustrates the utility of molecular cytogenetic and reverse transcriptase-polymerase chain reaction techniques in diagnosing an ins(22;12)(q12;q13q14) and associated EWS-CHOP fusion transcript in a myxoid/round cell liposarcoma exhibiting a der(16)t(1;16)(q11;q11).

Autism, ADHD, Mental Retardation and Behavior Problems in 100 Individuals with 22q11 Deletion Syndrome

Science.gov (United States)

Niklasson, Lena; Rasmussen, Peder; Oskarsdottir, Solveig; Gillberg, Christopher

2009-01-01

This study assessed the prevalence and type of associated neuropsychiatric problems in children and adults with 22q11 deletion syndrome. One-hundred consecutively referred individuals with 22q11 deletion syndrome were given in-depth neuropsychiatric assessments and questionnaires screens. Autism spectrum disorders (ASDs) and/or attention…

Refinement of the deletion in 8q22.2-q22.3: the minimum deletion size at 8q22.3 related to intellectual disability and epilepsy.

Science.gov (United States)

Kuroda, Yukiko; Ohashi, Ikuko; Saito, Toshiyuki; Nagai, Jun-ichi; Ida, Kazumi; Naruto, Takuya; Iai, Mizue; Kurosawa, Kenji

2014-08-01

Kuechler et al. [2011] reported five patients with interstitial deletions in 8q22.2-q22.3 who had intellectual disability, epilepsy, and dysmorphic features. We report on a new patient with the smallest overlapping de novo deletion in 8q22.3 and refined the phenotype. The proposita was an 8-year-old girl, who developed seizures at 10 months, and her epileptic seizure became severe and difficult to control with antiepileptic drugs. She also exhibited developmental delay and walked alone at 24 months. She was referred to us for evaluation for developmental delay and epilepsy at the age of 8 years. She had intellectual disability (IQ 37 at 7 years) and autistic behavior, and spoke two word sentences at 8 years. She had mild dysmorphic features, including telecanthus and thick vermilion of the lips. Array comparative genomic hybridization detected a 1.36 Mb deletion in 8q22.3 that encompassed RRM2B and NCALD, which encode the small subunit of p53-inducible ribonucleotide reductase and neurocalcin delta in the neuronal calcium sensor family of calcium-binding proteins, respectively. The minimum overlapping region between the present and previously reported patients is considered to be a critical region for the phenotype of the deletion in 8q22.3. We suggest that the deletion in 8q22.3 may represent a clinically recognizable condition, which is characterized by intellectual disability and epilepsy. © 2014 Wiley Periodicals, Inc.

Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion

Directory of Open Access Journals (Sweden)

Marcília S. Grassi

2014-11-01

Full Text Available Background: To alert for the diagnosis of the 22q11.2 deletion syndrome (22q11.2DS in patients with congenital heart disease (CHD. Objective: To describe the main CHDs, as well as phenotypic, metabolic and immunological findings in a series of 60 patients diagnosed with 22q11.2DS. Methods: The study included 60 patients with 22q11.2DS evaluated between 2007 and 2013 (M:F=1.3, age range 14 days to 20 years and 3 months at a pediatric reference center for primary immunodeficiencies. The diagnosis was established by detection of the 22q11.2 microdeletion using FISH (n = 18 and/or MLPA (n = 42, in association with clinical and laboratory information. Associated CHDs, progression of phenotypic facial features, hypocalcemia and immunological changes were analyzed. Results: CHDs were detected in 77% of the patients and the most frequent type was tetralogy of Fallot (38.3%. Surgical correction of CHD was performed in 34 patients. Craniofacial dysmorphisms were detected in 41 patients: elongated face (60% and/or elongated nose (53.3%, narrow palpebral fissure (50%, dysplastic, overfolded ears (48.3%, thin lips (41.6%, elongated fingers (38.3% and short stature (36.6%. Hypocalcemia was detected in 64.2% and decreased parathyroid hormone (PTH level in 25.9%. Decrease in total lymphocytes, CD4 and CD8 counts were present in 40%, 53.3% and 33.3%, respectively. Hypogammaglobulinemia was detected in one patient and decreased concentrations of immunoglobulin M (IgM in two other patients. Conclusion: Suspicion for 22q11.2DS should be raised in all patients with CHD associated with hypocalcemia and/or facial dysmorphisms, considering that many of these changes may evolve with age. The 22q11.2 microdeletion should be confirmed by molecular testing in all patients.

Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion

International Nuclear Information System (INIS)

Grassi, Marcília S.; Jacob, Cristina M. A.; Kulikowski, Leslie D.; Pastorino, Antonio C.; Dutra, Roberta L.; Miura, Nana; Jatene, Marcelo B.; Pegler, Stephanie P.; Kim, Chong A.; Carneiro-Sampaio, Magda

2014-01-01

To alert for the diagnosis of the 22q11.2 deletion syndrome (22q11.2DS) in patients with congenital heart disease (CHD). To describe the main CHDs, as well as phenotypic, metabolic and immunological findings in a series of 60 patients diagnosed with 22q11.2DS. The study included 60 patients with 22q11.2DS evaluated between 2007 and 2013 (M:F=1.3, age range 14 days to 20 years and 3 months) at a pediatric reference center for primary immunodeficiencies. The diagnosis was established by detection of the 22q11.2 microdeletion using FISH (n = 18) and/or MLPA (n = 42), in association with clinical and laboratory information. Associated CHDs, progression of phenotypic facial features, hypocalcemia and immunological changes were analyzed. CHDs were detected in 77% of the patients and the most frequent type was tetralogy of Fallot (38.3%). Surgical correction of CHD was performed in 34 patients. Craniofacial dysmorphisms were detected in 41 patients: elongated face (60%) and/or elongated nose (53.3%), narrow palpebral fissure (50%), dysplastic, overfolded ears (48.3%), thin lips (41.6%), elongated fingers (38.3%) and short stature (36.6%). Hypocalcemia was detected in 64.2% and decreased parathyroid hormone (PTH) level in 25.9%. Decrease in total lymphocytes, CD4 and CD8 counts were present in 40%, 53.3% and 33.3%, respectively. Hypogammaglobulinemia was detected in one patient and decreased concentrations of immunoglobulin M (IgM) in two other patients. Suspicion for 22q11.2DS should be raised in all patients with CHD associated with hypocalcemia and/or facial dysmorphisms, considering that many of these changes may evolve with age. The 22q11.2 microdeletion should be confirmed by molecular testing in all patients

Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion

Energy Technology Data Exchange (ETDEWEB)

Grassi, Marcília S., E-mail: marcilia.grassi@hc.fm.usp.br; Jacob, Cristina M. A. [Instituto da Criança - HC-FMUSP, São Paulo, SP (Brazil); Kulikowski, Leslie D. [Departamento de Patologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP (Brazil); Pastorino, Antonio C. [Instituto da Criança - HC-FMUSP, São Paulo, SP (Brazil); Dutra, Roberta L. [Departamento de Patologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP (Brazil); Miura, Nana; Jatene, Marcelo B. [Instituto do Coração - HC-FMUSP, São Paulo, SP (Brazil); Pegler, Stephanie P.; Kim, Chong A.; Carneiro-Sampaio, Magda [Instituto da Criança - HC-FMUSP, São Paulo, SP (Brazil)

2014-11-15

To alert for the diagnosis of the 22q11.2 deletion syndrome (22q11.2DS) in patients with congenital heart disease (CHD). To describe the main CHDs, as well as phenotypic, metabolic and immunological findings in a series of 60 patients diagnosed with 22q11.2DS. The study included 60 patients with 22q11.2DS evaluated between 2007 and 2013 (M:F=1.3, age range 14 days to 20 years and 3 months) at a pediatric reference center for primary immunodeficiencies. The diagnosis was established by detection of the 22q11.2 microdeletion using FISH (n = 18) and/or MLPA (n = 42), in association with clinical and laboratory information. Associated CHDs, progression of phenotypic facial features, hypocalcemia and immunological changes were analyzed. CHDs were detected in 77% of the patients and the most frequent type was tetralogy of Fallot (38.3%). Surgical correction of CHD was performed in 34 patients. Craniofacial dysmorphisms were detected in 41 patients: elongated face (60%) and/or elongated nose (53.3%), narrow palpebral fissure (50%), dysplastic, overfolded ears (48.3%), thin lips (41.6%), elongated fingers (38.3%) and short stature (36.6%). Hypocalcemia was detected in 64.2% and decreased parathyroid hormone (PTH) level in 25.9%. Decrease in total lymphocytes, CD4 and CD8 counts were present in 40%, 53.3% and 33.3%, respectively. Hypogammaglobulinemia was detected in one patient and decreased concentrations of immunoglobulin M (IgM) in two other patients. Suspicion for 22q11.2DS should be raised in all patients with CHD associated with hypocalcemia and/or facial dysmorphisms, considering that many of these changes may evolve with age. The 22q11.2 microdeletion should be confirmed by molecular testing in all patients.

Subthreshold Psychosis in 22q11.2 Deletion Syndrome: Multisite Naturalistic Study.

Science.gov (United States)

Weisman, Omri; Guri, Yael; Gur, Raquel E; McDonald-McGinn, Donna M; Calkins, Monica E; Tang, Sunny X; Emanuel, Beverly; Zackai, Elaine H; Eliez, Stephan; Schneider, Maude; Schaer, Marie; Kates, Wendy R; Antshel, Kevin M; Fremont, Wanda; Shashi, Vandana; Hooper, Stephen R; Armando, Marco; Vicari, Stefano; Pontillo, Maria; Kushan, Leila; Jalbrzikowski, Maria; Bearden, Carrie E; Cubells, Joseph F; Ousley, Opal Y; Walker, Elaine F; Simon, Tony J; Stoddard, Joel; Niendam, Tara A; van den Bree, Marianne B M; Gothelf, Doron

2017-09-01

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For

Angelman syndrome associated with an inversion of chromosome 15q11.2q24.3

Energy Technology Data Exchange (ETDEWEB)

Greger, V.; Knoll, J.H.M.; Wagstaff, J.; Lalande, M. [and others

1997-03-01

Angelman syndrome (AS) most frequently results from large ({ge}5 Mb) de novo deletions of chromosome 15q11-q13. The deletions are exclusively of maternal origin, and a few cases of paternal uniparental disomy of chromosome 15 have been reported. The latter finding indicates that AS is caused by the absence of a maternal contribution to the imprinted 15q11-q13 region. Failure to inherit a paternal 15q11-q13 contribution results in the clinically distinct disorder of Prader-Willi syndrome. Cases of AS resulting from translocations or pericentric inversions have been observed to be associated with deletions, and there have been no confirmed reports of balanced rearrangements in AS. We report the first such case involving a paracentric inversion with a breakpoint located {approximately}25 kb proximal to the reference marker D15S10. This inversion has been inherited from a phenotypically normal mother. No deletion is evident by molecular analysis in this case, by use of cloned fragments mapped to within {approximately}1 kb of the inversion breakpoint. Several hypotheses are discussed to explain the relationship between the inversion and the AS phenotype. 47 refs., 3 figs.

"You don't know until you get there": The positive and negative "lived" experience of parenting an adult child with 22q11.2 deletion syndrome.

Science.gov (United States)

Goodwin, Jane; McCormack, Lynne; Campbell, Linda E

2017-01-01

22q11.2 deletion syndrome (22q11DS), a complex genetic syndrome associated with more than 180 features, presents complex challenges for parents including gaining a diagnosis. This phenomenological study sought the "lived" interpretations of parents supporting an adult child with 22q11DS, a poorly researched area. Interpretative phenomenological analysis informed a detailed and open exploration of parenting a child through to adult life with 22q11DS. Using in-depth semistructured interviews, 8 parents (2 male, 6 female) of adult children with 22q11DS were individually interviewed; providing the data set for transcription and thematic analysis. Losing "I" Finding "self," overarched 6 subordinate themes that emerged from participants' articulated descriptions of psychological distress and psychological growth. Distress in parenting a child with 22q11DS was experienced through stigma, loss, grief, and guilt. Progressively, stigma undermined independence, friendships, and instinctual judgement. Ill-informed hierarchical structures experienced as layers of obstruction and lack of awareness of the syndrome triggered angry advocacy for their child. Diagnosis brought opposing relief and grief. In time, they came to value their unique "accomplishments," collected on their journey with 22q11DS, and in turn, consciously valued authentic "self" expressed through empathy, humility, gratitude, and pride. Parental distress through societal, educational, and health care invalidation persisted for decades for all participants. Conversely, distress facilitated psychological growth for redefining "self" and role as parents over time. Building on this phenomenological cameo, future research can educate against the plight of 22q11DS families. It can enlighten health care professionals in buffering against associated stigma, blame, and self-doubt, and in fostering psychological well-being. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

22q11 deletion syndrome: Parents' and children's experiences of educational and healthcare provision in the United Kingdom.

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Cohen, Wendy; McCartney, Elspeth; Crampin, Lisa

2017-06-01

22q11 deletion syndrome (22q11DS) is a genetic syndrome, prevalence around 1:4000-1:6000 live births, with a complex array of associated features, impacting on healthcare and educational support. This study reports the perceptions of families and individuals with 22q11DS in relation to these needs. Individuals and families of those with 22q11DS were approached though two national charities - the Max Appeal and 22Crew. An initial observational survey design was used to gather views via questions probing access to healthcare and educational experiences. Thirty-four responses were received and the data subjected to descriptive analysis. Over half of the respondents were diagnosed before the age of 1. Ninety-one percent reported ongoing difficulties with learning at school, compounded by school attendance being compromised as a result of medical interventions. Individuals reported engaging heavily with educational support and a high number of health professions (mean 9.5; mode 10). Age of diagnosis of 22q11DS ranged from birth to nine years. Families had ongoing concerns about aspects of education and healthcare services, and lack of knowledge and awareness of the difficulties faced by individuals with 22q11DS was raised. Healthcare and education providers should be aware of the range of services individuals required on a regular basis so as to provide a more holistic approach to care.

NEUROD2 and NEUROD3 genes map to human chromosomes 17q12 and 5q23-q31 and mouse chromosomes 11 and 13, respectively

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Tamimi, R.M.; Montgomery-Dyer, K.; Tapscott, S.J. [Fred Hutchinson Cancer Research Center, Seattle, WA (United States)] [and others

1997-03-01

NEUROD2 and NEUROD3 are transcription factors involved in neurogenesis that are related to the basic helix-loop-helix protein NEUROD. NEUROD2 maps to human chromosome 17q12 and mouse chromosome 11. NEUROD3 maps to human chromosome 5q23-q31 and mouse chromosome 13. 16 refs., 2 figs.

A 1.37-Mb 12p11.22–p11.21 deletion coincident with a 367-kb 22q11.2 duplication detected by array comparative genomic hybridization in an adolescent girl with autism and difficulty in self-care of menstruation

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Chih-Ping Chen

2014-03-01

Conclusion: An apparently balanced translocation may be in fact affected by concurrent deletion and duplication in two different chromosomal regions. Our presentation provides information on diagnostic phenotype of 12p11.22–p11.21 microdeletion and 22q11.2 microduplication.

Does Differential Visual Exploration Contribute to Visual Memory Impairments in 22Q11.2 Microdeletion Syndrome?

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Bostelmann, M.; Glaser, B.; Zaharia, A.; Eliez, S.; Schneider, M.

2017-01-01

Background: Chromosome 22q11.2 microdeletion syndrome (22q11.2DS) is a genetic syndrome characterised by a unique cognitive profile. Individuals with the syndrome present several non-verbal deficits, including visual memory impairments and atypical exploration of visual information. In this study, we seek to understand how visual attention may…

Vitamin D deficiency, behavioral atypicality, anxiety and depression in children with chromosome 22q11.2 deletion syndrome.

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Kelley, L; Sanders, A F P; Beaton, E A

2016-12-01

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a complex developmental disorder with serious medical, cognitive and emotional symptoms across the lifespan. This genetic deletion also imparts a lifetime risk for developing schizophrenia that is 25-30 times that of the general population. The origin of this risk is multifactorial and may include dysregulation of the stress response and immunological systems in relation to brain development. Vitamin D is involved in brain development and neuroprotection, gene transcription, immunological regulation and influences neuronal signal transduction. Low levels of vitamin D are associated with schizophrenia, depression and anxiety in the general population. Yet, little is known about how vitamin D levels in children with 22q11.2DS could mediate risk of psychosis in adulthood. Blood plasma levels of vitamin D were measured in children aged 7-16 years with (n=11) and without (n=16) 22q11.2DS in relation to parent reports of children's anxiety and atypicality. Anxiety and atypicality in childhood are risk indicators for the development of schizophrenia in those with 22q11.2DS and the general population. Children with 22q11.2DS had lower vitamin D levels, as well as elevated anxiety and atypicality compared with typical peers. Higher levels of anxiety, depression and internalizing problems but not atypicality were associated with lower levels of vitamin D. Vitamin D insufficiency may relate to higher levels of anxiety and depression, in turn contributing to the elevated risk of psychosis in this population. Further study is required to determine casual linkages between anxiety, stress, mood and vitamin D in children with 22q11.2DS.

Deviant dynamics of EEG resting state pattern in 22q11.2 deletion syndrome adolescents: A vulnerability marker of schizophrenia?

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Tomescu, Miralena I; Rihs, Tonia A; Becker, Robert; Britz, Juliane; Custo, Anna; Grouiller, Frédéric; Schneider, Maude; Debbané, Martin; Eliez, Stephan; Michel, Christoph M

2014-08-01

Previous studies have repeatedly found altered temporal characteristics of EEG microstates in schizophrenia. The aim of the present study was to investigate whether adolescents affected by the 22q11.2 deletion syndrome (22q11DS), known to have a 30 fold increased risk to develop schizophrenia, already show deviant EEG microstates. If this is the case, temporal alterations of EEG microstates in 22q11DS individuals could be considered as potential biomarkers for schizophrenia. We used high-density (204 channel) EEG to explore between-group microstate differences in 30 adolescents with 22q11DS and 28 age-matched controls. We found an increased presence of one microstate class (class C) in the 22q11DS adolescents with respect to controls that was associated with positive prodromal symptoms (hallucinations). A previous across-age study showed that the class C microstate was more present during adolescence and a combined EEG-fMRI study associated the class C microstate with the salience resting state network, a network known to be dysfunctional in schizophrenia. Therefore, the increased class C microstates could be indexing the increased risk of 22q11DS individuals to develop schizophrenia if confirmed by our ongoing longitudinal study comparing both the adult 22q11DS individuals with and without schizophrenia, as well as schizophrenic individuals with and without 22q11DS. Copyright © 2014 Elsevier B.V. All rights reserved.

Characterization of the past and current duplication activities in the human 22q11.2 region

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Morrow Bernice

2011-01-01

Full Text Available Abstract Background Segmental duplications (SDs on 22q11.2 (LCR22, serve as substrates for meiotic non-allelic homologous recombination (NAHR events resulting in several clinically significant genomic disorders. Results To understand the duplication activity leading to the complicated SD structure of this region, we have applied the A-Bruijn graph algorithm to decompose the 22q11.2 SDs to 523 fundamental duplication sequences, termed subunits. Cross-species syntenic analysis of primate genomes demonstrates that many of these LCR22 subunits emerged very recently, especially those implicated in human genomic disorders. Some subunits have expanded more actively than others, and young Alu SINEs, are associated much more frequently with duplicated sequences that have undergone active expansion, confirming their role in mediating recombination events. Many copy number variations (CNVs exist on 22q11.2, some flanked by SDs. Interestingly, two chromosome breakpoints for 13 CNVs (mean length 65 kb are located in paralogous subunits, providing direct evidence that SD subunits could contribute to CNV formation. Sequence analysis of PACs or BACs identified extra CNVs, specifically, 10 insertions and 18 deletions within 22q11.2; four were more than 10 kb in size and most contained young AluYs at their breakpoints. Conclusions Our study indicates that AluYs are implicated in the past and current duplication events, and moreover suggests that DNA rearrangements in 22q11.2 genomic disorders perhaps do not occur randomly but involve both actively expanded duplication subunits and Alu elements.

Characteristic face: a key indicator for direct diagnosis of 22q11.2 deletions in Chinese velocardiofacial syndrome patients.

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Wu, Dandan; Chen, Yang; Xu, Chen; Wang, Ke; Wang, Huijun; Zheng, Fengyun; Ma, Duan; Wang, Guomin

2013-01-01

Velocardiofacial syndrome (VCFS) is a disease in human with an expansive phenotypic spectrum and diverse genetic mechanisms mainly associated with copy number variations (CNVs) on 22q11.2 or other chromosomes. However, the correlations between CNVs and phenotypes remain ambiguous. This study aims to analyze the types and sizes of CNVs in VCFS patients, to define whether correlations exist between CNVs and clinical manifestations in Chinese VCFS patients. In total, 55 clinically suspected Chinese VCFS patients and 100 normal controls were detected by multiplex ligation-dependent probe amplification (MLPA). The data from MLPA and all the detailed clinical features of the objects were documented and analyzed. A total of 44 patients (80.0%) were diagnosed with CNVs on 22q11.2. Among them, 43 (78.2%) presented with 22q11.2 heterozygous deletions, of whom 40 (93.0%) had typical 3-Mb deletion, and 3 (7.0%) exhibited proximal 1.5-Mb deletion; no patient was found with atypical deletion on 22q11.2. One patient (1.8%) presented with a 3-Mb duplication mapping to the typical 3-Mb region on 22q11.2, while none of the chromosomal abnormalities in the MLPA kit were found in the other 11 patients and 100 normal controls. All the 43 patients with 22q11.2 deletions displayed characteristic face and palatal anomalies; 37 of them (86.0%) had cognitive or behavioral disorders, and 23 (53.5%) suffered from immune deficiencies; 10 patients (23.3%) manifested congenital heart diseases. Interestingly, all patients with the characteristic face had 22q11.2 heterozygous deletions, but no difference in phenotypic spectrum was observed between 3-Mb and 1.5-Mb deletions. Our data suggest that the characteristic face can be used as a key indicator for direct diagnosis of 22q11.2 deletions in Chinese VCFS patients.

Cortical Dysconnectivity Measured by Structural Covariance Is Associated With the Presence of Psychotic Symptoms in 22q11.2 Deletion Syndrome.

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Sandini, Corrado; Scariati, Elisa; Padula, Maria Carmela; Schneider, Maude; Schaer, Marie; Van De Ville, Dimitri; Eliez, Stephan

2018-05-01

22q11.2 deletion syndrome (22q11DS) is the third-largest known genetic risk factor for the development of psychosis. Dysconnectivity has consistently been implicated in the physiopathology of psychosis. Structural covariance of cortical morphology is a method of exploring connectivity among brain regions that to date has not been employed in 22q11DS. In the present study we employed structural covariance of cortical thickness to explore connectivity alterations in a group of 108 patients with 22q11DS compared with 96 control subjects. We subsequently divided patients into two subgroups of 31 subjects each according to the presence of attenuated psychotic symptoms. FreeSurfer software was used to obtain the mean cortical thickness in 148 brain regions from T1-weighted 3T images. For each population we reconstructed a brain graph using Pearson correlation between the average thickness of each couple of brain regions, which we characterized in terms of mean correlation strength and in terms of network architecture using graph theory. Patients with 22q11DS presented increased mean correlation strength, but there was no difference in global architecture compared with control subjects. However, symptomatic patients presented increased mean correlation strength coupled with increased segregation and decreased integration compared with both control subjects and nonsymptomatic patients. They also presented increased centrality for a cluster of anterior cingulate and dorsomedial prefrontal regions. These results confirm the importance of cortical dysconnectivity in the physiopathology of psychosis. Moreover they support the significance of aberrant anterior cingulate connectivity. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

22q11.2 Deletion syndrome is associated with perioperative outcome in tetralogy of Fallot.

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Mercer-Rosa, Laura; Pinto, Nelangi; Yang, Wei; Tanel, Ronn; Goldmuntz, Elizabeth

2013-10-01

We sought to investigate the impact of 22q11.2 deletion on perioperative outcome in tetralogy of Fallot. We conducted a retrospective review of patients with tetralogy of Fallot who underwent complete surgical reconstruction at The Children's Hospital of Philadelphia between 1995 and 2006. Inclusion criteria included diagnosis of tetralogy of Fallot and known genotype. Fisher exact and Mann-Whitney tests were used for categoric and continuous variables, respectively. Regression analysis was used to determine whether deletion status predicts outcome. We studied 208 subjects with tetralogy of Fallot, 164 (79%) without and 44 (20%) with 22q11.2 deletion syndrome. There were no differences in sex, race, gestational age, age at diagnosis, admission weight, and duration of mechanical ventilation. Presenting anatomy, survival, complications and reoperations were also comparable between patients with and without 22q11.2 deletion syndrome. Those with 22q11.2 deletion syndrome had more aortopulmonary shunts preceding complete surgical repair (21% vs 7%, P = .02). This association was present after adjustment for presenting anatomy (stenosis, atresia, or absence of pulmonary valve and common atrioventricular canal) and surgical era. In addition, those with 22q11.2 deletion syndrome had longer cardiopulmonary bypass time (84 vs 72 minutes, P = .02) and duration of intensive care (6 vs 4 days, P = .007). Genotype affects early operative outcomes in tetralogy of Fallot resulting, in particular, in longer duration of intensive care. Future studies are required to determine factors contributing to such differences in this susceptible population. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Axis I psychiatric diagnoses in adolescents and young adults with 22q11 deletion syndrome

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Ousley, O.Y.; Smearman, E.; Fernandez-Carriba, S.; Rockers, K.A.; Coleman, K.; Walker, E.F.; Cubells, J.F.

2017-01-01

Background 22q11.2 deletion syndrome (22q11DS) associates with schizophrenia spectrum disorders (SSDs), autism spectrum disorders (ASDs), and other psychiatric disorders, but co-occurrence of diagnoses are not well described. Methods We evaluated the co-occurrence of SSDs, ASDs and other axis I psychiatric diagnoses in 31 adolescents and adults with 22q11DS, assessing ASDs using either stringent Collaborative Program for Excellence in Autism (ASD-CPEA) criteria, or less stringent DSM-IV criteria alone (ASD-DSM-IV). Results Ten (32%) individuals met criteria for an SSD, five (16%) for ASD-CPEA, and five others (16%) for ASD-DSM-IV. Of those with ASD-CPEA, one (20%) met SSD criteria. Of those with ASD-DSM-IV, four (80%) met SSD criteria. Depressive disorders (8 individuals; 26%) and anxiety disorders (7; 23%) sometimes co-occurred with SSDs and ASDs. SSDs, ASDs, and anxiety occurred predominantly among males and depression predominantly among females. Conclusions Individuals with 22q11DS can manifest SSDs in the presence or absence of ASDs and other axis I diagnoses. The results suggest that standard clinical care should include childhood screening for ASDs, and later periodic screening for all axis I diagnoses. PMID:23916466

A cross-sectional analysis of the development of response inhibition in children with Chromosome 22q11.2 Deletion Syndrome

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Heather M Shapiro

2013-08-01

Full Text Available Chromosome 22q11.2 Deletion Syndrome (22q11.2DS is a neurogenetic disorder that is associated with cognitive impairments and significantly elevated risk for developing schizophrenia. While impairments in response inhibition are central to executive dysfunction in schizophrenia, the nature and development of such impairments in children with 22q11.2DS, a group at high risk for the disorder, are not clear. Here we used a classic Go/No-Go paradigm to quantify proactive (anticipatory stopping and reactive (actual stopping response inhibition in 47 children with 22q11.2DS and 36 typically developing (TD children, all ages 7-14. A cross-sectional design was used to examine age-related associations with response inhibition. When compared with TD individuals, children with 22q11.2DS demonstrated typical proactive response inhibition at all ages. By contrast, reactive response inhibition was impaired in children with 22q11.2DS relative to TD children. While older age predicted better reactive response inhibition in TD children, there was no age-related association with reactive response inhibition in children with 22q11.2DS. Closer examination of individual performance data revealed a wide range of performance abilities in older children with 22q11.2DS; some typical and others highly impaired. The results of this cross-sectional analysis suggest an impaired developmental trajectory of reactive response inhibition in some children with 22q11.2DS that might be related to atypical development of neuroanatomical systems underlying this cognitive process. As part of a larger study, this investigation might help identify risk factors for conversion to schizophrenia and lead to early diagnosis and preventive intervention.

The hippocampi of children with chromosome 22q11.2 deletion syndrome have localized anterior alterations that predict severity of anxiety.

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Scott, Julia A; Goodrich-Hunsaker, Naomi; Kalish, Kristopher; Lee, Aaron; Hunsaker, Michael R; Schumann, Cynthia M; Carmichael, Owen T; Simon, Tony J

2016-04-01

Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an elevated risk for schizophrenia, which increases with history of childhood anxiety. Altered hippocampal morphology is a common neuroanatomical feature of 22q11.2DS and idiopathic schizophrenia. Relating hippocampal structure in children with 22q11.2DS to anxiety and impaired cognitive ability could lead to hippocampus-based characterization of psychosis-proneness in this at-risk population. We measured hippocampal volume using a semiautomated approach on MRIs collected from typically developing children and children with 22q11.2DS. We then analyzed hippocampal morphology with Localized Components Analysis. We tested the modulating roles of diagnostic group, hippocampal volume, sex and age on local hippocampal shape components. Lastly, volume and shape components were tested as covariates of IQ and anxiety. We included 48 typically developing children and 69 children with 22q11.2DS in our study. Hippocampal volume was reduced bilaterally in children with 22q11.2DS, and these children showed greater variation in the shape of the anterior hippocampus than typically developing children. Children with 22q11.2DS had greater inward deformation of the anterior hippocampus than typically developing children. Greater inward deformation of the anterior hippocampus was associated with greater severity of anxiety, specifically fear of physical injury, within the 22q11.2DS group. Shape alterations are not specific to hippocampal subfields. Alterations in the structure of the anterior hippocampus likely affect function and may impact limbic circuitry. We suggest these alterations potentially contribute to anxiety symptoms in individuals with 22q11.2DS through modulatory pathways. Altered hippocampal morphology may be uniquely linked to anxiety risk factors for schizophrenia, which could be a powerful neuroanatomical marker of schizophrenia risk and hence protection.

A case of de novo duplication of 15q24-q26.3

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Hye Ran Kim

2011-06-01

Full Text Available Distal duplication, or trisomy 15q, is an extremely rare chromosomal disorder characterized by prenatal and postnatal overgrowth, mental retardation, and craniofacial malformations. Additional abnormalities typically include an unusually short neck, malformations of the fingers and toes, scoliosis and skeletal malformations, genital abnormalities, particularly in affected males, and, in some cases, cardiac defects. The range and severity of symptoms and physical findings may vary from case to case, depending upon the length and location of the duplicated portion of chromosome 15q. Most reported cases of duplication of the long arm of chromosome 15 frequently have more than one segmental imbalance resulting from unbalanced translocations involving chromosome 15 and deletions in another chromosome, as well as other structural chromosomal abnormalities. We report a female newborn with a de novo duplication, 15q24- q26.3, showing intrauterine overgrowth, a narrow asymmetric face with down-slanting palpebral fissures, a large, prominent nose, and micrognathia, arachnodactyly, camptodactyly, congenital heart disease, hydronephrosis, and hydroureter. Chromosomal analysis showed a 46,XX,inv(9(p12q13,dup(15(q24q26.3. Array comparative genomic hybridization analysis revealed a gain of 42 clones on 15q24-q26.3. This case represents the only reported patient with a de novo 15q24-q26.3 duplication that did not result from an unbalanced translocation and did not have a concomitant monosomic component in Korea.

De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy.

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Vari, Maria Stella; Traverso, Monica; Bellini, Tommaso; Madia, Francesca; Pinto, Francesca; Minetti, Carlo; Striano, Pasquale; Zara, Federico

2017-08-01

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and may be associated with acquired central nervous system lesions or could be genetic. Various susceptibility genes and environmental factors are believed to be involved in the aetiology of TLE, which is considered to be a heterogeneous, polygenic, and complex disorder. Rare point mutations in LGI1, DEPDC5, and RELN as well as some copy number variations (CNVs) have been reported in families with TLE patients. We perform a genetic analysis by Array-CGH in a patient with dysmorphic features and temporal lobe epilepsy. We report a de novo duplication of the long arm of chromosome 12. We confirm that 12q22-q23.3 is a candidate locus for familial temporal lobe epilepsy with febrile seizures and highlight the role of chromosomal rearrangements in patients with epilepsy and intellectual disability. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome

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Bassett, Anne S.; Lowther, Chelsea; Merico, Daniele; Costain, Gregory; Chow, Eva W C; Van Amelsvoort, Therese; McDonald-Mcginn, Donna M.; Gur, Raquel E.; Swillen, Ann; van den Bree, Marianne B M; Murphy, Kieran C.; Gothelf, Doron; Bearden, Carrie E.; Eliez, Stephan; Kates, Wendy R.; Philip, Nicole; Sashi, Vandana; Campbell, Linda E.; Vorstman, Jacob; Cubells, Joseph; Repetto, Gabriela M.; Simon, Tony J.; Boot, Erik; Heung, Tracy; Evers, Rens; Vingerhoets, Claudia; Van Duin, Esther; Zackai, Elaine; Vergaelen, Elfi; Devriendt, Koen; Vermeesch, Joris R.; Owen, Michael J; Murphy, Clodagh M.; Michaelovosky, Elena; Kushan, Leila; Schneider, Maude; Fremont, Wanda; Busa, Tiffany; Hooper, Stephen R.; McCabe, Kathryn; Duijff, Sasja; Isaev, Karin; Pellecchia, Giovanna; Wei, John; Gazzellone, Matthew J.; Scherer, Stephen W.; Emanuel, Beverly S.; Guo, Tingwei; Morrow, Bernice E.; Marshall, Christian R.

2017-01-01

Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this studywas to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. Method: Through an

White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents.

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Sundram, Frederick; Campbell, Linda E; Azuma, Rayna; Daly, Eileen; Bloemen, Oswald J N; Barker, Gareth J; Chitnis, Xavier; Jones, Derek K; van Amelsvoort, Therese; Murphy, Kieran C; Murphy, Declan G M

2010-06-01

Young people with 22q11 Deletion Syndrome (22q11DS) are at substantial risk for developing psychosis and have significant differences in white matter (WM) volume. However, there are few in vivo studies of both WM microstructural integrity (as measured using Diffusion Tensor (DT)-MRI) and WM volume in the same individual. We used DT-MRI and structural MRI (sMRI) with voxel based morphometry (VBM) to compare, respectively, the fractional anisotropy (FA) and WM volume of 11 children and adolescents with 22q11DS and 12 controls. Also, within 22q11DS we related differences in WM to severity of schizotypy, and polymorphism of the catechol-O-methyltransferase (COMT) gene. People with 22q11DS had significantly lower FA in inter-hemispheric and brainstem and frontal, parietal and temporal lobe regions after covarying for IQ. Significant WM volumetric increases were found in the internal capsule, anterior brainstem and frontal and occipital lobes. There was a significant negative correlation between increased schizotypy scores and reduced WM FA in the right posterior limb of internal capsule and the right body and left splenium of corpus callosum. Finally, the Val allele of COMT was associated with a significant reduction in both FA and volume of WM in the frontal lobes, cingulum and corpus callosum. Young people with 22q11DS have significant differences in both WM microstructure and volume. Also, there is preliminary evidence that within 22q11DS, some regional differences in FA are associated with allelic variation in COMT and may perhaps also be associated with schizotypy.

Deletion of 11q12.3-11q13.1 in a patient with intellectual disability and childhood facial features resembling Cornelia de Lange syndrome

DEFF Research Database (Denmark)

Boyle, Martine Isabel; Jespersgaard, Cathrine; Nazaryan, Lusine

2015-01-01

Deletions within 11q12.3-11q13.1 are very rare and to date only two cases have been described in the literature. In this study we describe a 23-year-old male patient with intellectual disability, behavioral problems, dysmorphic features, dysphagia, gastroesophageal reflux and skeletal abnormalities...

Chronic myeloid leukemia with variation of translocation at (Ph) [ins (22;9) (q11;q21q34)]: a case report.

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Wang, Zhiqiong; Zen, Wen; Meng, Fankai; Xin, Xing; Luo, Li; Sun, Hanying; Zhou, Jianfeng; Huang, Lifang

2015-01-01

Chronic myeloid leukemia (CML) is most frequently observed in middle-aged individuals. In most patients, normal marrow cells are replaced by cells with an abnormal G-group chromosome, the Philadelphia (Ph) chromosome. The Ph chromosome that is characterized by the translocation (9;22) (q34;q11) is noted in 90-95% of patients diagnosed with CML. Studies have also shown that CML can be associated with various other cytogenetic abnormalities, with 5-10% of these cases showing complex translocation involving another chromosome in addition to the Ph chromosome. Here, we report the case of a Ph(+) CML patient with an inserted karyotype who presented clinically in the chronic phase but with atypical features. This case highlights the significance of cytogenetic abnormalities on the prognosis in CML.

Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome

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Starnawska, A; Hansen, C S; Sparsø, T

2017-01-01

Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous...... deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate...

Constitutional t(5;7)(q11;p15) rearranged to acquire monosomy 7q and trisomy 1q in a patient with myelodysplastic syndrome transforming to acute myelocytic leukemia.

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Ganly, Peter; McDonald, Margaret; Spearing, Ruth; Morris, Christine M

2004-03-01

We report the case of a 61-year-old woman who presented with a myelodysplastic syndrome (MDS) and a t(5;7)(q11.2;p15) in her bone marrow cells. Subsequent analysis of phytohemagglutinin-stimulated peripheral blood lymphocytes and cultured skin fibroblasts showed that the translocation was constitutional. Disruption of chromosome bands 5q11.2 and 7p15 has been described recurrently in MDS and acute myelocytic leukemia (AML) and, although the age of onset was not earlier than usual, it is nonetheless possible that genes interrupted by this translocation may been a predisposing factor for her condition. With progression to AML, a further rearrangement of the constitutional der(7)t(5;7) occurred, involving chromosome arm 1q. Fluorescence in situ hybridization (FISH) with whole-chromosome paints showed that the result of the second rearrangement, a t(1;7)(q32.1;q32), was observed, leading to trisomy of the segment 1q32.1 approximately qter and monosomy of the segment 7q32.1 approximately qter. The acquired imbalances, particularly loss of 7q, are commonly associated with MDS/AML and a poor prognosis; however, this patient remained in remission after treatment for more than two years before AML relapse, perhaps because the affected regions fall outside of the critical regions of imbalance.

Comparative analysis of vertebrate EIF2AK2 (PKR genes and assignment of the equine gene to ECA15q24–q25 and the bovine gene to BTA11q12–q15

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Zharkikh Andrey A

2006-09-01

Full Text Available Abstract The structures of the canine, rabbit, bovine and equine EIF2AK2 genes were determined. Each of these genes has a 5' non-coding exon as well as 15 coding exons. All of the canine, bovine and equine EIF2AK2 introns have consensus donor and acceptor splice sites. In the equine EIF2AK2 gene, a unique single nucleotide polymorphism that encoded a Tyr329Cys substitution was detected. Regulatory elements predicted in the promoter region were conserved in ungulates, primates, rodents, Afrotheria (elephant and Insectifora (shrew. Western clawed frog and fugu EIF2AK2 gene sequences were detected in the USCS Genome Browser and compared to those of other vertebrate EIF2AK2 genes. A comparison of EIF2AK2 protein domains in vertebrates indicates that the kinase catalytic domains were evolutionarily more conserved than the nucleic acid-binding motifs. Nucleotide substitution rates were uniform among the vertebrate sequences with the exception of the zebrafish and goldfish EIF2AK2 genes, which showed substitution rates about 20% higher than those of other vertebrates. FISH was used to physically assign the horse and cattle genes to chromosome locations, ECA15q24–q25 and BTA11q12–15, respectively. Comparative mapping data confirmed conservation of synteny between ungulates, humans and rodents.

Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge (22q11 deletion syndrome

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Beverly A. Karpinski

2014-02-01

Full Text Available We assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS, a common developmental disorder that frequently includes perinatal dysphagia – debilitating feeding, swallowing and nutrition difficulties from birth onward – within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V, glossopharyngeal (IX or vagus (X cranial nerves (CNs that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS.

22q11.2 deletion syndrome: behaviour problems of children and adolescents and parental stress.

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Briegel, W; Schneider, M; Schwab, K Otfried

2008-11-01

22q11.2 deletion syndrome can be associated with a variety of somatic symptoms, developmental delays and psychiatric disorders. At present, there is little information on behaviour problems, parental stress and possible relations between these factors. Therefore, this study investigates behaviour problems of children and adolescents with 22q11.2DS, and their primary caregivers' stress. Parents of 4-17 year old subjects known to the German 22q11.2 deletion syndrome foundation were anonymously asked to fill out several questionnaires, e.g. the Child Behavior Checklist 4-18 (CBCL/4-18). The primary caregivers of 77/126 children [43 males, 34 females, mean age: 8;0 (4;0-16;11) years] sent back filled-out questionnaires. Forty-six of 76 subjects were rated as clinical on at least one of the CBCL-scales. Males had significantly higher scores on the total problems scale and the internalizing problems scale than females. The patients' age correlated with several CBCL-scales. Eleven of 49 subjects were suspicious of an autism spectrum disorder. Compared with the general population, but not with other parents of mentally and/or physically handicapped children, the primary caregivers experienced higher levels of stress, but showed normal life satisfaction. In spite of high rates of clinical behaviour problems among children and adolescents with 22q11.2DS and despite increased parental stress, most primary caregivers seem to have effective coping strategies, e.g. partnership support, to sustain normal levels of life satisfaction.

Multimodal MRI reveals structural connectivity differences in 22q11 deletion syndrome related to impaired spatial working memory

NARCIS (Netherlands)

O'Hanlon, Erik; Howley, Sarah; Prasad, Sarah; McGrath, Jane; Leemans, Alexander; McDonald, Colm; Garavan, Hugh; Murphy, Kieran C

2016-01-01

INTRODUCTION: Impaired spatial working memory is a core cognitive deficit observed in people with 22q11 Deletion syndrome (22q11DS) and has been suggested as a candidate endophenotype for schizophrenia. However, to date, the neuroanatomical mechanisms describing its structural and functional

Extracorporeal membrane oxygenation in children with heart disease and del22q11 syndrome: a review of the Extracorporeal Life Support Organization Registry.

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Prodhan, P; Gossett, J M; Rycus, P T; Gupta, P

2015-11-01

The study objective was to evaluate outcomes among children with del22q11 (DiGeorge) syndrome supported on ECMO for heart disease. The ELSO registry database was queried to include all children syndrome and with no del22q11 syndrome. Eighty-eight ECMO runs occurred in children with del22q11 syndrome while 2694 ECMO runs occurred in children without del22q11 syndrome. For patients with heart defects receiving ECMO, del22q11 syndrome did not confer a significant mortality risk or an increased risk of infectious complications before or while on ECMO support. Neither the duration of ECMO nor mechanical ventilation prior to ECMO deployment were prolonged in patients with del22q11 syndrome compared to the controls. © The Author(s) 2015.

Low thymic output in the 22q11.2 deletion syndrome measured by CCR9+CD45RA+ T cell counts and T cell receptor rearrangement excision circles

DEFF Research Database (Denmark)

Lima, K; Abrahamsen, Gitte Meldgaard; Foelling, I

2010-01-01

Thymic hypoplasia is a frequent feature of the 22q11.2 deletion syndrome, but we know little about patients' age-related thymic output and long-term consequences for their immune system. We measured the expression of T cell receptor rearrangement excision circles (TREC) and used flow cytometry...

Social cognitive training in adolescents with chromosome 22q11.2 deletion syndrome: feasibility and preliminary effects of the intervention.

Science.gov (United States)

Shashi, V; Harrell, W; Eack, S; Sanders, C; McConkie-Rosell, A; Keshavan, M S; Bonner, M J; Schoch, K; Hooper, S R

2015-10-01

Children with chromosome 22q11.2 deletion syndrome (22q11DS) often have deficits in social cognition and social skills that contribute to poor adaptive functioning. These deficits may be of relevance to the later occurrence of serious psychiatric illnesses such as schizophrenia. Yet, there are no evidence-based interventions to improve social cognitive functioning in children with 22q11DS. Using a customised social cognitive curriculum, we conducted a pilot small-group-based social cognitive training (SCT) programme in 13 adolescents with 22q11DS, relative to a control group of nine age- and gender-matched adolescents with 22q11DS. We found the SCT programme to be feasible, with high rates of compliance and satisfaction on the part of the participants and their families. Our preliminary analyses indicated that the intervention group showed significant improvements in an overall social cognitive composite index. SCT in a small-group format for adolescents with 22q11DS is feasible and results in gains in social cognition. A larger randomised controlled trial would permit assessment of efficacy of this promising novel intervention. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Restriction of the Patau syndrome to duplication of 13q22{yields}q.32 and possible role of interphase nuclear structure

Energy Technology Data Exchange (ETDEWEB)

Helali, A.N.; Jafolla, A.K.; Oumsiych, M.B. [Duke Univ. Medical Center, Durham, NC (United States)

1994-09-01

A 10-year-old white male presented with mild microcephaly, slight growth and psychomotor retardation, soft fleshy ears, and normal facial features except for thin lips. No other significant anomalies were reported except for tethered cord discovered at age 8 years. The karyotype was found to be 46,XY,der(18)t(13;18)(q32;p11.32)pat. The mild phenotype appears to be primarily due to the duplication of 13q32{yields}qter. None of the cardinal features of trisomy 13 are found in cases of duplication of bands 13q22 to qter. This case shows that Patau syndrome phenotype does not originate by duplication of 13q32{yields}qter and may thus be restricted to 13q22 to 13q32. The variability in phenotypes points to an alternative explanation to the classical one of additive and interactive gene effects. This model involves effects of changes in chromosome position in the interphase nucleus on gene expression.

TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia.

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Tsutomu Ogata

Full Text Available BACKGROUND: Although TBX1 mutations have been identified in patients with 22q11.2 deletion syndrome (22q11.2DS-like phenotypes including characteristic craniofacial features, cardiovascular anomalies, hypoparathyroidism, and thymic hypoplasia, the frequency of TBX1 mutations remains rare in deletion-negative patients. Thus, it would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22q11.2DS-like phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We studied three subjects with craniofacial features and hypocalcemia (group 1, two subjects with craniofacial features alone (group 2, and three subjects with normal phenotype within a single Japanese family. Fluorescence in situ hybridization analysis excluded chromosome 22q11.2 deletion, and genomewide array comparative genomic hybridization analysis revealed no copy number change specific to group 1 or groups 1+2. However, exome sequencing identified a heterozygous TBX1 frameshift mutation (c.1253delA, p.Y418fsX459 specific to groups 1+2, as well as six missense variants and two in-frame microdeletions specific to groups 1+2 and two missense variants specific to group 1. The TBX1 mutation resided at exon 9C and was predicted to produce a non-functional truncated protein missing the nuclear localization signal and most of the transactivation domain. CONCLUSIONS/SIGNIFICANCE: Clinical features in groups 1+2 are well explained by the TBX1 mutation, while the clinical effects of the remaining variants are largely unknown. Thus, the results exemplify the usefulness of exome sequencing in the identification of disease-causing mutations in familial disorders. Furthermore, the results, in conjunction with the previous data, imply that TBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS phenotypes.

Persistent monoclonality after histological remission in gastric mucosa-associated lymphoid tissue lymphoma treated with chemotherapy and/or surgery: influence of t(11;18)(q21;q21).

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Santón, Almudena; García-Cosio, Mónica; Bellosillo, Beatriz; Rodríguez, Patricia; Cristóbal, Eva; Serrano, Sergio; Besses, Carlos; Abraira, Victor; Salar, Antonio; Montalbán, Carlos

2008-08-01

The purpose of this work was to study retrospectively the molecular response and outcome of 19 gastric mucosa associated lymphoid tissue (MALT) lymphoma patients achieving histological remission after chemotherapy or surgery. Immunoglobulin heavy chain variable (IgV(H)) gene rearrangements were studied by PCR in biopsies obtained at diagnosis and follow-up. Presence of t(11;18)(q21;q21) was studied by FISH or RT-PCR. Sequencing analysis of three t(11;18)(q21;q21) positive and two negative lymphomas with persistent monoclonal IgV(H) rearrangements was also performed. Long-term IgV(H) monoclonality was demonstrated in 11/19 patients (58%); in five of them monoclonal rearrangements were present in all samples throughout the follow-up. Persistent IgV(H) monoclonality was detected a median of 49 months after the achievement of histological response and did not condition histological relapse in most cases. All three t(11;18)(q21;q21) positive patients had maintained IgV(H) monoclonality and sequencing analyses revealed the same mutated IgV(H) alleles in the diagnostic and the follow-up samples. Over half of the patients with gastric MALT lymphoma with histological response after chemotherapy and/or surgery have long-term persistent monoclonality. The presence of t(11;18)(q21;q21) seems to condition long-term persistence of the initial lymphoma clone.trade mark.

Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome.

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Chantal Sellier

Full Text Available Deletion of the 1.5-3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS, also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%, conotruncal defects of the heart (CHD; 70-80%, hypocalcemia (20-60%, and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy number or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to combinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS.

The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome

NARCIS (Netherlands)

Hidding, E.; Swaab, H.; de Sonneville, L. M J; van Engeland, H.; Vorstman, J. A S

2016-01-01

This paper examines how COMT158 genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism

Prenatal Diagnosis of a 2.5 Mb De Novo 17q24.1q24.2 Deletion Encompassing KPNA2 and PSMD12 Genes in a Fetus with Craniofacial Dysmorphism, Equinovarus Feet, and Syndactyly

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Marie-Emmanuelle Naud

2017-01-01

Full Text Available Interstitial 17q24.1 or 17q24.2 deletions were reported after conventional cytogenetic analysis or chromosomal microarray analysis in patients presenting intellectual disability, facial dysmorphism, and/or malformations. We report on a fetus with craniofacial dysmorphism, talipes equinovarus, and syndactyly associated with a de novo 2.5 Mb 17q24.1q24.2 deletion. Among the deleted genes, KPNA2 and PSMD12 are discussed for the correlation with the fetal phenotype. This is the first case of prenatal diagnosis of 17q24.1q24.2 deletion.

Comparing the Broad Socio-Cognitive Profile of Youth with Williams Syndrome and 22Q11.2 Deletion Syndrome

Science.gov (United States)

Weisman, O.; Feldman, R.; Burg-Malki, M.; Keren, M.; Geva, R.; Diesendruck, G.; Gothelf, D.

2017-01-01

Background: Numerous studies have assessed the socio-cognitive profile in Williams syndrome (WS) and, independently, in 22q11.2 deletion syndrome (22q11.2DS). Yet, a cross-syndrome comparison of these abilities between individuals with these two syndromes with known social deficits has not been conducted. Methods: Eighty-two children participated…

Working Memory Impairments in Chromosome 22q11.2 Deletion Syndrome: The Roles of Anxiety and Stress Physiology

Science.gov (United States)

Sanders, Ashley F.; Hobbs, Diana A.; Stephenson, David D.; Laird, Robert D.; Beaton, Elliott A.

2017-01-01

Stress and anxiety have a negative impact on working memory systems by competing for executive resources and attention. Broad memory deficits, anxiety, and elevated stress have been reported in individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS). We investigated anxiety and physiological stress reactivity in relation to visuospatial…

Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12)

DEFF Research Database (Denmark)

Panagopoulos, Ioannis; Kerndrup, Gitte; Carlsen, Niels

2007-01-01

Three NUP98 chimaeras have previously been reported in T cell acute lymphoblastic leukaemia (T-ALL): NUP98/ADD3, NUP98/CCDC28A, and NUP98/RAP1GDS1. We report a T-ALL with t(11;18)(p15;q12) resulting in a novel NUP98 fusion. Fluorescent in situ hybridisation showed NUP98 and SET binding protein 1(...... in leukaemias; however, it encodes a protein that specifically interacts with SET, fused to NUP214 in a case of acute undifferentiated leukaemia.......Three NUP98 chimaeras have previously been reported in T cell acute lymphoblastic leukaemia (T-ALL): NUP98/ADD3, NUP98/CCDC28A, and NUP98/RAP1GDS1. We report a T-ALL with t(11;18)(p15;q12) resulting in a novel NUP98 fusion. Fluorescent in situ hybridisation showed NUP98 and SET binding protein 1...

Mother-Child Interaction as a Window to a Unique Social Phenotype in 22q11.2 Deletion Syndrome and in Williams Syndrome

Science.gov (United States)

Weisman, Omri; Feldman, Ruth; Burg-Malki, Merav; Keren, Miri; Geva, Ronny; Diesendruck, Gil; Gothelf, Doron

2015-01-01

Mother-child interactions in 22q11.2 Deletion syndrome (22q11.2DS) and Williams syndrome (WS) were coded for maternal sensitivity/intrusiveness, child's expression of affect, levels of engagement, and dyadic reciprocity. WS children were found to express more positive emotions towards their mothers compared to 22q11.2DS children and those with…

Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11(q21;q23/MLL-AF4 Positive B-Cell Acute Lymphoblastic Leukemia

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F. Marchesi

2011-01-01

Full Text Available Translocation t(4;11(q21;q23 leading to formation of MLL-AF4 fusion gene is found in about 10% of newly diagnosed B-cell acute lymphoblastic leukemia (ALL in adult patients. Patients expressing this chromosomal aberration present typical biological, immunophenotypic, and clinical features. This form of leukemia is universally recognized as high-risk leukemia and treatment intensification with allogeneic hematopoietic stem cell transplantation (HSCT in first complete remission (CR could be a valid option to improve prognosis, but data obtained from the literature are controversial. In this review, we briefly describe pathogenetic, clinical, and prognostic characteristics of adult t(4;11(q21;q23/MLL-AF4 positive ALL and provide a review of the clinical outcome reported by the most important cooperative groups worldwide.

Various endocrine disorders in children with t(13;14(q10;q10 Robertsonian translocation

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Byung Ho Choi

2013-09-01

Full Text Available Purpose45,XY,t(13;14(q10;q10 karyotype can suggest infertility associated with more or less severe oligospermia in male adults. In addition, 45,XX,t(13;14(q10;q10 karyotype carries reproductive risks such as miscarriage or infertility in female adults. However, reports on the phenotype of this karyotype in children are very rare. This study was done to observe various phenotypes of this karyotype in children.MethodsBetween January 2007 and December 2012, children diagnosed with 45,XY,t(13;14(q10;q10 or 45,XX,t(13;14(q10;q10 karyotype by chromosome analysis were analyzed retrospectively.ResultsEight children (5 boys and 3 girls were diagnosed with 45,XY,t(13;14(q10;q10 or 45,XX,t(13;14(q10;q10 karyotype. They ranged in age from 5 years and 6 months to 12 years and 4 months. The phenotypes of the study patients consisted of 1 hypogonadotrophic hypogonadism, 1 precocious puberty, 3 early puberty, 2 growth hormone deficiency (GHD (partial and 1 idiopathic short stature. As shown here t(13;14(q10;q10 Robertsonian translocation shows a wide range of phenotypes.ConclusionIt can be said that t(13;14(q10;q10 Robertsonian translocation shows various phenotypes from GHD to precocious puberty in children. Further large-scale studies are necessary.

Cortical morphology development in patients with 22q11.2 deletion syndrome at ultra-high risk of psychosis.

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Padula, Maria Carmela; Schaer, Marie; Armando, Marco; Sandini, Corrado; Zöller, Daniela; Scariati, Elisa; Schneider, Maude; Eliez, Stephan

2018-01-17

Patients with 22q11.2 deletion syndrome (22q11DS) present a high risk of developing psychosis. While clinical and cognitive predictors for the conversion towards a full-blown psychotic disorder are well defined and largely used in practice, neural biomarkers do not yet exist. However, a number of investigations indicated an association between abnormalities in cortical morphology and higher symptoms severities in patients with 22q11DS. Nevertheless, few studies included homogeneous groups of patients differing in their psychotic symptoms profile. In this study, we included 22 patients meeting the criteria for an ultra-high-risk (UHR) psychotic state and 22 age-, gender- and IQ-matched non-UHR patients. Measures of cortical morphology, including cortical thickness, volume, surface area and gyrification, were compared between the two groups using mass-univariate and multivariate comparisons. Furthermore, the development of these measures was tested in the two groups using a mixed-model approach. Our results showed differences in cortical volume and surface area in UHR patients compared with non-UHR. In particular, we found a positive association between surface area and the rate of change of global functioning, suggesting that higher surface area is predictive of improved functioning with age. We also observed accelerated cortical thinning during adolescence in UHR patients with 22q11DS. These results, although preliminary, suggest that alterations in cortical volume and surface area as well as altered development of cortical thickness may be associated to a greater probability to develop psychosis in 22q11DS.

Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2

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Matsuoka, Rumiko; Takao, Atsuyoshi; Kimura, Misa; Kondo, Chisato; Ando, Masahiko; Momma, Kazuo; Imamura, Shin-ichiro [Heart Institute, Tokyo (Japan); Joh-o, Kunitaka [Welfare Pension Hospital, Kyushu (Japan); Ikeda, Kazuo [Sapporo Medical Univ. (Japan); Nishibatake, Makoto [Kagoshima Seikyo Hospital (Japan)

1994-11-15

The so-called {open_quotes}conotruncal anomaly face syndrome{close_quotes} (CTAFS) is characterized by a peculiar facial appearance associated with congenital heart disease (CHD), especially cardiac outflow tract defects such as tetralogy of Fallot (TOF), double outlet ring ventricle (DORV), and truncus arteriosus (TAC). CTAFS and the DiGeorge anomaly (DGA) have many similar phenotypic characteristics, suggesting that they share a common cause. In many cases DGA is known to be associated with monosomy for a region of chromosome 22q11.2. Fifty CTAFS patients and 10 DGA patients, 11 parents couples and 10 mothers of CTAFS patients, and 3 parents couples and 2 mothers of DGA patients were examined by fluorescent in situ hybridization (FISH) using the N25 (D22S75) DGCR probe (Oncor). Monosomy for a region of 22q11.2 was found in 42 CTAFS, 9 DGA, 4 mothers, and 1 father who had CTAF without CHD. The remaining 8 CTAFS patients, 1 DGA patient and 1 mother who had questionable CTAF without CHD, showed no such chromosome abnormality. For the control, 60 patients who had CHD without CTAF or other know malformation syndromes were examined and had no deletion of 22q11.2. Therefore, we conclude that CTAFS is a part of the CATCH 22 syndrome; cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia (CATCH) resulting from 22q11.2 deletions. 20 refs., 3 figs., 2 tabs.

Analysis of 22q11.2 deletions by FISH in a series of velocardiofacial syndrome patients

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Ravnan, J.B.; Golabi, M.; Lebo, R.V. [Univ. of California, San Francisco, CA (United States)

1994-09-01

Deletions in chromosome 22 band q11.2 have been associated with velocardiofacial (VCF or Shprintzen) syndrome and the DiGeorge anomaly. A study of VCF patients evaluated at the UCSF Medical Center was undertaken to correlate disease phenotype with presence or absence of a deletion. Patients referred for this study had at least two of the following: dysmorphic facial features, frequent ear infections or hearing loss, palate abnormalities, thymic hypoplasia, hypocalcemia, congenital heart defect, hypotonia, and growth or language delay. Fluorescence in situ hybridization (FISH) using the DiGeorge critical region probe N25 was used to classify patients according to the presence or absence of a deletion in 22q11.2, and the results were compared to clinical characteristics. We have completed studies on 58 patients with features of VCF. Twenty-one patients (36%) were found to have a deletion in 22q11.2 by FISH. A retrospective study of archived slides from 14 patients originally studied only by prometaphase GTG banding found six patients had a deletion detected by FISH; of these, only two had a microscopically visible chromosome deletion. Our study of 11 sets of parents of children with the deletion found two clinically affected mothers with the deletion, including one with three of three children clinically affected. A few patients who did not fit the classical VCF description had a 22q11.2 deletion detected by FISH. These included one patient with both cleft lip and palate, and another with developmental delay and typical facial features but no cardiac or palate abnormalities. Both patients with the DiGeorge anomaly as part of VCF had the deletion. On the other hand, a number of patients diagnosed clinically with classical VCF did not have a detectable deletion. This raises the question whether they represent a subset of patients with a defect of 22q11.2 not detected by the N25 probe, or whether they represent a phenocopy of VCF.

Relationship between reaction time, fine motor control, and visual-spatial perception on vigilance and visual-motor tasks in 22q11.2 Deletion Syndrome.

LENUS (Irish Health Repository)

Howley, Sarah A

2012-10-15

22q11.2 Deletion Syndrome (22q11DS) is a common microdeletion disorder associated with mild to moderate intellectual disability and specific neurocognitive deficits, particularly in visual-motor and attentional abilities. Currently there is evidence that the visual-motor profile of 22q11DS is not entirely mediated by intellectual disability and that these individuals have specific deficits in visual-motor integration. However, the extent to which attentional deficits, such as vigilance, influence impairments on visual motor tasks in 22q11DS is unclear. This study examines visual-motor abilities and reaction time using a range of standardised tests in 35 children with 22q11DS, 26 age-matched typically developing (TD) sibling controls and 17 low-IQ community controls. Statistically significant deficits were observed in the 22q11DS group compared to both low-IQ and TD control groups on a timed fine motor control and accuracy task. The 22q11DS group performed significantly better than the low-IQ control group on an untimed drawing task and were equivalent to the TD control group on point accuracy and simple reaction time tests. Results suggest that visual motor deficits in 22q11DS are primarily attributable to deficits in psychomotor speed which becomes apparent when tasks are timed versus untimed. Moreover, the integration of visual and motor information may be intact and, indeed, represent a relative strength in 22q11DS when there are no time constraints imposed. While this may have significant implications for cognitive remediation strategies for children with 22q11DS, the relationship between reaction time, visual reasoning, cognitive complexity, fine motor speed and accuracy, and graphomotor ability on visual-motor tasks is still unclear.

Velo-Cardio-Facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region

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Nickel, R.E.; Pillers, D.M.; Merkens, M.; Magenis, R.E.; Zonana, J. [Oregon Health Sciences Univ., Portland, OR (United States); Driscoll, D.A.; Emanuel, B.S. [Univ. of Pennsylvania Medical Center, Philadelphia, PA (United States)

1994-10-01

Approximately 5% of children with neural tube defects (NTDs) have a congenital heart defect and/or cleft lip and palate. The cause of isolated meningomyelocele, congenital heart defects, or cleft lip and palate has been largely thought to be multifactorial. However, chromosomal, teratogenic, and single gene causes of combinations of NTDs with congenital heart defects and/or cleft lip and palate have been reported. We report on 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of velo-cardio-facial syndrome (VCFS); both have bifid uvula. The third child had DiGeorge sequence (DGS). The association of NTDs with 22q11 deletion has not been reported previously. An accurate diagnosis of the 22q11 deletion is critical as this micro-deletion and its associated clinical problems is transmitted as an autosomal dominant trait due to the inheritance of the deletion-bearing chromosome. We recommend that all children with NTDs and congenital heart defects, with or without cleft palate, have cytogenetic and molecular studies performed to detect 22q11 deletions. 31 refs., 3 figs.

Development of a multiplex Q-PCR to detect Trichoderma harzianum Rifai strain T22 in plant roots.

Science.gov (United States)

Horn, Ivo R; van Rijn, Menno; Zwetsloot, Tom J J; Basmagi, Said; Dirks-Mulder, Anita; van Leeuwen, Willem B; Ravensberg, Willem J; Gravendeel, Barbara

2016-02-01

The fungal species Trichoderma harzianum is widely used as a biological agent in crop protection. To verify the continued presence of this fungus on plant roots manually inoculated with T. harzianum strain T22, a Q-PCR was designed using specific probes for this particular strain. To develop these molecular diagnostic tools, genome mining was first carried out to retrieve putative new regions by which different strains of T. harzianum could be distinguished. Subsequently, Sanger sequencing of the L-aminoacid oxidase gene (aox1) in T. harzianum was applied to determine the mutations differing between various strains isolated from the Trichoderma collection of Koppert Biological Systems. Based on the sequence information obtained, a set of hydrolysis probes was subsequently developed which discriminated T. harzianum T22 strains varying in only a single nucleotide. Probes designed for two strains uniquely recognized the respective strains in Q-PCR with a detection limit of 12,5ng DNA. Titration assays in which T. harzianum DNA from distinct strains was varied further underscored the specificity of the probes. Lastly, fungal DNA extracted from roots of greenhouse cultured tomato plants was analyzed using the probe-based assay. DNA from T. harzianum strain T22 could readily be identified on roots of greenhouse reared tomato plants inoculated with varying concentrations up to one week after treatment with a detection limit of 3e6 colony forming units of T. harzianum T22. We conclude that the Q-PCR method is a reliable and robust method for assessing the presence and quantity of T. harzianum strain T22 in manually inoculated plant material. Our method provides scope for the development of DNA based strain specific identification of additional strains of Trichoderma and other fungal biological control agents. Copyright © 2015 Elsevier B.V. All rights reserved.

Oral health and 22q11 deletion syndrome: thoughts and experiences from the parents' perspectives.

Science.gov (United States)

Klingberg, Gunilla; Hallberg, Ulrika; Oskarsdóttir, Sólveig

2010-07-01

22q11 deletion syndrome (22q11DS) is one of the most common multiple anomaly syndromes, and many dentists are likely to meet patients with the syndrome. Odontological research has focused on describing and analysing conditions/concepts based on the current state of knowledge within the dental profession. Yet, these research topics are not necessarily the most important issues for the patients. To explore and describe, by use of Grounded theory, parents' experiences of oral health issues and needs for dental care in their children with 22q11DS. Twelve parents from different regions in Sweden were interviewed. Analyses were carried out according to Grounded theory. Parents recognised good oral health as important for the wellbeing of their children. Oral health was a concern and the parents described the fight for this as struggling in vain for good oral health in their child. Parents not only described their children's oral health as important but also hard to gain. Thus, it is important that all patients with disabilities, regardless of whether there is a defined medical diagnosis or not, are identified and well taken care of in the dental care system.

Failure to thrive as presentation in a patient with 22q11.2 microdeletion.

Science.gov (United States)

Bossi, Grazia; Gertosio, Chiara; Meazza, Cristina; Farello, Giovanni; Bozzola, Mauro

2016-02-11

Abnormalities of chromosome 22q11, including deletions and translocations, have been described in association with different birth defects and malformations occurring in many combinations and degrees of severity. We describe the case of an 8 month-old infant with no dysmorphic signs who showed progressive postnatal growth failure and no chronic systemic diseases. We found a 22q11.2 microdeletion, inherited from the mother, suggesting the diagnosis of DiGeorge syndrome. The patient had an isolated growth hormone (GH) deficiency and a significant increase in linear growth during the first and the second year of GH therapy, and a recovery of weight was shown. Sometimes, in infants with growth failure a genetic analysis is strongly suggested, since chromosomal abnormalities may be present.

Individuals with 22q11.2 Deletion Syndrome Are Impaired at Explicit, but Not Implicit, Discrimination of Local Forms Embedded in Global Structures

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Giersch, Anne; Glaser, Bronwyn; Pasca, Catherine; Chabloz, Mélanie; Debbané, Martin; Eliez, Stephan

2014-01-01

Individuals with 22q11.2 deletion syndrome (22q11.2DS) are impaired at exploring visual information in space; however, not much is known about visual form discrimination in the syndrome. Thirty-five individuals with 22q11.2DS and 41 controls completed a form discrimination task with global forms made up of local elements. Affected individuals…

Familial DiGeorge/velocardiofacial syndrome with deletions of chromosome area 22q11.2: Report of five families with a review of the literature

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Leana-Cox, J.; Pangkanon, Suthipong; Eanet, K.R. [Univ. of Maryland School of Medicine, Baltimore, MD (United States)] [and others

1996-11-11

The DiGeorge (DG), velocardiofacial (VCF), and conotruncal anomaly-face (CTAF) syndromes were originally described as distinct disorders, although overlapping phenotypes have been recognized. It is now clear that all three syndromes result from apparently similar or identical 22q11.2 deletions, suggesting that they represent phenotypic variability of a single genetic syndrome. We report on 12 individuals in five families with del(22)(q11.2) by fluorescent in situ hybridization, and define the frequency of phenotypic abnormalities in those cases and in 70 individuals from 27 del(22)(q11.2) families from the literature. Common manifestations include mental impairment (97%), abnormal face (93%), cardiac malformations (681%), thymic (64%) and parathyroid (63%) abnormalities, and cleft palate or velopharyngeal insufficiency (48%). Familial DG, VCF, and CTAF syndromes due to del(22)(q11.2) show significant inter- and intrafamilial clinical variability consistent with the hypothesis that a single gene or group of tightly linked genes is the common cause of these syndromes. Up to 25% of 22q deletions are inherited, indicating that parents of affected children warrant molecular cytogenetic evaluation. We propose use of the compound term {open_quotes}DiGeorge/velocardiofacial (DGNCF) syndrome{close_quotes} in referring to this condition, as it calls attention to the phenotypic spectrum using historically familiar names. 41 refs., 2 figs., 2 tabs.

Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome.

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Thompson, Carlie A; Karelis, Jason; Middleton, Frank A; Gentile, Karen; Coman, Ioana L; Radoeva, Petya D; Mehta, Rashi; Fremont, Wanda P; Antshel, Kevin M; Faraone, Stephen V; Kates, Wendy R

2017-04-01

22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with 22q11.2DS develop schizophrenia, though little is known about the underlying mechanisms. We hypothesized that allelic variation in functional polymorphisms in seven genes unique to the deleted region would affect lobar brain volumes, which would predict risk for psychosis in youth with 22q11.2DS. Participants included 56 individuals (30 males) with 22q11.2DS. Anatomic MR images were collected and processed using Freesurfer. Participants were genotyped for 10 SNPs in the COMT, DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms of psychosis. Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. Our results suggest that RTN4R, a relatively under-studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Syntenic homology of human unique DNA sequences within chromossome regions 5q31, 10q22, 13q32-33 and 19q13.1 in the great apes

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Rhea U. Vallente-Samonte

2000-09-01

Full Text Available Homologies between chromosome banding patterns and DNA sequences in the great apes and humans suggest an apparent common origin for these two lineages. The availability of DNA probes for specific regions of human chromosomes (5q31, 10q22, 13q32-33 and 19q13.1 led us to cross-hybridize these to chimpanzee (Pan troglodytes, PTR, gorilla (Gorilla gorilla, GGO and orangutan (Pongo pygmaeus, PPY chromosomes in a search for equivalent regions in the great apes. Positive hybridization signals to the chromosome 5q31-specific DNA probe were observed at HSA 5q31, PTR 4q31, GGO 4q31 and PPY 4q31, while fluorescent signals using the chromosome 10q22-specific DNA probe were noted at HSA 10q22, PTR 8q22, GGO 8q22 and PPY 7q22. The chromosome arms showing hybridization signals to the Quint-EssentialTM 13-specific DNA probe were identified as HSA 13q32-33, PTR 14q32-33, GGO 14q32-33 and PPY 14q32-33, while those presenting hybridization signals to the chromosome 19q13.1-specific DNA probe were identified as HSA 19q13.1, PTR 20q13, GGO 20q13 and PPY 20q13. All four probes presumably hybridized to homologous chromosomal locations in the apes, which suggests a homology of certain unique DNA sequences among hominoid species.Homologias entre os padrões de bandamento de cromossomos e seqüências de DNA em grandes macacos e humanos sugerem uma aparente origem comum para estas duas linhagens. A disponibilidade de sondas de DNA para regiões específicas de cromossomos humanos (5q31, 10q22, 13q32-33 e 19q13.1 nos levou a realizar hibridação cruzada com cromossomos de chimpanzé (Pan troglodytes, PTR, gorila (Gorilla gorilla, GGO e orangotango (Pongo pygmaeus, PPY em um pesquisa de regiões equivalentes em grandes macacos. Sinais positivos de hibridação para a sonda de DNA específica para o cromossomo 5q31 foram observados em HSA 5q31, PTR 4q31, GGO 4q31 e PPY 4q31, enquanto que sinais fluorescentes usando a sonda de DNA específica para o cromossomo 10q22 foram

Deletions at chromosome regions 7q11.23 and 7q36 in a patient with Williams syndrome

NARCIS (Netherlands)

Wouters, C. H.; Meijers-Heijboer, H. J.; Eussen, B. J.; van der Heide, A. A.; van Luijk, R. B.; van Drunen, E.; Beverloo, B. B.; Visscher, F.; van Hemel, J. O.

2001-01-01

We report on a patient with Williams syndrome and a complex de novo chromosome rearrangement, including microdeletions at 7q11.23 and 7q36 and additional chromosomal material at 7q36. The nature of this additional material was elucidated by spectral karyotyping and first assigned to chromosome 22.

Performance on the Modified Card Sorting Test and Its Relation to Psychopathology in Adolescents and Young Adults with 22Q11.2 Deletion Syndrome

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Rockers, K.; Ousley, O.; Sutton, T.; Schoenberg, E.; Coleman, K.; Walker, E.; Cubells, J. F.

2009-01-01

Background: Approximately one-third of individuals with 22q11.2 deletion syndrome (22q11DS), a common genetic disorder highly associated with intellectual disabilities, may develop schizophrenia, likely preceded by a mild to moderate cognitive decline. Methods: We examined adolescents and young adults with 22q11DS for the presence of executive…

Fine mapping of the human renal oncocytoma-associated translocation (5;11)(q35;q13) breakpoint

NARCIS (Netherlands)

Sinke, RJ; Dijkhuizen, T; Janssen, B; Weghuis, DO; Merkx, G; vandenBerg, E; Schuuring, E; Meloni, AM; deJong, B; vanKessel, AG

1997-01-01

Recent cytogenetic analysis of a series of human renal oncocytomas revealed the presence of a recurring chromosomal translocation (5;11)(q35;q13) as sole anomaly in a subset of the tumors. The molecular characterization of this translocation was initiated using two primary t(5;11)-positive renal

Mapping Cortical Morphology in Youth with Velocardiofacial (22q11.2 Deletion) Syndrome

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Kates, Wendy R.; Bansal, Ravi; Fremont, Wanda; Antshel, Kevin M.; Hao, Xuejun; Higgins, Anne Marie; Liu, Jun; Shprintzen, Robert J.; Peterson, Bradley S.

2011-01-01

Objective: Velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) represents one of the highest known risk factors for schizophrenia. Insofar as up to 30% of individuals with this genetic disorder develop schizophrenia, VCFS constitutes a unique, etiologically homogeneous model for understanding the pathogenesis of schizophrenia. Method:…

Partial deletion 11q

DEFF Research Database (Denmark)

Hertz, Jens Michael; Tommerup, N; Sørensen, F B

1995-01-01

We describe the cytogenetic findings and the dysmorphic features in a stillborn girl with a large de novo terminal deletion of the long arm of chromosome 11. The karyotype was 46,XX,del(11)(q21qter). By reviewing previous reports of deletion 11q, we found that cleft lip and palate are most...

The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome.

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Hidding, E; Swaab, H; de Sonneville, L M J; van Engeland, H; Vorstman, J A S

2016-11-01

This paper examines how COMT 158 genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer-based test-paradigms. Associations with COMT 158 genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMT MET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMT MET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT 158 genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Formula: see text]Executive functioning and its relation to ASD and ADHD symptomatology in 22q11.2 deletion syndrome.

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de Sonneville, Leo M J; Hidding, Elske; van Engeland, Herman; Vorstman, Jacob A S; Sijmens-Morcus, Monique E J; Swaab, Hanna

2018-01-01

Children with 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial-syndrome) are at risk for the developmental disorders, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this study, the relation between executive functioning (EF) and the severity of ADHD and ASD symptoms is examined, since EF is known to be important in relation to emotional and behavioral problems. The participants consist of 58 children (38 females) with a mean age of 13.5 years (SD 2.6). Standardized assessment was used to evaluate the severity of ASD and ADHD symptomatology. The major aspects of EF, i.e., cognitive flexibility, inhibition, sustained attention, distractibility, working memory and reaction speed, were evaluated. The profile of EF in 22q11DS was found to be characterized by weaker performance compared to the norms on all subdomains of EF. Poor cognitive flexibility and inhibition, as well as high distractibility, were found to be related to more severe ASD symptoms, while poor quality of sustained attention and high distractibility were found to be related to more severe ADHD symptoms. It is concluded that children with 22q11DS experience impairments in EF, and that the degree of impairment on specific EF subdomains is related to the severity of ASD and/or ADHD symptomatology. These results may help in defining the mediating role of neurocognitive dysfunctions in the development of social and behavioral problems in 22q11DS.

22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease.

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Falah, Nadia; Posey, Jennifer E; Thorson, Willa; Benke, Paul; Tekin, Mustafa; Tarshish, Brocha; Lupski, James R; Harel, Tamar

2017-04-01

Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., (2004); AJMGA 127: 149-151], of an individual with 22q duplication and sex-reversal syndrome. The subject's phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain of function rather than dominant negative activity underlies PCWH. © 2017 Wiley Periodicals, Inc.

Memory in Intellectually Matched Groups of Young Participants with 22q11.2 Deletion Syndrome and Those with Schizophrenia

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Kravariti, Eugenia; Jacobson, Clare; Morris, Robin; Frangou, Sophia; Murray, Robin M.; Tsakanikos, Elias; Habel, Alex; Shearer, Jo

2010-01-01

The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors…

Physical mapping of a commonly deleted region, the site of a candidate tumor suppressor gene, at 12q22 in human male germ cell tumors

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Murty, V.V.V.S.; Bosl, G.J.; Chaganti, R.S.K. [Memorial Sloan-Kettering Cancer Center, New York, NY (United States)] [and others

1996-08-01

A candidate tumor suppressor gene (TSG) site at 12q22 characterized by a high frequency of loss of heterozygosity (LOH) and a homozygous deletion has previously (LOH) and a homozygous deletion has previously been reported in human male germ cell tumors (GCTs). In a detailed deletion mapping analysis of 67 normal-tumor DNAs utilizing 20 polymorphic markers mapped to 12q22-q24, we identified the limits of the minimal region of deletion at 12q22 between D12S377 (priximal) and D12S296 (distal). We have constructed a YAC contig map of a 3-cM region of this band between the proximal marker D12S101 and the distal marker D12S346, which contained the minimal region of deletion in GCTs. The map is composed of 53 overlapping YACs and 3 cosmids onto which 25 polymorphic and nonpolymorphic sequence-tagged sites (STSs) were placed in a unique order. The size of the minimal region of deletion was approximately 2 Mb from overlapping, nonchimeric YACs that spanned the region. We also developed a radiation hybrid (RH) map of the region between D12S101 and D12S346 containing 17 loci. The consensus order developed by RH mapping is in good agreement with the YAC STS-content map order. The RH map estimated the distance between D12S101 and D12S346 to be 246 cR{sub 8000} and the minimal region of deletion to be 141 cR{sub 8000}. In addition, four genes that were previously mapped to 12q22 have been excluded as candidate genes. The leads gained from the deletion mapping and physical maps should expedite the isolation and characterization of the TSG at 12q22. 35 refs., 4 figs., 2 tabs.

Analysis of autism susceptibility gene loci on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q in Finnish multiplex families.

Science.gov (United States)

Auranen, M; Nieminen, T; Majuri, S; Vanhala, R; Peltonen, L; Järvelä, I

2000-05-01

The role of genetic factors in the etiology of the autistic spectrum of disorders has clearly been demonstrated. Ten chromosomal regions, on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q have potentially been linked to autism.1-8 We have analyzed these chromosomal regions in a total of 17 multiplex families with autism originating from the isolated Finnish population by pairwise linkage analysis and sib-pair analysis. Mild evidence for putative contribution was found only with the 1p chromosomal region in the susceptibility to autism. Our data suggest that additional gene loci exist for autism which will be detectable in and even restricted to the isolated Finnish population.

A Case of AML Characterized by a Novel t(4;15(q31;q22 Translocation That Confers a Growth-Stimulatory Response to Retinoid-Based Therapy

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Justin M. Watts

2017-07-01

Full Text Available Here we report the case of a 30-year-old woman with relapsed acute myeloid leukemia (AML who was treated with all-trans retinoic acid (ATRA as part of investigational therapy (NCT02273102. The patient died from rapid disease progression following eight days of continuous treatment with ATRA. Karyotype analysis and RNA-Seq revealed the presence of a novel t(4;15(q31;q22 reciprocal translocation involving the TMEM154 and RASGRF1 genes. Analysis of primary cells from the patient revealed the expression of TMEM154-RASGRF1 mRNA and the resulting fusion protein, but no expression of the reciprocal RASGRF1-TMEM154 fusion. Consistent with the response of the patient to ATRA therapy, we observed a rapid proliferation of t(4;15 primary cells following ATRA treatment ex vivo. Preliminary characterization of the retinoid response of t(4;15 AML revealed that in stark contrast to non-t(4;15 AML, these cells proliferate in response to specific agonists of RARα and RARγ. Furthermore, we observed an increase in the levels of nuclear RARγ upon ATRA treatment. In summary, the identification of the novel t(4;15(q31;q22 reciprocal translocation opens new avenues in the study of retinoid resistance and provides potential for a new biomarker for therapy of AML.

Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population-A Nationwide Register Study

DEFF Research Database (Denmark)

Vangkilde, Anders; Olsen, Line; Hoeffding, Louise K

2016-01-01

OBJECTIVE: Cross-sectional studies have shown associations between 22q11.2 deletion syndrome and schizophrenia. However, large-scale prospective studies have been lacking. We, therefore, conducted the first large-scale population based study on the risk of being diagnosed with schizophrenia...... in persons identified with 22q11.2 deletion syndrome. METHODS: Danish nationwide registers were linked to establish a cohort consisting of all Danish citizens born during 1955-2004 and the cohort was followed from January 1, 1994 until December 31, 2013. Data were analyzed using survival analyses...... and adjusted for calendar year, age, sex, and parental mental health history. RESULTS: A total of 156 individuals with 22q11.2 deletion syndrome were identified, out of which 6 individuals were diagnosed with schizophrenia spectrum disorders following identification with 22q11 deletion syndrome. Identified...

A new case of Beckwith-Wiedemann syndrome with an 11p15 duplication of paternal origin [46,XY,-21,+der(21), t(11;21)(p15.2;q22.3)pat].

Science.gov (United States)

Krajewska-Walasek, M; Gutkowska, A; Mospinek-Krasnopolska, M; Chrzanowska, K

1996-01-01

We present a new case of 11p15 duplication (trisomy 11p15) in a boy (46,XY,-21,+der(21), t(11;21)(p15.2;q22.3)] suffering from Beckwith-Wiedemann syndrome (BWS), whose phenotypically normal father carries a balanced translocation between chromosomes 11 and 21[46,XY, t(11;21)(p15.2;q22.3)]. The paternal grandmother has the same balanced translocation and is also clinically normal. BWS was suspected when the boy was 6 months old because of gigantism, macroglossia, visceromegaly, ear lobe creases and abdominal distention. Apart from the characteristic BWS phenotype, the boy has other features which are almost exclusively observed in 11p trisomy (high forehead with frontal upsweep of hair, wide central nose bridge, slightly beaked nose, chubby cheeks and severe mental retardation). So far, at least eight cases of 11p15 duplication have been described as patients with BWS. In six of these, the duplication was due to inheritance of a translocated or rearranged paternal chromosome. This was also the case in our patient. In the two other previously published cases, the 11p15 duplications were de novo, but in one of these, DNA analysis has subsequently shown that the duplication was of paternal origin. We discuss our observations in relation to the above-mentioned previous cases of 11p15 duplication and the possible role of genomic imprinting in the etiology of BWS.

Double-hit lymphoma demonstrating t(6;14;18)(p25;q32;q21), suggesting two independent dual-hit translocations, MYC/BCL-2 and IRF4/BCL-2.

Science.gov (United States)

Tabata, Rie; Yasumizu, Ryoji; Tabata, Chiharu; Kojima, Masaru

2013-01-01

Here, we report a rare case of double-hit lymphoma, demonstrating t(6;14;18)(p25;q32;q21), suggesting two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2. The present case had a rare abnormal chromosome, t(6;14;18)(p25;q32;q21), independently, in addition to known dual-hit chromosomal abnormalities, t(14;18)(q32;q21) and t(8;22)(q24;q11.2). Lymph node was characterized by a follicular and diffuse growth pattern with variously sized neoplastic follicles. The intrafollicular area was composed of centrocytes with a few centroblasts and the interfollicular area was occupied by uniformly spread medium- to large-sized lymphocytes. CD23 immunostaining demonstrated a disrupted follicular dendritic cell meshwork. The intrafollicular tumor cells had a germinal center phenotype with the expression of surface IgM, CD10, Bcl-2, Bcl-6, and MUM1/IRF4. However, the interfollicular larger cells showed plasmacytic differentiation with diminished CD20, Bcl-2, Bcl-6, and positive intracytoplasmic IgM, and co-expression of MUM1/IRF4 and CD138 with increased Ki-67-positive cells (> 90%). MUM1/IRF4 has been found to induce c-MYC expression, and in turn, MYC transactivates MUM1/IRF4, creating a positive autoregulatory feedback loop. On the other hand, MUM1/IRF4 functions as a tumor suppressor in c-MYC-induced B-cell leukemia. The present rare case arouses interest in view of the possible "dual" activation of both c-MYC and MUM1/IRF4 through two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2.

Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes

DEFF Research Database (Denmark)

Luukkonen, Tiia Maria; Mehrjouy, Mana M; Pöyhönen, Minna

2018-01-01

BACKGROUND: The risk of serious congenital anomaly for de novo balanced translocations is estimated to be at least 6%. We identified two apparently independent families with a balanced t(1;12)(q43;q21.1) as an outcome of a "Systematic Survey of Balanced Chromosomal Rearrangements in Finns." In th...

Inversion of chromosome 7q22 and q36 as a sole abnormality presenting in myelodysplastic syndrome: a case report.

Science.gov (United States)

Kaneko, Hiroto; Shimura, Kazuho; Kuwahara, Saeko; Ohshiro, Muneo; Tsutsumi, Yasuhiko; Iwai, Toshiki; Horiike, Shigeo; Yokota, Shouhei; Ohkawara, Yasuo; Taniwaki, Masafumi

2014-08-05

Deletions of chromosome 7 are often detected in myelodysplastic syndrome. The most commonly deleted segments are clustered at band 7q22. A critical gene is therefore suggested to be located in this region. We report a patient with myelodysplastic syndrome whose marrow cells carried an inversion of 7q22 and q36 as a sole karyotypic abnormality. How this extremely rare chromosomal aberration contributes to the pathogenesis of myelodysplastic syndrome should be clarified by accumulating clinical data of such cases. A 74-year-old Japanese man presented with pancytopenia incidentally detected by routine medical check-up. His complete blood cell counts revealed that his white blood cells had decreased to 2100/mm3, neutrophils 940/mm3, red blood cells 320×104/mm3, hemoglobin 11.1g/dL, hematocrit 33.1%, and platelets 12.6×104/mm3. Bone marrow examination showed normal cellularity with nucleated cells of 9.4×104/mm3. The proportion of blasts was 4%. A morphological examination showed only basophilic stippling of erythroblasts which was seen as dysplasia. According to World Health Organization classification, the diagnosis was myelodysplastic syndrome-u. Karyotypic analysis showed 46,XY,inv(7)(q22q36) in all of 20 metaphases examined. Additional analysis revealed the karyotype of his lymphocytes was 46,XY. He is asymptomatic and cytopenia has slowly progressed. To the best of our knowledge, this karyotype from a clinical sample of de novo malignancies has never been documented although the identical karyotype from secondary myelodysplastic syndrome was reported. Despite the extremely low frequency, inversion of 7q22 appears to play a crucial role for myelodysplastic syndrome in this patient.

Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk

Science.gov (United States)

Broderick, Peter; Chen, Bowang; Johnson, David C; Försti, Asta; Vijayakrishnan, Jayaram; Migliorini, Gabriele; Dobbins, Sara E; Holroyd, Amy; Hose, Dirk; Walker, Brian A; Davies, Faith E; Gregory, Walter A; Jackson, Graham H; Irving, Julie A; Pratt, Guy; Fegan, Chris; Fenton, James AL; Neben, Kai; Hoffmann, Per; Nöthen, Markus M; Mühleisen, Thomas W; Eisele, Lewin; Ross, Fiona M; Straka, Christian; Einsele, Hermann; Langer, Christian; Dörner, Elisabeth; Allan, James M; Jauch, Anna; Morgan, Gareth J; Hemminki, Kari; Houlston, Richard S; Goldschmidt, Hartmut

2016-01-01

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 cases and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P=8.70x10-14), 6p21.33 (rs2285803, PSORS1C2; P= 9.67x10-11), 17p11.2 (rs4273077, TNFRSF13B; P=7.67x10-9) and 22q13.1 (rs877529, CBX7; P=7.63x10-16). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy and insight into the biological basis of predisposition. PMID:23955597

Allelic variations at the haploid TBX1 locus do not influence the cardiac phenotype in cases of 22q11 microdeletion.

Science.gov (United States)

Voelckel, Marie-Antoinette; Girardot, Lydie; Giusiano, Bernard; Levy, Nicolas; Philip, Nicole

2004-01-01

Microdeletion at the 22q11 locus is characterised by a high clinical variability. Congenital heart defects (CHD) are the most life-threatening manifestations of the syndrome and affect approximately 50% of patients carrying the deleted chromosome 22. The causes of this phenotype variability remain unknown although several hypotheses have been raised. It has been suggested that allelic variations at the haploid locus could modify the phenotypic expression. Regarding this hypothesis, TBX1 was thought to be a major candidate to the cardiac phenotype or its severity in patients carrying the 22q11 microdeletion. A mutational screening was performed in this gene, in a series of 39 deleted patients, with and without CHD. The results indicate that mutations in TBX1 are not likely to be involved in the cardiac phenotype observed in del22q11 patients.

Detecting 22q11.2 deletions by use of multiplex ligation-dependent probe amplification on DNA from neonatal dried blood spot samples

DEFF Research Database (Denmark)

Sørensen, Karina M; Agergaard, Peter; Olesen, Charlotte

2010-01-01

The 22q11 deletion syndrome, which is caused by a 1.5- to 3.0-megabase hemizygous deletion in chromosome 22q11.2, has a prevalence of 1/2000 to 1/4000. However, the syndrome presents with highly variable phenotypes and thus may be underestimated among Danish newborns. To establish a true incidenc...

Dopamine in high-risk populations: A comparison of subjects with 22q11.2 deletion syndrome and subjects at ultra high-risk for psychosis.

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Vingerhoets, Claudia; Bloemen, Oswald J N; Boot, Erik; Bakker, Geor; de Koning, Mariken B; da Silva Alves, Fabiana; Booij, Jan; van Amelsvoort, Thérèse A M J

2018-02-28

Striatal dopamine (DA) dysfunction has been consistently reported in psychotic disorders. Differences and similarities in the pathogenesis between populations at clinical and genetic risk for developing psychosis are yet to be established. Here we explored markers of dopamine (DA) function in subjects meeting clinically ultra-high risk criteria for psychosis (UHR) and in subjects with 22q11.2 deletion syndrome (22q11DS), a genetic condition associated with significant risk for developing psychotic disorders. Single Photon Emission Computed Tomography (SPECT) with 123 I-labelled iodobenzamide ([ 123 I]IBZM) was used to measure striatal DA D 2/3 receptor binding potential (D 2 R BP ND ). Also, peripheral DAergic markers were assessed in serum and urine (plasma prolactin (pPRL), plasma homovanillic acid (pHVA) and urine DA(uDA)). No significant difference in striatal D 2 R BP ND was found between UHR and 22q11DS subjects. Compared to UHR subjects, pPRL and pHVA were lower and uDA levels were higher in the 22q11DS subjects. However, after correcting for age and gender, only pPRL as significantly lower in the 22q11DS patients. These results may suggest that there are differences in DAergic markers between subjects with UHR and with 22q11DS that may reflect differences in the pathways to psychosis. However, bigger samples are needed to replicate these findings. Copyright © 2017 Elsevier B.V. All rights reserved.

Array-based gene expression, CGH and tissue data defines a 12q24 gain in neuroblastic tumors with prognostic implication

Directory of Open Access Journals (Sweden)

Kilpinen Sami

2010-05-01

Full Text Available Abstract Background Neuroblastoma has successfully served as a model system for the identification of neuroectoderm-derived oncogenes. However, in spite of various efforts, only a few clinically useful prognostic markers have been found. Here, we present a framework, which integrates DNA, RNA and tissue data to identify and prioritize genetic events that represent clinically relevant new therapeutic targets and prognostic biomarkers for neuroblastoma. Methods A single-gene resolution aCGH profiling was integrated with microarray-based gene expression profiling data to distinguish genetic copy number alterations that were strongly associated with transcriptional changes in two neuroblastoma cell lines. FISH analysis using a hotspot tumor tissue microarray of 37 paraffin-embedded neuroblastoma samples and in silico data mining for gene expression information obtained from previously published studies including up to 445 healthy nervous system samples and 123 neuroblastoma samples were used to evaluate the clinical significance and transcriptional consequences of the detected alterations and to identify subsequently activated gene(s. Results In addition to the anticipated high-level amplification and subsequent overexpression of MYCN, MEIS1, CDK4 and MDM2 oncogenes, the aCGH analysis revealed numerous other genetic alterations, including microamplifications at 2p and 12q24.11. Most interestingly, we identified and investigated the clinical relevance of a previously poorly characterized amplicon at 12q24.31. FISH analysis showed low-level gain of 12q24.31 in 14 of 33 (42% neuroblastomas. Patients with the low-level gain had an intermediate prognosis in comparison to patients with MYCN amplification (poor prognosis and to those with no MYCN amplification or 12q24.31 gain (good prognosis (P = 0.001. Using the in silico data mining approach, we identified elevated expression of five genes located at the 12q24.31 amplicon in neuroblastoma (DIABLO, ZCCHC

On the Hopf structure of Up,q(gl(1/1)) and the universal Τ-matrix of Funp,q(GL(1/1))

International Nuclear Information System (INIS)

Chakrabarti, R.; Jagannathan, R.

1994-08-01

Using the technique developed by Fronsdal and Galindo (Lett. Math. Phys, 27 (1993) 57) for studying the Hopf duality between the quantum algebras Fun p,q (GL(2)) and U p,q (gl(2)), the Hopf structure of U p,q (gl(1/1)), dual to Fun p,q (GL(1/1)), is derived and the corresponding universal Τ-matrix of Fun p,q (GL(1/1)), embodying the suitably modified exponential relationship U p,q (gl(1/1)) → Fun p,q (GL(1/1)), is obtained. (author). 10 refs

Phenotypic variability in Waardenburg syndrome resulting from a 22q12.3-q13.1 microdeletion involving SOX10.

Science.gov (United States)

Jelena, Brezo; Christina, Lam; Eric, Vilain; Fabiola, Quintero-Rivera

2014-06-01

Waardenburg syndrome (WS) is a neurocristopathy characterized by pigmentation abnormalities of the skin, hair, and iris, as well as sensorineural hearing loss. Contiguous gene deletions encompassing SOX10 are rare, which limits conclusions about genotype-phenotype correlation regarding patient prognosis and management. This study adds to the existing body of knowledge by characterizing a 2.4 Mb deletion [arr[hg19] 22q12.3-q13.1 (36467502-38878207)x1] encompassing SOX10 and 53 additional RefSeq genes in a 15-year-old female with atypical WS. The patient presented with developmental delay, profound bilateral sensorineural hearing loss, heterochromia iridis, hypotonia, and bilateral finger contractures. Published genomic and phenotypic profiles of patients with SOX10-encompassing deletions point toward several plausible candidate gene that could account for the considerable clinical heterogeneity. These studies suggest the existence of modifiers among the co-deleted, dosage-sensitive genes (e.g., MYH9) and among genes whose effect may depend on the unmasking of recessive mutations (e.g., PLA2G6). Finally, we highlight evidence illustrating extensive interconnectivity of SOX10-hypothesizing that haploinsufficiency of SOX10 may "unmask" subtler effects on expression or epistasis associated with variants in SOX10 targets (e.g., DHH), in its partners (e.g., PAX3, EGR2), and in genes with functional overlap (e.g., SOX8, SOX9). © 2014 Wiley Periodicals, Inc.

White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents

NARCIS (Netherlands)

Sundram, Frederick; Campbell, Linda E.; Azuma, Rayna; Daly, Eileen; Bloemen, Oswald J. N.; Barker, Gareth J.; Chitnis, Xavier; Jones, Derek K.; van Amelsvoort, Therese; Murphy, Kieran C.; Murphy, Declan G. M.

2010-01-01

Young people with 22q11 Deletion Syndrome (22q11DS) are at substantial risk for developing psychosis and have significant differences in white matter (WM) volume. However, there are few in vivo studies of both WM microstructural integrity (as measured using Diffusion Tensor (DT)-MRI) and WM volume

High rates of de novo 15q11q13 inversions in human spermatozoa

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Molina Òscar

2012-02-01

Full Text Available Abstract Low-Copy Repeats predispose the 15q11-q13 region to non-allelic homologous recombination. We have already demonstrated that a significant percentage of Prader-Willi syndrome (PWS fathers have an increased susceptibility to generate 15q11q13 deletions in spermatozoa, suggesting the participation of intrachromatid exchanges. This work has been focused on assessing the incidence of de novo 15q11q13 inversions in spermatozoa of control donors and PWS fathers in order to determine the basal rates of inversions and to confirm the intrachromatid mechanism as the main cause of 15q11q13 anomalies. Semen samples from 10 control donors and 16 PWS fathers were processed and analyzed by triple-color FISH. Three differentially labeled BAC-clones were used: one proximal and two distal of the 15q11-q13 region. Signal associations allowed the discrimination between normal and inverted haplotypes, which were confirmed by laser-scanning confocal microscopy. Two types of inversions were detected which correspond to the segments involved in Class I and II PWS deletions. No significant differences were observed in the mean frequencies of inversions between controls and PWS fathers (3.59% ± 0.46 and 9.51% ± 0.87 vs 3.06% ± 0.33 and 10.07% ± 0.74. Individual comparisons showed significant increases of inversions in four PWS fathers (P Results suggest that the incidence of heterozygous inversion carriers in the general population could reach significant values. This situation could have important implications, as they have been described as predisposing haplotypes for genomic disorders. As a whole, results confirm the high instability of the 15q11-q13 region, which is prone to different types of de novo reorganizations by intrachromatid NAHR.

Genomic Anatomy of a Premier Major Histocompatibility Complex Paralogous Region on Chromosome 1q21–q22

Science.gov (United States)

Shiina, Takashi; Ando, Asako; Suto, Yumiko; Kasai, Fumio; Shigenari, Atsuko; Takishima, Nobusada; Kikkawa, Eri; Iwata, Kyoko; Kuwano, Yuko; Kitamura, Yuka; Matsuzawa, Yumiko; Sano, Kazumi; Nogami, Masahiro; Kawata, Hisako; Li, Suyun; Fukuzumi, Yasuhito; Yamazaki, Masaaki; Tashiro, Hiroyuki; Tamiya, Gen; Kohda, Atsushi; Okumura, Katsuzumi; Ikemura, Toshimichi; Soeda, Eiichi; Mizuki, Nobuhisa; Kimura, Minoru; Bahram, Seiamak; Inoko, Hidetoshi

2001-01-01

Human chromosomes 1q21–q25, 6p21.3–22.2, 9q33–q34, and 19p13.1–p13.4 carry clusters of paralogous loci, to date best defined by the flagship 6p MHC region. They have presumably been created by two rounds of large-scale genomic duplications around the time of vertebrate emergence. Phylogenetically, the 1q21–25 region seems most closely related to the 6p21.3 MHC region, as it is only the MHC paralogous region that includes bona fide MHC class I genes, the CD1 and MR1 loci. Here, to clarify the genomic structure of this model MHC paralogous region as well as to gain insight into the evolutionary dynamics of the entire quadriplication process, a detailed analysis of a critical 1.7 megabase (Mb) region was performed. To this end, a composite, deep, YAC, BAC, and PAC contig encompassing all five CD1 genes and linking the centromeric +P5 locus to the telomeric KRTC7 locus was constructed. Within this contig a 1.1-Mb BAC and PAC core segment joining CD1D to FCER1A was fully sequenced and thoroughly analyzed. This led to the mapping of a total of 41 genes (12 expressed genes, 12 possibly expressed genes, and 17 pseudogenes), among which 31 were novel. The latter include 20 olfactory receptor (OR) genes, 9 of which are potentially expressed. Importantly, CD1, SPTA1, OR, and FCERIA belong to multigene families, which have paralogues in the other three regions. Furthermore, it is noteworthy that 12 of the 13 expressed genes in the 1q21–q22 region around the CD1 loci are immunologically relevant. In addition to CD1A-E, these include SPTA1, MNDA, IFI-16, AIM2, BL1A, FY and FCERIA. This functional convergence of structurally unrelated genes is reminiscent of the 6p MHC region, and perhaps represents the emergence of yet another antigen presentation gene cluster, in this case dedicated to lipid/glycolipid antigens rather than antigen-derived peptides. [The nucleotide sequence data reported in this paper have been submitted to the DDBJ, EMBL, and GenBank databases under

Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25.

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Burkardt, Deepika D'Cunha; Rosenfeld, Jill A; Helgeson, Maria L; Angle, Brad; Banks, Valerie; Smith, Wendy E; Gripp, Karen W; Moline, Jessica; Moran, Rocio T; Niyazov, Dmitriy M; Stevens, Cathy A; Zackai, Elaine; Lebel, Robert Roger; Ashley, Douglas G; Kramer, Nancy; Lachman, Ralph S; Graham, John M

2011-06-01

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome. Copyright © 2011 Wiley-Liss, Inc.

22q13.3 Deletion Syndrome: An Underdiagnosed Cause of Mental Retardation

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ilknur Erol

2015-03-01

Full Text Available Phelan-McDermid syndrome, also known as 22q13.3 deletion syndrome, is characterized by global developmental delay, absent or delayed speech, generalized hypotonia, and minor physical anomalies. The deletion typically involves the terminal band 22q13.3 and has been associated with both familial and de-novo translocations. We report the case of an 11-year-old Turkish girl with 22q13.3 deletion syndrome presenting with repeated seizures during the course of a rubella infection. We also review the clinical features of 22q13.3 deletion syndrome and emphasize the importance of considering a rare microdeletion syndrome for idiopathic mental retardation when results of a routine karyotype analysis are normal. To the best of our knowledge, this is the first reported case of a Turkish patient with isolated 22q13.3 deletion syndrome. [Cukurova Med J 2015; 40(1.000: 169-173

A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients

DEFF Research Database (Denmark)

Lund, A.B. Kiholm; Hove, H.D.; Kirchhoff, M.

2008-01-01

A 15q24 microduplication, reciprocal to the minimal critical region for the recently described 15q24 microdeletion syndrome, was found in a 2-year-old boy by 244k Agilent oligoarray CGH analysis. The boy had global developmental delay and dysmorphic facial features, digital and genital abnormalit...

Identification of a region of frequent loss of heterozygosity at 11q24 in colorectal cancer.

Science.gov (United States)

Connolly, K C; Gabra, H; Millwater, C J; Taylor, K J; Rabiasz, G J; Watson, J E; Smyth, J F; Wyllie, A H; Jodrell, D I

1999-06-15

Loss of heterozygosity (LOH) at 11q23-qter occurs frequently in ovarian and other cancers, but for colorectal cancer, the evidence is conflicting. Seven polymorphic loci were analyzed between D11S897 and D11S969 in 50 colorectal tumors. Two distinct LOH regions were detected, suggesting possible sites for tumor-suppressor genes involved in colorectal neoplasia: a large centromeric region between D11S897 and D11S925, and a telomeric 4.9-Mb region between D11S912 and D11S969. There was no correlation with clinicopathological features. This analysis describes a region of LOH in the region 11q23.3-24.3 for the first time in colorectal cancer and provides complementary evidence for the ongoing effort to identify the gene(s) involved.

Histology of the pharyngeal constrictor muscle in 22q11.2 deletion syndrome and non-syndromic children with velopharyngeal insufficiency.

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Josine C C Widdershoven

Full Text Available Plastic surgeons aim to correct velopharyngeal insufficiency manifest by hypernasal speech with a velopharyngoplasty. The functional outcome has been reported to be worse in patients with 22q11.2 deletion syndrome than in patients without the syndrome. A possible explanation is the hypotonia that is often present as part of the syndrome. To confirm a myogenic component of the etiology of velopharyngeal insufficiency in children with 22q11.2 deletion syndrome, specimens of the pharyngeal constrictor muscle were taken from children with and without the syndrome. Histologic properties were compared between the groups. Specimens from the two groups did not differ regarding the presence of increased perimysial or endomysial space, fiber grouping by size or type, internalized nuclei, the percentage type I fibers, or the diameters of type I and type II fibers. In conclusion, a myogenic component of the etiology of velopharyngeal insufficiency in children with 22q11.2 deletion syndrome could not be confirmed.

Histology of the pharyngeal constrictor muscle in 22q11.2 deletion syndrome and non-syndromic children with velopharyngeal insufficiency.

Science.gov (United States)

Widdershoven, Josine C C; Spruijt, Nicole E; Spliet, Wim G M; Breugem, Corstiaan C; Kon, Moshe; Mink van der Molen, Aebele B

2011-01-01

Plastic surgeons aim to correct velopharyngeal insufficiency manifest by hypernasal speech with a velopharyngoplasty. The functional outcome has been reported to be worse in patients with 22q11.2 deletion syndrome than in patients without the syndrome. A possible explanation is the hypotonia that is often present as part of the syndrome. To confirm a myogenic component of the etiology of velopharyngeal insufficiency in children with 22q11.2 deletion syndrome, specimens of the pharyngeal constrictor muscle were taken from children with and without the syndrome. Histologic properties were compared between the groups. Specimens from the two groups did not differ regarding the presence of increased perimysial or endomysial space, fiber grouping by size or type, internalized nuclei, the percentage type I fibers, or the diameters of type I and type II fibers. In conclusion, a myogenic component of the etiology of velopharyngeal insufficiency in children with 22q11.2 deletion syndrome could not be confirmed.

Central diabetes insipidus preceding acute myeloid leukemia with t(3;12)(q26;p12)

NARCIS (Netherlands)

Nieboer, P; Vellenga, E; Adriaanse, R; van de Loosdrecht, AA

A 52-year-old woman presented with polyuria and polydipsia. ii diagnosis of central diabetes insipidus (DI) was made, which turned out to be the first sign of acute myeloid leukemia (AML). Cytogenetic analysis revealed a balanced translocation between chromosome 3 and 12 t(3;12)(q26;p12). The

A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome.

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Joel Frohlich

Full Text Available Duplications of 15q11.2-q13.1 (Dup15q syndrome are highly penetrant for autism spectrum disorder (ASD. A distinct electrophysiological (EEG pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome.In the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11, age-and-IQ-matched children with ASD (n = 10 and age-matched typically developing (TD children (n = 9 and computed relative power in 6 frequency bands for 9 regions of interest (ROIs. Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27 across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions.In the first study, spontaneous beta1 (12-20 Hz and beta2 (20-30 Hz power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1-4 Hz was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1. In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome.Here, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome.

Sperm FISH analysis of a 44,X,der(Y),t(Y;15)(q12;q10)pat,rob(13;14)(q10;q10)mat complex chromosome rearrangement.

Science.gov (United States)

Ferfouri, F; Boitrelle, F; Clement, P; Molina Gomes, D; Selva, J; Vialard, F

2014-06-01

Complex chromosome rearrangements (CCR) with two independent chromosome rearrangements are rare. Although CCRs lead to high unbalanced gamete rates, data on meiotic segregation in this context are scarce. A male patient was referred to our clinic as part of a family screening programme prompted by the observation of a 44,X,der(Y),t(Y;15)(q12;q10)pat,rob(13;14)(q10;q10)mat karyotype in his brother. Karyotyping identified the same CCR. Sperm FISH (with locus-specific probes for the segments involved in the translocations and nine chromosomes not involved in both rearrangements) was used to investigate the rearrangements meiotic segregation products and establish whether or not an inter-chromosomal effect was present. Sperm nuclear DNA fragmentation was also evaluated. For rob(13;14) and der(Y), the proportions of unbalanced products were, respectively, 26.4% and 60.6%. Overall, 70.3% of the meiotic segregation products were unbalanced. No evidence of an inter-chromosomal effect was found, and the sperm nuclear DNA fragmentation rate was similar to our laboratory's normal cut-off value. In view of previously published sperm FISH analyses of Robertsonian translocations (and even though the mechanism is still unknown), we hypothesise that cosegregation of der(Y) and rob(13;14) could modify rob(13;14) meiotic segregation. © 2013 Blackwell Verlag GmbH.

Distinct regions of loss of heterozygosity on 22q in different sites of head and neck squamous cell carcinomas

DEFF Research Database (Denmark)

dos Reis, Patricia Pintor; Poli-Frederico, Regina Célia; dos Santos, Rodrigo Mattos

2002-01-01

laryngeal, and 31 pharyngeal carcinomas. RESULTS: Two separate regions of LOH were identified in the laryngeal (22q11.2-12.1) and oral cavity (22q13.1-13.31) tumors. When the different anatomical sites were compared, a statistically significant difference was found between the presence of LOH at D22S421 (p......pharyngeal tumors and genes...

Clinical, Molecular, and Prognostic Significance of WHO Type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and Various Other 3q Abnormalities in Acute Myeloid Leukemia

NARCIS (Netherlands)

Lugthart, Sanne; Groschel, Stefan; Beverloo, H. Berna; Kayser, Sabine; Valk, Peter J. M.; van Zelderen-Bhola, Shama Lydia; Ossenkoppele, Gert Jan; Vellenga, Edo; van den Berg-de Ruiter, Eva; Schanz, Urs; Verhoef, Gregor; Vandenberghe, Peter; Ferrant, Augustin; Kohne, Claus-Henning; Pfreundschuh, Michael; Horst, Heinz A.; Koller, Elisabeth; von Lilienfeld-Toal, Marie; Bentz, Martin; Ganser, Arnold; Schlegelberger, Brigitte; Jotterand, Martine; Krauter, Jurgen; Pabst, Thomas; Theobald, Matthias; Schlenk, Richard F.; Delwel, Ruud; Dohner, Konstanze; Lowenberg, Bob; Doehner, Hartmut

2010-01-01

Purpose Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3; 3)(q21; q26.2) inv(3)/t(3; 3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3; 3) remain largely

Comparing the neural bases of self-referential processing in typically developing and 22q11.2 adolescents.

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Schneider, Maude; Debbané, Martin; Lagioia, Annalaura; Salomon, Roy; d'Argembeau, Arnaud; Eliez, Stephan

2012-04-01

The investigation of self-reflective processing during adolescence is relevant, as this period is characterized by deep reorganization of the self-concept. It may be the case that an atypical development of brain regions underlying self-reflective processing increases the risk for psychological disorders and impaired social functioning. In this study, we investigated the neural bases of self- and other-related processing in typically developing adolescents and youths with 22q11.2 deletion syndrome (22q11DS), a rare neurogenetic condition associated with difficulties in social interactions and increased risk for schizophrenia. The fMRI paradigm consisted in judging if a series of adjectives applied to the participant himself/herself (self), to his/her best friend or to a fictional character (Harry Potter). In control adolescents, we observed that self- and other-related processing elicited strong activation in cortical midline structures (CMS) when contrasted with a semantic baseline condition. 22q11DS exhibited hypoactivation in the CMS and the striatum during the processing of self-related information when compared to the control group. Finally, the hypoactivation in the anterior cingulate cortex was associated with the severity of prodromal positive symptoms of schizophrenia. The findings are discussed in a developmental framework and in light of their implication for the development of schizophrenia in this at-risk population. Copyright © 2011 Elsevier Ltd. All rights reserved.

De novo 14q24.2q24.3 microdeletion including IFT43 is associated with intellectual disability, skeletal anomalies, cardiac anomalies, and myopia.

Science.gov (United States)

Stokman, Marijn F; Oud, Machteld M; van Binsbergen, Ellen; Slaats, Gisela G; Nicolaou, Nayia; Renkema, Kirsten Y; Nijman, Isaac J; Roepman, Ronald; Giles, Rachel H; Arts, Heleen H; Knoers, Nine V A M; van Haelst, Mieke M

2016-06-01

We report an 11-year-old girl with mild intellectual disability, skeletal anomalies, congenital heart defect, myopia, and facial dysmorphisms including an extra incisor, cup-shaped ears, and a preauricular skin tag. Array comparative genomic hybridization analysis identified a de novo 4.5-Mb microdeletion on chromosome 14q24.2q24.3. The deleted region and phenotype partially overlap with previously reported patients. Here, we provide an overview of the literature on 14q24 microdeletions and further delineate the associated phenotype. We performed exome sequencing to examine other causes for the phenotype and queried genes present in the 14q24.2q24.3 microdeletion that are associated with recessive disease for variants in the non-deleted allele. The deleted region contains 65 protein-coding genes, including the ciliary gene IFT43. Although Sanger and exome sequencing did not identify variants in the second IFT43 allele or in other IFT complex A-protein-encoding genes, immunocytochemistry showed increased accumulation of IFT-B proteins at the ciliary tip in patient-derived fibroblasts compared to control cells, demonstrating defective retrograde ciliary transport. This could suggest a ciliary defect in the pathogenesis of this disorder. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Altered auditory processing and effective connectivity in 22q11.2 deletion syndrome

DEFF Research Database (Denmark)

Larsen, Kit Melissa; Mørup, Morten; Birknow, Michelle Rosgaard

2018-01-01

. Mismatch negativity (MMN), a brain marker of change detection, is reduced in people with schizophrenia compared to healthy controls. Using dynamic causal modelling (DCM), previous studies showed that top-down effective connectivity linking the frontal and temporal cortex is reduced in schizophrenia......11.2 deletion carriers. DCM showed reduced intrinsic connection within right primary auditory cortex as well as in the top-down, connection from the right inferior frontal gyrus to right superior temporal gyrus for 22q11.2 deletion carriers although not surviving correction for multiple comparison...

Integrable Equations of the Form qt=L1(x,t,q,qx,qxx)qxxx+L2(x,t,q,qx,qxx)

International Nuclear Information System (INIS)

Satir, Ahmet

2003-01-01

Integrable equations of the form q t =L 1 (x,t,q,q x ,q xx )q xxx +L 2 (x,t,q,q x ,q xx ) are considered using linearization. A new type of integrable equations which are the generalization of the integrable equations of Fokas and Ibragimov and Shabat are given

Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium.

Science.gov (United States)

Devaraju, P; Yu, J; Eddins, D; Mellado-Lagarde, M M; Earls, L R; Westmoreland, J J; Quarato, G; Green, D R; Zakharenko, S S

2017-09-01

Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity that contributes to working-memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal short-term potentiation (STP), a major form of short-term synaptic plasticity. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia.

A leukemic double-hit follicular lymphoma associated with a complex variant translocation, t(8;14;18)(q24;q32;q21), involving BCL2, MYC, and IGH.

Science.gov (United States)

Minakata, Daisuke; Sato, Kazuya; Ikeda, Takashi; Toda, Yumiko; Ito, Shoko; Mashima, Kiyomi; Umino, Kento; Nakano, Hirofumi; Yamasaki, Ryoko; Morita, Kaoru; Kawasaki, Yasufumi; Sugimoto, Miyuki; Yamamoto, Chihiro; Ashizawa, Masahiro; Hatano, Kaoru; Oh, Iekuni; Fujiwara, Shin-Ichiro; Ohmine, Ken; Kawata, Hirotoshi; Muroi, Kazuo; Miura, Ikuo; Kanda, Yoshinobu

2018-01-01

Double-hit lymphoma (DHL) is defined as lymphoma with concurrent BCL2 and MYC translocations. While the most common histological subtype of DHL is diffuse large B-cell lymphoma, the present patient had leukemic follicular lymphoma (FL). A 52-year-old man was admitted to our hospital due to general fatigue and cervical and inguinal lymph node swelling. The patient was leukemic and the pathological diagnosis of the inguinal lymph node was FL grade 1. Chromosomal analysis revealed a complex karyotype including a rare three-way translocation t(8;14;18)(q24;q32;q21) involving the BCL2, MYC, and IGH genes. Based on a combination of fluorescence in situ hybridization (FISH), using BCL2, MYC and IGH, and spectral karyotyping (SKY), the karyotype was interpreted as being the result of a multistep mechanism in which the precursor B-cell gained t(14;18) in the bone marrow and acquired a translocation between der(14)t(14;18) and chromosome 8 in the germinal center, resulting in t(8;14;18). The pathological diagnosis was consistently FL, not only at presentation but even after a second relapse. The patient responded well to standard chemotherapies but relapsed after a short remission. This patient is a unique case of leukemic DH-FL with t(8;14;18) that remained in FL even at a second relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

Fluorescence in situ hybridization (FISH screening for the 22q11.2 deletion in patients with clinical features of velocardiofacial syndrome but without cardiac anomalies

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Paula Sandrin-Garcia

2007-01-01

Full Text Available The velocardiofacial syndrome (VCFS, a condition associated with 22q11.2 deletions, is characterized by a typical facies, palatal anomalies, learning disabilities, behavioral disturbances and cardiac defects. We investigated the frequency of these chromosomal deletions in 16 individuals with VCFS features who presented no cardiac anomalies, one of the main characteristics of VCFS. Fluorescent in situ hybridization (FISH with the N25 (D22S75; 22q11.2 probe revealed deletions in ten individuals (62%. Therefore, even in the absence of cardiac anomalies testing for the 22q11.2 microdeletions in individuals showing other clinical features of this syndrome is recommended.

Deletion 22q13.3 syndrome

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Phelan Mary C

2008-05-01

Full Text Available Abstract The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The diagnosis of deletion 22q13 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH or array comparative genomic hybridization (CGH is recommended for confirmation. Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like affect (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders, cerebral palsy. Genetic counseling is recommended and parental laboratory studies should be considered to identify cryptic rearrangements and detect parental mosaicism. Prenatal diagnosis should be offered for future pregnancies in those families with inherited rearrangements

Identifying patterns of anxiety and depression in children with chromosome 22q11.2 deletion syndrome: comorbidity predicts behavioral difficulties and impaired functional communications.

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Stephenson, David D; Beaton, Elliott A; Weems, Carl F; Angkustsiri, Kathleen; Simon, Tony J

2015-01-01

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a complex genetic disorder with a variable clinical presentation that can include cardiac, neural, immunological, and psychological issues. Previous studies have measured elevated anxiety and depression in children with 22q11.2DS. Comorbity of anxiety and depression is well established in the pediatric literature but the nature of comorbidity patterns has not been empirically established in children with 22q11.2DS. Comorbidity of anxiety and depression has important implications for treatment and prognosis, and may be a marker of risk in this population of children at high-risk for developing schizophrenia. Participants were 131 boys and girls ages 8-14 with (n=76) and without (n=55) 22q11.2DS and their mothers. Children and mothers independently completed self- and parent-report measures of anxiety and depression. Mothers also completed measures of behavioral functioning including the Behavioral Assessment for Children, 2nd ed. (BASC-2). Cluster analyses were conducted to test if theoretically based groupings of anxiety and depression could be identified. We hypothesized four psychological profiles based on child- and mother-reports: low/no anxiety and low/no depression, higher depression and low/no anxiety, higher anxiety and no/low depression, and a comorbid profile of higher anxiety and higher depression. BASC-2 subscale scores were then compared across subgroups of children to determine if a comorbid profile would predict greater behavioral difficulties. In the full sample of children both with and without 22q11.2DS, cluster analyses of self and maternal reported anxiety and depression revealed the expected subgroups: (1) a group of children with higher anxiety/lower depression (anxious); (2) a group with primary depression (lower anxiety/higher depression (depressed)); (3) a comorbid group with higher anxiety/higher depression (comorbid); and, (4) a lowest anxiety/lowest depression group (NP). Mothers

Social Cognition Dysfunction in Adolescents with 22q11.2 Deletion Syndrome (Velo-Cardio-Facial Syndrome): Relationship with Executive Functioning and Social Competence/Functioning

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Campbell, L. E.; McCabe, K. L.; Melville, J. L.; Strutt, P. A.; Schall, U.

2015-01-01

Background: Social difficulties are often noted among people with intellectual disabilities. Children and adults with 22q.11.2 deletion syndrome (22q11DS) often have poorer social competence as well as poorer performance on measures of executive and social-cognitive skills compared with typically developing young people. However, the relationship…

Alterations of social interaction through genetic and environmental manipulation of the 22q11.2 gene Sept5 in the mouse brain.

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Harper, Kathryn M; Hiramoto, Takeshi; Tanigaki, Kenji; Kang, Gina; Suzuki, Go; Trimble, William; Hiroi, Noboru

2012-08-01

Social behavior dysfunction is a symptomatic element of schizophrenia and autism spectrum disorder (ASD). Although altered activities in numerous brain regions are associated with defective social cognition and perception, the causative relationship between these altered activities and social cognition and perception-and their genetic underpinnings-are not known in humans. To address these issues, we took advantage of the link between hemizygous deletion of human chromosome 22q11.2 and high rates of social behavior dysfunction, schizophrenia and ASD. We genetically manipulated Sept5, a 22q11.2 gene, and evaluated its role in social interaction in mice. Sept5 deficiency, against a high degree of homogeneity in a congenic genetic background, selectively impaired active affiliative social interaction in mice. Conversely, virally guided overexpression of Sept5 in the hippocampus or, to a lesser extent, the amygdala elevated levels of active affiliative social interaction in C57BL/6J mice. Congenic knockout mice and mice overexpressing Sept5 in the hippocampus or amygdala were indistinguishable from control mice in novelty and olfactory responses, anxiety or motor activity. Moreover, post-weaning individual housing, an environmental condition designed to reduce stress in male mice, selectively raised levels of Sept5 protein in the amygdala and increased active affiliative social interaction in C57BL/6J mice. These findings identify this 22q11.2 gene in the hippocampus and amygdala as a determinant of social interaction and suggest that defective social interaction seen in 22q11.2-associated schizophrenia and ASD can be genetically and environmentally modified by altering this 22q11.2 gene.

De novo microdeletions of chromosome 6q14.1-q14.3 and 6q12.1-q14.1 in two patients with intellectual disability - further delineation of the 6q14 microdeletion syndrome and review of the literature

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Becker, Kerstin; Di Donato, Nataliya; Holder-Espinasse, Muriel

2012-01-01

with broad nasal tip, anteverted nares, long philtrum, and thin upper lip. In this study we describe two patients with overlapping 6q14 deletions presenting with developmental delay and characteristic dysmorphism. Molecular karyotyping using array CGH analysis revealed a de novo 8.9 Mb deletion at 6q14.1-q14.......3 and a de novo 11.3 Mb deletion at 6q12.1-6q14.1, respectively. We provide a review of the clinical features of twelve other patients with 6q14 deletions detected by array CGH analysis. By assessing all reported data we could not identify a single common region of deletion. Possible candidate genes in 6q14...

Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

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Kilarski, L. L.; Achterberg, S.; Devan, W. J.; Traylor, M.; Malik, R.; Lindgren, A.; Pare, G.; Sharma, P.; Slowik, A.; Thijs, V.; Walters, M.; Worrall, B. B.; Sale, M. M.; Algra, A.; Kappelle, L. J.

2014-01-01

textabstractResults: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p 5 7.12 3 10-11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p 5 0.695).Conclusion: Our resu...

Inactivation of the P16INK4/MTS1 gene by a chromosome translocation t(9;14)(p21-22;q11) in an acute lymphoblastic leukemia of B-cell type.

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Duro, D; Bernard, O; Della Valle, V; Leblanc, T; Berger, R; Larsen, C J

1996-02-15

We have reported previously a preliminary study of a t(9;14)(p21-22; q11) in B-cell acute lymphoblastic leukemia. This translocation had rearranged the TCRA/D locus on chromosome band 14q11 and the locus encoding the tumor suppressor gene P16INK4/MTS1 (P16) on band 9p21 (D. Duro et al., Oncogene, 11: 21-29, 1995). In the present report, the breakpoints were precisely localized on each chromosome partner. On the 14q- derivative, the sequence derived from chromosome 9 was interrupted at 1.0 kb upstream of the first exon of P16, close to a consensus recombination heptamer, CACTGTG. In addition, the chromosome 14 breakpoint was localized at the end of the TCRD2 (delta 2) segment, and 22 residues with unknown origin were present at the translocation junction. On the 9p+ derivative, chromosome 9 sequences were in continuity with those displaced onto chromosome 14, and the 14q11 breakpoint was located within TCRJA29 segment. These features are consistent with aberrant activity of the TCR gene recombinase complex. Although all three coding exons of P16 were displaced onto the chromosome 14q-derivative, no P16 transcript was detected in the leukemic cells. Because the region spanning the P16 exon 1 was not inactivated by methylation and because the other P16 allele was deleted, the implication is that the chromosome breakpoint was likely to disrupt regulatory elements involved in the normal expression of the gene. As a whole, then, our results show that translocations affecting band 9p21 can participate to the inactivation of P16, thus justifying a systematic survey of translocations of the 9p21 band in acute lymphoblastic leukemia.

Candidate region for Coffin-Siris syndrome at 7q32-->34.

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McGhee, E M; Klump, C J; Bitts, S M; Cotter, P D; Lammer, E J

2000-07-31

Coffin-Siris syndrome is characterized by intrauterine growth retardation, mental deficiency, coarse face, hypoplastic fifth fingers and nails, hirsutism, and initial difficulties with feeding. The etiology of this syndrome is unknown. We report on an 11-year-old girl with Coffin-Siris syndrome and a de novo, apparently balanced reciprocal translocation between chromosomes 7 and 22 [t(7;22)(q32;q11.2)]. The 7q breakpoint in our patient is very similar to the breakpoint reported in a previous case [McPherson et al., 1997: Am J Med Genet 71:430-433] with a balanced t(1;7)(q21.3;q34). Together, these patients provide evidence that the region 7q32-->34 is a candidate region for the gene responsible for Coffin-Siris syndrome.

Complex three-way translocation involving MLL, ELL, RREB1, and CMAHP genes in an infant with acute myeloid leukemia and t(6;19;11)(p22.2;p13.1;q23.3)

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Tuborgh, A; Meyer, C; Marschalek, R

2013-01-01

until progression to acute myeloid leukemia, AML-M5. The leukemic cells harbored a novel apparent 3-way translocation t(6;19;11)(p22.2;p13.1;q23.3). We utilized advanced molecular cytogenetic methods including 24-color karyotyping, high-resolution array comparative genomic hybridization (aCGH) and DNA...... in the initial stages of disease before clear morphological signs of bone marrow involvement. The patient responded well to therapy and remains in remission>6 years from diagnosis. This apparent 3-way translocation is remarkable because of its rarity and presentation with myeloid sarcoma, and may, as more cases...

Prader-Willi syndrome due to an unbalanced de novo translocation [t(15;19)(q12;p13.3)

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Dang, Vy; Surampalli, Abhilasha; Manzardo, Ann M; Youn, Stephanie; Butler, Merlin G; Gold, June-Anne; Kimonis, Virginia

2018-01-01

Background and Aims Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by endocrine, neurologic and behavioral abnormalities. We report the first case of an unbalanced de-novo reciprocal translocation of chromosome 15 and 19: 45,XY,-15, der (19)t(15;19)(q12;p13.3) resulting in monosomy for the PWS chromosome critical region. We performed high resolution SNP microarray to characterize the breakpoints. Case report Our patient had several typical features for PWS including infantile hypotonia, a poor suck and feeding difficulties, tantrums, skin picking, compulsions, small hands and feet and food seeking but not hypopigmentation, a micropenis, cryptorchidism or obesity as common findings seen in PWS at the time of examination at 6 years of age. He had seizures noted from 1 to 3 years of age and marked cognitive delay. Results High resolution SNP microarray analysis identified an atypical PWS Type I deletion of chromosome 15 involving proximal breakpoint BP1. The deletion extended beyond the GABRB3 gene but was proximal to the usual distal breakpoint (BP3) within the 15q11-q13 region and GABRA5, GABRG3 and OCA2 genes were intact. Conclusion We report a case with atypical features for PWS associated with an unbalanced de-novo reciprocal translocation resulting in monosomy for the 15q11.1–15q12 with intact GABRA5, GABRG3 and OCA2 genes. No deletion of 19p13.3 band was detected therefore the patient was not at an increased risk of tumors from Peutz-Jeghers syndrome associated with a deletion of the STK11 gene. PMID:27894106

Benign chronic neutropenia with abnormalities involving 16q22, affecting mother and daughter.

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Glasser, Lewis; Meloni-Ehrig, Aurelia; Joseph, Plakyil; Mendiola, Jennifer

2006-04-01

We report a case of familial, chronic, benign neutropenia in a 17-year-old female showing (1) the spontaneous expression of a heritable rare fragile site at 16q22 and (2) a deletion at the same region. The del(16)(q22), which most likely originated from the fragile site, was the main clonal abnormality detected in the patient's bone marrow cells, whereas a few cells with either del(16)(q22) or fra(16)(q22) were seen in the patient's peripheral blood. Interestingly, the del(16q) was also detected in the patient's uncultured cells, as demonstrated by FISH, excluding an in vitro origin of the del(16q) during culture. The bone marrow was hypocellular with decreased neutrophils and their precursors. Absolute neutrophil counts ranged from (0.62 to 1.24) x 10(9)/L with a median value of 1.02 x 10(9)/L. The patient had a more severe neutropenia than her mother, which correlated with the presence of more cells with del(16q) in the marrow. The patient's mother, who was also diagnosed with neutropenia, revealed only a few cells with the rare fra(16)(q22) in her peripheral blood cells, whereas her bone marrow showed cells with both fra(16)(q22) and del(16)(q22), although the del(16q) was present in only 2/20 cells. Some possible candidate genes contributing to the pathogenesis of the neutropenia are discussed. Chromosome abnormalities involving the 16q22 breakpoint have been observed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this patient, the del(16)(q22) risk factor is unknown for subsequent development of MDS or AML. Another point to consider is the need to determine the origin of a chromosome abnormality, particularly when the clinical picture does not fit the chromosome findings. Although, the observation of a constitutional structural abnormality in a mosaic form is an extremely rare event, it is somewhat different in the case of a fragile site expression, which can, as in this case, be present in some cells and not in others. Copyright 2006

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

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2012-01-01

Introduction Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers. PMID:22348646

Prolonged Q-T(c) interval in mild portal hypertensive cirrhosis

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Ytting, Henriette; Henriksen, Jens Henrik; Fuglsang, Stefan

2005-01-01

BACKGROUND/AIMS: The Q-T(c) interval is prolonged in a substantial fraction of patients with cirrhosis, thus indicating delayed repolarisation. However, no information is available in mild portal hypertensive patients. We therefore determined the Q-T(c) interval in cirrhotic patients with hepatic...... venous pressure gradient (HVPG) portal hypertension (HVPG> or = 12 mmHg) and controls without liver disease. RESULTS......), values which are significantly above that of the controls (0.410 s(1/2), P portal hypertensive group, the Q-T(c) interval was inversely related to indicators of liver function, such as indocyanine green clearance (r = -0.34, P

[22q11.2 deletion: handicap-related problems and coping strategies of primary caregivers].

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Briegel, Wolfgang; Schneider, Marco; Schwab, K Otfried

2009-11-01

To investigate handicap-related problems of children and adolescents with 22q11.2 deletion syndrome and their primary caregivers' coping strategies. Primary caregivers of 153 subjects aged 2-16 years were anonymously asked to fill out questionnaires, e.g., the Handicap Related Problems for Parents Inventory. Primary caregivers of 96 subjects (53 males, 43 females; mean age: 7;0 [2;1-16;11] years) sent back questionnaires. Patient's behaviour and discipline were the most important handicap-related problems. Significant correlations could be found between the patient's age and his/her relationship with the primary caregiver (rho=0.228; p=.029) and other family members (rho=0.293; p=.004). Compared to other parents of physically handicapped children or those with multiple handicaps, these parents did not experience increased stress. The more the coping strategies "self-fulfillment" and "intensification of partnership" were used, the lower parental stress was (p=.012, p=.025, respectively). "Focusing on the handicapped child" was positively correlated with high parental stress (p=.000). With regard to parental stress and coping strategies, primary caregivers of children and adolescents with 22q11.2 deletion do not significantly differ from other parents of physically handicapped children. As handicap-related family problems increase with the patient's age, a growing need for counseling, especially for aspects of parenting and discipline, and for treatment can be presumed.

Severe intellectual disability, omphalocele, hypospadia and high blood pressure associated to a deletion at 2q22.1q22.3: case report

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Mulatinho Milene

2012-06-01

Full Text Available Abstract Background Recently, array-comparative genomic hybridization (aCGH platforms have significantly improved the resolution of chromosomal analysis allowing the identification of genomic copy number gains and losses smaller than 5 Mb. Here we report on a young man with unexplained severe mental retardation, autism spectrum disorder, congenital malformations comprising hypospadia and omphalocele, and episodes of high blood pressure. An ~ 6 Mb interstitial deletion that includes the causative genes is identified by oligonucleotide-based aCGH. Results Our index case exhibited a de novo chromosomal abnormality at 2q22 [del(2(q22.1q22.3dn] which was not visible at the 550 haploid band level. The deleted region includes eight genes: HNMT, SPOPL, NXPH2, LOC64702, LRP1B, KYNU, ARHGAP15 and GTDC1. Discussion aCGH revealed an ~ 6 Mb deletion in 2q22.1 to 2q22.3 in an as-yet unique clinical case associated with intellectual disability, congenital malformations and autism spectrum disorder. Interestingly, the deletion is co-localized with a fragile site (FRA2K, which could be involved in the formation of this chromosomal aberration. Further studies are needed to determine if deletions of 2q22.1 to 2q22.3 define a new microdeletion syndrome.

Overlapping Numerical Cognition Impairments in Children with Chromosome 22q11.2 Deletion or Turner Syndromes

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Simon, T. J.; Takarae, Y.; DeBoer, T.; McDonald-McGinn, D. M.; Zackai, E. H.; Ross, J. L.

2008-01-01

Children with one of two genetic disorders (chromosome 22q11.2 deletion syndrome and Turner syndrome) as well typically developing controls, participated in three cognitive processing experiments. Two experiments were designed to test cognitive processes involved in basic aspects numerical cognition. The third was a test of simple manual motor…

t(4;11 (q21;q23 in acute myeloid leukemia-M0 following treatment [EW92 Protocol] for Ewing's sarcoma Leucemia mielóide aguda-M0 com t(4;11 (q21;q23 após tratamento para sarcoma de Ewing com o protocolo EW92

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Terezinha J. Marques Salles

2004-01-01

Full Text Available We report on a 7-year-old girl with Ewing's Sarcoma (ES who developed a poorly differentiated acute myeloid leukemia (AML-M0 20 months after beginning the EW92 protocol for the treatment of the primary tumor. She received a total dose of 1500 mg of etoposide, a tumor cumulative radiation dose of 35Gy and granulocyte colony-stimulating factor (G-CSF was as predicted in the protocol regimen. At onset of secondary malignancy her laboratorial analysis revealed immature blast cells characterized by CD34+/CD33-/a-MPO+ and a t(4;11(q21;q23 abnormality. This serious complication of ES treatment, which associates etoposide, irradiation and G-CSF schedule, should be weighed against its therapeutic benefits.Nós descrevemos o caso clínico de uma criança do sexo feminino, com 7 anos de idade, portadora de sarcoma de Ewing, que evoluiu com leucemia aguda mielóide pouco diferenciada (LMA-M0 após vinte meses de tratamento utilizando o protocolo EW92. Ela recebeu uma dose total de 1.500 mg de etoposídio, irradiação tumoral na dose total de 35G, e fator de estimulação de colônia granulocítica (G-CSF conforme programação do protocolo terapêutico. Os exames laboratoriais, por ocasião do diagnóstico da segunda malignidade, mostraram células blásticas imaturas caracterizadas pela expressão de CD34+/CD33-/aMPO+ e a translocação t(4;11 (q 21;q23. A exclusão do G-CSF nos esquemas terapêuticos que associam etoposídio e irradiação tumoral se justifica devido a esta séria complicação no tratamento do sarcoma de Ewing.

MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del.

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Dejian Zhao

Full Text Available We are using induced pluripotent stem cell (iPSC technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del, the most common known schizophrenia (SZ-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA biogenesis. We carried out miRNA expression profiling (miRNA-seq on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher. Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05, including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p. Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.

Fine mapping of a de novo interstitial 10q22-q23 duplication in a patient with congenital heart disease and microcephaly

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Erdogan, F; Belloso, J M; Gabau, E

2008-01-01

deletions or duplications elsewhere in the genome. The main clinical features of the patient are microcephaly and congenital heart disease, which are likely to be caused by dosage effect of one or several genes in the duplicated region. Similar phenotypes have been found in other patients with 10q11-q22...

Regional assignment of seven loci to 12p 13. 2-pter by PCR analysis of somatic cell hybrids containing the der(12) or the der(X) chromosome from a mesothelioma showing t(X; 12)(q22; p13)

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Aerssens, J.; Chaffanet, M.; Baens, M.; Matthijs, G.; Van Den Berche, H.; Cassiman, J.J.; Marynen, P. (Arthritis and Metabolic Bone Disease Research Unit, Leuven (Belgium))

1994-03-01

Two somatic cell hybrids containing the der(12) or the der(X) from a mesothelioma with a translocation t(X;12) (q22;p13) as the only chromosomal change were generated to characterize the region of 12p12 containing the translocation breakpoint. Fluorescence in situ hybridization analysis showed the breakpoint on chromosome 12 to occur between VWF and D12S158. On the linkage map developed by J. Weissenbach et al., the breakpoints were located between DXS1106 and DCS1001 on chromosome X. PCR analysis based on genomic sequences, with DNA from both somatic cell hybrids, enabled mapping of CACNL1A1, FGF6, D12S370, D12S38OE, D12S381E, and D12S382E distally to the 12p13 breakpoint and to VWF. 11 refs., 2 figs., 1 tab.

Clinical and cytogenetic features of a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: rare T-cell receptor gene rearrangements are associated with poor outcome

DEFF Research Database (Denmark)

Karrman, Kristina; Forestier, Erik; Heyman, Mats

2009-01-01

-cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34....... In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of > or =200 x 10(9)/l (P rearrangements (P = 0.001). In conclusion, in this large series of childhood T-ALLs from the Nordic countries, the cytogenetic findings were not associated...

Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15(q27;q11.2 associated with Prader-Willi syndrome

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Slater Howard R

2005-05-01

Full Text Available Abstract Background Prader-Willi syndrome (MIM #176270; PWS is caused by lack of the paternally-derived copies, or their expression, of multiple genes in a 4 Mb region on chromosome 15q11.2. Known mechanisms include large deletions, maternal uniparental disomy or mutations involving the imprinting center. De novo balanced reciprocal translocations in 5 reported individuals had breakpoints clustering in SNRPN intron 2 or exon 20/intron 20. To further dissect the PWS phenotype and define the minimal critical region for PWS features, we have studied a 22 year old male with a milder PWS phenotype and a de novo translocation t(4;15(q27;q11.2. Methods We used metaphase FISH to narrow the breakpoint region and molecular analyses to map the breakpoints on both chromosomes at the nucleotide level. The expression of genes on chromosome 15 on both sides of the breakpoint was determined by RT-PCR analyses. Results Pertinent clinical features include neonatal hypotonia with feeding difficulties, hypogonadism, short stature, late-onset obesity, learning difficulties, abnormal social behavior and marked tolerance to pain, as well as sticky saliva and narcolepsy. Relative macrocephaly and facial features are not typical for PWS. The translocation breakpoints were identified within SNRPN intron 17 and intron 10 of a spliced non-coding transcript in band 4q27. LINE and SINE sequences at the exchange points may have contributed to the translocation event. By RT-PCR of lymphoblasts and fibroblasts, we find that upstream SNURF/SNRPN exons and snoRNAs HBII-437 and HBII-13 are expressed, but the downstream snoRNAs PWCR1/HBII-85 and HBII-438A/B snoRNAs are not. Conclusion As part of the PWCR1/HBII-85 snoRNA cluster is highly conserved between human and mice, while no copy of HBII-438 has been found in mouse, we conclude that PWCR1/HBII-85 snoRNAs is likely to play a major role in the PWS- phenotype.

Estudio de la psicopatología en una población de pacientes con microdeleción 22q11.2

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Robles Sánchez, Fuensanta

2016-01-01

El síndrome de deleción 22q11.2 (22q11.2 DS; OMIM # 188400) es un trastorno genético que puede presentar diversas malformaciones físicas, déficit cognitivo y trastornos psicopatológicos. Los objetivos del estudio han consistido en evaluar el nivel de inteligencia y los trastornos psiquiátricos de los pacientes con este síndrome en la etapa infanto-juvenil y determinar los factores genéticos, clínicos y sociodemográficos asociados. Hemos estudiado el perfil cognitivo y los trastornos psi...

Cortical Development Requires Mesodermal Expression of Tbx1, a Gene Haploinsufficient in 22q11.2 Deletion Syndrome.

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Flore, Gemma; Cioffi, Sara; Bilio, Marchesa; Illingworth, Elizabeth

2017-03-01

In mammals, proper temporal control of neurogenesis and neural migration during embryonic development ensures correct formation of the cerebral cortex. Changes in the distribution of cortical projection neurons and interneurons are associated with behavioral disorders and psychiatric diseases, including schizophrenia and autism, suggesting that disrupted cortical connectivity contributes to the brain pathology. TBX1 is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS), a chromosomal deletion disorder characterized by a greatly increased risk for schizophrenia. We have previously shown that Tbx1 heterozygous mice have reduced prepulse inhibition, a behavioral abnormality that is associated with 22q11.2DS and nonsyndromic schizophrenia. Here, we show that loss of Tbx1 disrupts corticogenesis in mice by promoting premature neuronal differentiation in the medio-lateral embryonic cortex, which gives rise to the somatosensory cortex (S1). In addition, we found altered polarity in both radially migrating excitatory neurons and tangentially migrating inhibitory interneurons. Together, these abnormalities lead to altered lamination in the S1 at the terminal stages of corticogenesis in Tbx1 null mice and similar anomalies in Tbx1 heterozygous adult mice. Finally, we show that mesoderm-specific inactivation of Tbx1 is sufficient to recapitulate the brain phenotype indicating that Tbx1 exerts a cell nonautonomous role in cortical development from the mesoderm. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations.

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Córdova-Fletes, Carlos; Domínguez, Ma Guadalupe; Delint-Ramirez, Ilse; Martínez-Rodríguez, Herminia G; Rivas-Estilla, Ana María; Barros-Núñez, Patricio; Ortiz-López, Rocío; Neira, Vivian Alejandra

2015-10-01

We report a girl with intellectual disability (ID), neuropsychiatric alterations, and a de novo balanced t(10;19)(q22.3;q13.33) translocation. After chromosome sorting, fine mapping of breakpoints by array painting disclosed disruptions of the zinc finger, MIZ-type containing 1 (ZMIZ1) (on chr10) and proline-rich 12 (PRR12) (on chr19) genes. cDNA analyses revealed that the translocation resulted in gene fusions. The resulting hybrid transcripts predict mRNA decay or, if translated, formation of truncated proteins, both due to frameshifts that introduced premature stop codons. Though other molecular mechanisms may be operating, these results suggest that haploinsufficiency of one or both genes accounts for the patient's phenotype. ZMIZ1 is highly expressed in the brain, and its protein product appears to interact with neuron-specific chromatin remodeling complex (nBAF) and activator protein 1 (AP-1) complexes which play a role regulating the activity of genes essential for normal synapse and dendrite growth/behavior. Strikingly, the patient's phenotype overlaps with phenotypes caused by mutations in SMARCA4 (BRG1), an nBAF subunit presumably interacting with ZMIZ1 in brain cells as suggested by our results of coimmunoprecipitation in the mouse brain. PRR12 is also expressed in the brain, and its protein product possesses domains and residues thought to be related in formation of large protein complexes and chromatin remodeling. Our observation from E15 mouse brain cells that a Prr12 isoform was confined to nucleus suggests a role as a transcription nuclear cofactor likely involved in neuronal development. Moreover, a pilot transcriptome analysis from t(10;19) lymphoblastoid cell line suggests dysregulation of genes linked to neurodevelopment processes/neuronal communication (e.g., NRCAM) most likely induced by altered PRR12. This case represents the first constitutional balanced translocation disrupting and fusing both genes and provides clues for the potential

Characterization of a t(5;8)(q31;q21) translocation in a patient with mental retardation and congenital heart disease: implications for involvement of RUNX1T1 in human brain and heart development

DEFF Research Database (Denmark)

Zhang, Litu; Tümer, Zeynep; Møllgård, Kjeld

2009-01-01

The chromosome break points of the t(8;21)(q21.3;q22.12) translocation associated with acute myeloid leukemia disrupt the RUNX1 gene (also known as AML1) and the RUNX1T1 gene (also known as CBFA2T3, MTG8 and ETO) and generate a RUNX1-RUNX1T1 fusion protein. Molecular characterization of the trans...... development and support the notion that disruption of the RUNX1T1 gene is associated with the patient's phenotype.European Journal of Human Genetics advance online publication, 28 January 2009; doi:10.1038/ejhg.2008.269....

Self-Reported Speech Problems in Adolescents and Young Adults with 22q11.2 Deletion Syndrome: A Cross-Sectional Cohort Study

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Nicole E Spruijt

2014-09-01

Full Text Available BackgroundSpeech problems are a common clinical feature of the 22q11.2 deletion syndrome. The objectives of this study were to inventory the speech history and current self-reported speech rating of adolescents and young adults, and examine the possible variables influencing the current speech ratings, including cleft palate, surgery, speech and language therapy, intelligence quotient, and age at assessment.MethodsIn this cross-sectional cohort study, 50 adolescents and young adults with the 22q11.2 deletion syndrome (ages, 12-26 years, 67% female filled out questionnaires. A neuropsychologist administered an age-appropriate intelligence quotient test. The demographics, histories, and intelligence of patients with normal speech (speech rating=1 were compared to those of patients with different speech (speech rating>1.ResultsOf the 50 patients, a minority (26% had a cleft palate, nearly half (46% underwent a pharyngoplasty, and all (100% had speech and language therapy. Poorer speech ratings were correlated with more years of speech and language therapy (Spearman's correlation= 0.418, P=0.004; 95% confidence interval, 0.145-0.632. Only 34% had normal speech ratings. The groups with normal and different speech were not significantly different with respect to the demographic variables; a history of cleft palate, surgery, or speech and language therapy; and the intelligence quotient.ConclusionsAll adolescents and young adults with the 22q11.2 deletion syndrome had undergone speech and language therapy, and nearly half of them underwent pharyngoplasty. Only 34% attained normal speech ratings. Those with poorer speech ratings had speech and language therapy for more years.

Trisomy 2q11.2-->q21.1 resulting from an unbalanced insertion in two generations.

Science.gov (United States)

Glass, I A; Stormer, P; Oei, P T; Hacking, E; Cotter, P D

1998-01-01

In this communication, we describe two cases of proximal 2q trisomy (2q11.2--> q21.1) resulting from an interchromosomal insertion. The chromosomal origin of the insertion was confirmed by fluorescence in situ hybridisation. An unbalanced karyotype, 46,XX,der(8) ,ins(8;2) (p21.3; q21.1q11.2), was found in the proband and her mother, who both have mild mental retardation, short stature, dysmorphic features, insulin dependent diabetes mellitus, and a psychotic illness. This family is a rare example of direct transmission of a partial autosomal trisomy. Images PMID:9598728

Complex Variant t(9;22 Chromosome Translocations in Five Cases of Chronic Myeloid Leukemia

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Ana Valencia

2009-01-01

Full Text Available The Philadelphia (Ph1 chromosome arising from the reciprocal t(9;22 translocation is found in more than 90% of chronic myeloid leukemia (CML patients and results in the formation of the chimeric fusion gene BCR-ABL. However, a small proportion of patients with CML have simple or complex variants of this translocation, involving various breakpoints in addition to 9q34 and 22q11. We report five CML cases carrying variant Ph translocations involving both chromosomes 9 and 22 as well as chromosomes 3, 5, 7, 8, or 10. G-banding showed a reciprocal three-way translocation involving 3q21, 5q31, 7q32, 8q24, and 10q22 bands. BCR-ABL fusion signal on der(22 was found in all of the cases by FISH.

A t (11; 22 (p13; q12 EWS-WT 1 positive desmoplastic small round cell tumor of the maxilla: An unusual case indicating the role of molecular diagnosis in round cell sarcomas

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Rekhi B

2010-01-01

Full Text Available A desmoplastic small round cell tumor (DSRCT is an uncommon tumor characterized by polyphenotypic expression and a specific reciprocal translocation t (11; 22 (p13; q12. It has been rarely identified in the head and neck region. Herein, we describe a DSRCT in the maxilla of a young man, who was initially diagnosed with a primitive neuroectodermal tumor (PNET, based on histopathological appearance of a round cell tumor, with MIC2 and -FLI-1 positivity, on immunohistochemistry (IHC. Diagnosis of a DSRCT was confirmed on molecular analysis with positive -RT-PCR and sequencing results for EWS-WT1 transcript and negativity for EWS-FL1. The case is presented to highlight the value of molecular diagnosis in round cell sarcomas at uncommon sites, especially when similar IHC markers can be expressed in a PNET and a DSRCT. An exact diagnosis of a round cell sarcoma has a therapeutic relevance.

AML with t(7;12)(q36;p13) is associated with infancy and trisomy 19. Data from NOPHO-AML and review of the literature

DEFF Research Database (Denmark)

Espersen, Anne Dorte Lerche; Noren-Nyström, Ulrika; Abrahamsson, Jonas

2018-01-01

The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children ...). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation...

Loss of 11q and 16q in Wilms tumors is associated with anaplasia, tumor recurrence, and poor prognosis.

Science.gov (United States)

Wittmann, Stefanie; Zirn, Birgit; Alkassar, Muhannad; Ambros, Peter; Graf, Norbert; Gessler, Manfred

2007-02-01

Allele loss of chromosome arms 11q and 16q in Wilms tumors has been associated with different clinical parameters in prior studies. To substantiate these findings in a large collection of tumors treated according to the GPOH/SIOP protocol and to narrow down critical regions, we performed loss of heterozygosity (LOH) analyses of chromosome arms 11q and 16q on 225 Wilms tumors. On chromosome arm 11q an overall rate of allele loss of 19.6% (44 of 225 tumors) was found using eleven markers that were almost evenly distributed along the long arm. Chromosome arm 16q was analyzed with six markers selected from gene-rich regions that identified an LOH rate of 18.4% (41/223). Evaluation of LOH with respect to clinical data revealed significant associations of LOH 11q with histology: LOH 11q was 3-4 times more frequent in mixed type and diffuse anaplastic tumors. In contrast, epithelial as well as stromal type tumors never exhibited allele loss on 11q. Furthermore, a significant correlation with tumor recurrence and death was detected, but only for tumors that lost the entire long arm of chromosome 11. Similarly, LOH 16q was correlated with higher risks of later relapse, especially in tumors with complete loss of the long arm. Hence, analyses of LOH on 11q and 16q appear to be helpful to identify tumors with a higher risk of relapse and adverse outcome, which need adjusted therapeutic approaches. Copyright 2006 Wiley-Liss, Inc.

Evaluación citogenética y de pérdida de la heterocigosidad de la región 22q11.2 en pacientes con el Síndrome de DiGeorge = Cytogenetic evaluation and loss of heterozigocity of chromosome 22q11.2 in patients with the DiGeorge syndrome

Directory of Open Access Journals (Sweden)

Gallego García, Germán Andreo

2011-09-01

Full Text Available Objetivo: evaluar la utilidad de la PCR para marcadores microsatélites (PCR-STR en la región 22q11.2 en el ADN genómico, para identificar microdeleciones en pacientes con síndrome de DiGeorge (SDG. Materiales y Métodos: se hizo un análisis de las historias clínicas de tres niñas con SDG y se investigaron deleciones en el cromosoma 22q11.2 mediante FISH y PCR-STR. Resultados: la FISH logró detectar deleciones en 22q11.2 en dos de las tres pacientes. Por su parte, por medio de la PCR-STR, se logró establecer que la paciente n.º 1 presentaba una deleción de 1,5 Mb proximal al centrómero, la segunda de mayor frecuencia en los pacientes con SDG. La deleción fue de origen paterno. Para caracterizar el defecto molecular en las otras pacientes, sería necesario acoplar estudios de cromatografía a este método, que permitan determinar el tamaño molecular de cada uno de los alelos parentales, o bien, ampliar este análisis con más microsatélites informativos ubicados en la región 22q11.2 para así definir más precisamente el tamaño de la deleción. Conclusiones: la PCR-STR en el ADN genómico es una alternativa para identificar deleciones que afectan microsatélites en la región 22q11.2 a un menor costo que la FISH y con resultados más rápidos; al mismo tiempo permite definir el origen parental y el tamaño de la microdeleción. Esta información es valiosa para identificar los genes asociados con las características clínicas del síndrome.

A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

Science.gov (United States)

Siddiq, Afshan; Couch, Fergus J.; Chen, Gary K.; Lindström, Sara; Eccles, Diana; Millikan, Robert C.; Michailidou, Kyriaki; Stram, Daniel O.; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B.; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Berg, Christine D.; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M.; Buring, Julie E.; Buys, Saundra S.; Campa, Daniele; Carpenter, Jane E.; Chasman, Daniel I.; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S.; Czene, Kamila; Deming, Sandra L.; Diasio, Robert B.; Diver, W. Ryan; Dunning, Alison M.; Durcan, Lorraine; Ekici, Arif B.; Fasching, Peter A.; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D.; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M.; Gerty, Susan M.; Rodriguez-Gil, Jorge L.; Giles, Graham G.; van Gils, Carla H.; Godwin, Andrew K.; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E.; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N.; Hopper, John L.; Hu, Jennifer J.; Huntsman, Scott; Ingles, Sue A.; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B.; John, Esther M.; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N.; Coetzee, Gerhard A.; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M.; Lee, I-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G.; McLean, Catriona A.; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R.; Montgomery, Grant W.; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J.; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J.; Palmer, Julie R.; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F.; Schmutzler, Rita K.; Slager, Susan; Southey, Melissa C.; Stevens, Kristen N.; Sinn, Hans-Peter; Press, Michael F.; Ross, Eric; Riboli, Elio; Ridker, Paul M.; Schumacher, Fredrick R.; Severi, Gianluca; dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J.; Thun, Michael J.; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, JoEllen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R.; Van Den Berg, David; Zheng, Wei; Ziegler, Regina G.; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F.; Hunter, David J.; Henderson, Brian E.; Chanock, Stephen J.; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A.; Vachon, Celine M.

2012-01-01

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5 in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10–6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10−9), and with both ER-positive (OR = 1.09; P = 1.5 × 10−5) and ER-negative (OR = 1.16, P = 2.5 × 10−7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci. PMID:22976474

Co-existence of t(6;13)(p21;q14.1) and trisomy 12 in chronic lymphocytic leukemia.

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de Oliveira, Fábio Morato; de Figueiredo Pontes, Lorena Lobo; Bassi, Sarah Cristina; Dalmazzo, Leandro Felipe Figueiredo; Falcão, Roberto Passetto

2012-06-01

We report a case of a 57-year-old man diagnosed with chronic lymphocytic leukemia (CLL) and presence of a rare t(6;13)(p21;q14.1) in association with an extra copy of chromosome 12. Classical cytogenetic analysis using the immunostimulatory combination of DSP30 and IL-2 showed the karyotype 47,XY,t(6;13)(p21;q14.1), +12 in 75% of the metaphase cells. Spectral karyotype analysis (SKY) confirmed the abnormality previously seen by G-banding. Additionally, interphase fluorescence in situ hybridization using an LSI CEP 12 probe performed on peripheral blood cells without any stimulant agent showed trisomy of chromosome 12 in 67% of analyzed cells (134/200). To the best of our knowledge, the association of t(6;13)(p21;q14.1) and +12 in CLL has never been described. The prognostic significance of these new findings in CLL remains to be elucidated. However, the patient has been followed up since 2009 without any therapeutic intervention and has so far remained stable.

Supporting Children with Genetic Syndromes in the Classroom: The Example of 22q Deletion Syndrome

Science.gov (United States)

Reilly, Colin; Stedman, Lindsey

2013-01-01

An increasing number of children are likely to have a known genetic cause for their special educational needs. One such genetic condition is 22q11.2 deletion syndrome (22qDS), a genetic syndrome associated with early speech and language difficulties, global and specific cognitive impairments, difficulties with attention and difficulties with…

Novel susceptibility locus at 22q11 for diabetic nephropathy in type 1 diabetes

DEFF Research Database (Denmark)

Wessman, Maija; Forsblom, Carol; Kaunisto, Mari A

2011-01-01

Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21-q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci...

Recurrent duplications of 17q12 associated with variable phenotypes

DEFF Research Database (Denmark)

Mitchell, Elyse; Douglas, Andrew; Kjaegaard, Susanne

2015-01-01

The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information......, potentially contributory copy number changes in a subset of patients, including one patient each with 16p11.2 deletion and 15q13.3 deletion. Our data further define and expand the clinical spectrum associated with duplications of 17q12 and provide support for the role of genomic modifiers contributing...... to phenotypic variability....

Clinical, Cytogenetic, and Biochemical Analyses of a Family with a t(3;13(q26.2;p11.2: Further Delineation of 3q Duplication Syndrome

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M. Abreu-González

2013-01-01

Full Text Available Chromosomal abnormalities that result in genomic imbalances are a major cause of congenital and developmental anomalies. Partial duplication of chromosome 3q syndrome is a well-described condition, and the phenotypic manifestations include a characteristic facies, microcephaly, hirsutism, synophrys, broad nasal bridge, congenital heart disease, genitourinary disorders, and mental retardation. Approximately 60%–75% of cases are derived from a balanced translocation. We describe a family with a pure typical partial trisomy 3q syndrome derived from a maternal balanced translocation t(3;13(q26.2;p11.2. As the chromosomal rearrangement involves the short arm of an acrocentric chromosome, the phenotype corresponds to a pure trisomy 3q26.2-qter syndrome. There are 4 affected individuals and several carriers among three generations. The report of this family is relevant because there are few cases of pure duplication 3q syndrome reported, and the cases described here contribute to define the phenotype associated with the syndrome. Furthermore, we confirmed that the survival until adulthood is possible. This report also identified the presence of glycosaminoglycans in urine in this family, not related to the chromosomal abnormality or the phenotype.

Structural genomic abnormalities in autism and schizophrenia. With a focus on the 22q11.2 deletion syndrome

NARCIS (Netherlands)

Vorstman, J.A.S.

2008-01-01

The research presented in this thesis is centered around one question: What can we learn from the study of psychiatric phenotypes related to structural genomic abnormalities? In this thesis this subject is examined, with most studies focused on the clinical and genetic aspects of the 22q11.2

Genetics Home Reference: 22q13.3 deletion syndrome

Science.gov (United States)

... 5 links) Diagnostic Tests Drug Therapy Genetic Counseling Palliative Care Surgery and Rehabilitation Related Information How are genetic ... Veltman JA, de Vries BB. Molecular characterisation of patients with subtelomeric 22q ... L, Enns GM, Hoyme HE. Terminal 22q deletion syndrome: a newly recognized cause of ...

'At the end of the day, it is more important that he stays happy': an interpretative phenomenological analysis of people who have a sibling with 22q11.2 deletion syndrome.

Science.gov (United States)

Goodwin, J; Alam, S; Campbell, L E

2017-09-01

22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome. However, there is little research examining the effect of this multisystem disorder on the family, particularly siblings. The current study was a phenomenological exploration of sense-making in siblings of a person with 22q11.2DS. Interpretative phenomenological analysis informed a detailed and open examination of being a sibling of a person with 22q11.2DS. Using in-depth semistructured interviews, five typically developing siblings (two men, three women) of people with 22q11.2DS were individually interviewed, providing the data set for transcription and thematic analysis. The theme 'They are the priority' overarched two subordinate themes that emerged from participants' descriptions of the struggle with acceptance and finding positive meaning. Participants oscillated between conflicting feelings about their sibling with 22q11.2DS always taking centre stage. For example, they felt anger, guilt and resentment; yet, they also embraced patience, empathy and gratitude. This phenomenological study provides a foundation for future research relating to 22q11.2DS and fostering family wellbeing, particularly around acceptance and psychological growth. The siblings in this study actively withdrew from their family to allow prioritisation of their affected sibling. However, this does not mean that their needs should be overlooked. There are easily accessible resources to support siblings of individuals with disabilities, and it is important for health professionals and parents to consider these options. © 2017 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

(q24: q12) translocation is common in Ewing's sarcoma/peripheral ...

Indian Academy of Sciences (India)

The Ewing's sarcoma family can present diagnostic difficulties. In the past the basis of diagnosis has been a exclusion. Identification of a specific translocation especially t(11; 22) (EWS-FLI 1 fusion gene), which is seen in nearly 85% of Ewing's sarcoma cases can help in precise diagnosis. We have carried out a study on ...

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

DEFF Research Database (Denmark)

Glubb, Dylan M; Johnatty, Sharon E; Quinn, Michael C J

2017-01-01

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D...... and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity...... and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates...

Schizophrenia patients and 22q11.2 deletion syndrome adolescents at risk express the same deviant patterns of resting state EEG microstates: A candidate endophenotype of schizophrenia

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Miralena I. Tomescu

2015-09-01

Full Text Available Schizophrenia is a complex psychiatric disorder and many of the factors contributing to its pathogenesis are poorly understood. In addition, identifying reliable neurophysiological markers would improve diagnosis and early identification of this disease. The 22q11.2 deletion syndrome (22q11DS is one major risk factor for schizophrenia. Here, we show further evidence that deviant temporal dynamics of EEG microstates are a potential neurophysiological marker by showing that the resting state patterns of 22q11DS are similar to those found in schizophrenia patients. The EEG microstates are recurrent topographic distributions of the ongoing scalp potential fields with temporal stability of around 80 ms that are mapping the fast reconfiguration of resting state networks. Five minutes of high-density EEG recordings was analysed from 27 adult chronic schizophrenia patients, 27 adult controls, 30 adolescents with 22q11DS, and 28 adolescent controls. In both patient groups we found increased class C, but decreased class D presence and high transition probabilities towards the class C microstates. Moreover, these aberrant temporal dynamics in the two patient groups were also expressed by perturbations of the long-range dependency of the EEG microstates. These findings point to a deficient function of the salience and attention resting state networks in schizophrenia and 22q11DS as class C and class D microstates were previously associated with these networks, respectively. These findings elucidate similarities between individuals at risk and schizophrenia patients and support the notion that abnormal temporal patterns of EEG microstates might constitute a marker for developing schizophrenia.

9q22 Deletion - First Familial Case

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Yamamoto Toshiyuki

2011-06-01

Full Text Available Abstract Background Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400 due to haploinsufficiency of the PTCH1 gene (MIM *601309. Methods and Results We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K. The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337 which causing both brachydactyly type 1 (MIM #113000 and Robinow syndrome (MIM #268310, and the immunologically active SYK gene (MIM *600085. The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations. Conclusions This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling.

Long‐distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region upregulating the allele‐specific MYC expression in HeLa cells

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Shen, Congle; Liu, Yongzhen; Shi, Shu; Zhang, Ruiyang; Zhang, Ting; Xu, Qiang; Zhu, Pengfei; Lu, Fengmin

2017-01-01

Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer development. In HeLa cell line, the HPV viral genome is integrated at 8q24 in one allele of chromosome 8. It has been reported that the HPV fragment integrated in HeLa genome can cis‐activate the expression of proto‐oncogene MYC, which is located at 500 kb downstream of the integrated site. However, the underlying molecular mechanism of this regulation is unknown. A recent study reported that MYC was highly expressed exclusively from the HPV‐integrated haplotype, and a long‐range chromatin interaction between the integrated HPV fragment and MYC gene has been hypothesized. In this study, we provided the experimental evidences supporting this long‐range chromatin interaction in HeLa cells by using Chromosome Conformation Capture (3C) method. We found that the integrated HPV fragment, MYC and 8q24.22 was close to each other and might form a trimer in spatial location. When knocking out the integrated HPV fragment or 8q24.22 region from chromosome 8 by CRISPR/Cas9 system, the expression of MYC reduced dramatically in HeLa cells. Interestingly, decreased expression was only observed in three from eight cell clones, when only one 8q24.22 allele was knocked out. Functionally, HPV knockout caused senescence‐associated acidic β‐gal activity in HeLa cells. These data indicate a long‐distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region, providing an alternative mechanism relevant to the carcinogenicity of HPV integration. PMID:28470669

Quasi quantum group covariant q-oscillators

International Nuclear Information System (INIS)

Schomerus, V.

1992-05-01

If q is a p-th root of unity there exists a quasi-co-associative truncated quantum group algebra U T q (sl 2 ) whose indecomposable representations are the physical representations of U q (sl 2 ), whose co-product yields the truneated tensor product of physical representations of U q (sl 2 ), and whose R-matrix satisfies quasi Yang Baxter equations. For primitive p-th roots q, we consider a 2-dimensional q-oscillator which admits U T q (sl 2 ) as a symmetry algebra. Its wave functions lie in a space F T q of 'functions on the truncated quantum plane', i.e. of polynomials in noncommuting complex coordinate functions z a , on which multiplication operators Z a and the elements of U T q (sl 2 ) can act. This illustrates the concept of quasi quantum planes. Due to the truncation, the Hilbert space of states is finite dimensional. The subspaces F T(n) of monomials in x a of n-th degree vanish for n ≥ p-1, and F T(n) carries the 2J+1 dimensional irreducible representation of U T q (sl 2 ) if n=2J, J=0, 1/2, ... 1/2(p-2). Partial derivatives δ a are introduced. We find a *-operation on the algebra of multiplication operators Z i and derivatives δ b such that the adjoints Z * a act as differentiation on the truncated quantum plane. Multiplication operators Z a ('creation operators') and their adjoints ('annihilation operators') obey q -1/2 -commutation relations. The *-operation is used to determine a positive definite scalar product on the truncated quantum plane F T q . Some natural candidates of Hamiltonians for the q-oscillators are determined. (orig./HSI)

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