Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders

Ben‐Shachar, Shay; Lanpher, Brendan C.; German, Jennifer R.; Qasaymeh, Mohammad M.; Potocki, Lorraine; Nagamani, Sandesh C. Sreenath; Franco, Luis M.; Malphrus, Amy D.; Bottenfield, G. W.; Spence, J. Edward; Amato, Stephen; Rousseau, Justine; Moghaddam, Billur; Skinner, Cindy; Skinner, Steven A.; Bernes, Saunder; Armstrong, Nicole L.; Shinawi, Marwan; Stankiewicz, Paweł; Patel, Ankita; Cheung, Sau Wai; Lupski, James R.; Beaudet, Arthur L.; Sahoo, Trilochan

doi:10.1136/jmg.2008.064378

Cited by 214 publications

(166 citation statements)

References 37 publications

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“…[1][2][3][4][5][6][7] To date, all individuals with the homozygous 15q13.3 deletion are reported to have a similar and much more severe developmental encephalopathy and neuromuscular disorder than those with the heterozygous deletion. [13][14][15][16][17] We hypothesized that the 15q13.3 deletion had detectable effects on downstream gene expression and the effects of downstream gene dysfunction might contribute to the syndrome.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

Pichon

Kibiryeva

et al. 2013

Eur J Hum Genet

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We identified a novel homozygous 15q13.3 microdeletion in a young boy, with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness, congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper, we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. We identified 267 genes with apparent differential expression between the proband with the homozygous deletion and 3 age-and sex-matched typically developing controls. Several of the differentially expressed genes are known to influence neurodevelopment and muscular function, and thus may contribute to the observed cognitive impairment and hypotonia. We further investigated the role of CHRNA7 by measuring TNFa modulation (a potentially important pathway in regulating synaptic plasticity). We found that the cell line with the homozygous deletion lost the ability to inhibit the activation of tumor necrosis factor-a secretion. Our findings suggest downstream genes that may have been altered by the 15q13.3 homozygous deletion, and thus contributed to the severe developmental encephalopathy of the proband. Furthermore, we show that a potentially important pathway in learning and development is affected by the deletion of CHRNA7.

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Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8] The phenotype varies in spectrum and severity owing to incomplete penetrance or variable expressivity. The 15q13.3 deletion is typically 1.6 Mb, harboring at least seven genes, ARHGAP11B, MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

Pichon

Kibiryeva

et al. 2013

Eur J Hum Genet

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“…29 Recently several groups have implicated CHRNA7 as a candidate gene for the 15q13.3 microdeletion syndrome whose clinical manifestations include facial and digital dysmorphology, expressive language deficit, and various neuropsychiatric disorders, such as schizophrenia, autism, epilepsy and mental retardation. [30][31][32][33] The finding that cases 6 and 7 had large deletions encompassing the 15q13.3 region prompted us to request an EEG be done on both of them. Similar to those with the 15q13.3 microdeletion, case 6 had both clinical and EEG-documented seizure activities.…”

Section: Discussionmentioning

confidence: 99%

“…A great deal of variability in clinical features has been described for individuals with the 15q13.3 microdeletion including some parents with the deletion who lack the clinical features found in their offspring. 33 Furthermore, the 15q13.3 region, like the 22q11.2 and 16p12.1 regions, may be another example of a 'susceptibility region' that requires a 'second hit' elsewhere in the genome to become fully penetrant as a neurodevelopmental phenotype. 34,35 Third, the DKFZp434L187 transcript (deleted in case 7) downstream to CHRNA7 may require further evaluation for its potential role in the more severe developmental delay and failure-to-thrive, although this is very unlikely given that this transcript has not been shown to code for any important function to our knowledge.…”

Section: Discussionmentioning

confidence: 99%

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

et al. 2011

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Prader-Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1-BP3 and BP2-BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylationspecific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n¼5) or larger (n¼2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in B8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.

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“…In three instances, de novo CNVs were identified in a pair of nonmonozygotic siblings representing potential germline mosaicism and were counted as single events. Several de novo CNVs occur both at loci previously associated with variable phenotypes, including autism (AmosLandgraf et al 1999;McDermid and Morrow 2002;Veltman et al 2005; The International Schizophrenia Consortium 2008; Kumar et al 2008;Mefford et al 2008;Weiss et al 2008;Ben-Shachar et al 2009;Bijlsma et al 2009;Miller et al 2009), as well as sites of recurrent CNV not previously associated with autism (Kurotaki et al 2002;Bochukova et al 2010;Walters et al 2010). …”

Section: Agre Autism Analysismentioning

confidence: 99%

De novo rates and selection of large copy number variation

et al. 2010

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While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (>100 kbp) events, we estimate the rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of~30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of m = 1.2 3 10 -2 CNVs per genome per transmission (m = 6.5 3 10 -3 for CNVs >500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (>500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 3 10 -3 ) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied.

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Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders

Abstract: Background-Microdeletions within chromosome 15q13.3 are associated both with a recently recognised syndrome of mental retardation, seizures, and dysmorphic features, and with schizophrenia.

Cited by 214 publications

References 37 publications

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

De novo rates and selection of large copy number variation

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