Sharp, A.J. et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat. Genet. 40, 322-328

Department of Genome Sciences, University of Washington School of Medicine, 1705 NE Pacific St., Seattle, Washington 98195, USA.
Nature Genetics (Impact Factor: 29.35). 04/2008; 40(3):322-8. DOI: 10.1038/ng.93
Source: PubMed

ABSTRACT We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes.

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    • "Among recurrent CNVs, the 15q13.3 microdeletion is highly but not always fully penetrant, and it is significantly enriched in cases of intellectual disability, autism, epilepsy, schizophrenia, and bipolar disorder [Sharp et al., 2008; Stefansson et al., 2008; Ben-Shachar et al., 2009 Dibbens et al., 2009; Helbig et al., 2009; Miller et al., 2009; Pagnamenta et al., 2009; van Bon et al., 2009; Cooper et al., 2011]. This 15q13.3 "
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    ABSTRACT: Chromosome 15q13.3 recurrent microdeletions are causally associated with a wide range of phenotypes, including autism spectrum disorder (ASD), seizures, intellectual disability, and other psychiatric conditions. Whether the reciprocal microduplication is pathogenic is less certain. CHRNA7, encoding for the alpha7 subunit of the neuronal nicotinic acetylcholine receptor, is considered the likely culprit gene in mediating neurological phenotypes in 15q13.3 deletion cases. To assess if CHRNA7 rare variants confer risk to ASD, we performed copy number variant analysis and Sanger sequencing of the CHRNA7 coding sequence in a sample of 135 ASD cases. Sequence variation in this gene remains largely unexplored, given the existence of a fusion gene, CHRFAM7A, which includes a nearly identical partial duplication of CHRNA7. Hence, attempts to sequence coding exons must distinguish between CHRNA7 and CHRFAM7A, making next-generation sequencing approaches unreliable for this purpose. A CHRNA7 microduplication was detected in a patient with autism and moderate cognitive impairment; while no rare damaging variants were identified in the coding region, we detected rare variants in the promoter region, previously described to functionally reduce transcription. This study represents the first sequence variant analysis of CHRNA7 in a sample of idiopathic autism. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2015; 167(4). DOI:10.1002/ajmg.a.36847 · 2.16 Impact Factor
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    • "In this region, several significant deletions or duplications were found in which the beginning and end points vary across individuals. The region implicated by 15q13 CNVs spans several genes, including CHRNA7 (cholinergic receptor, nicotinic, alpha 7), KLF13 (Kruppel-like factor 13), TRPM1 (transient receptor potential cation channel, subfamily M, member 1), MTMR10 (myotubularin-related protein 10), and OTUD7A (OTU domain containing 7A) (Sharp et al., 2008; Ben-Shachar et al., 2009; Miller et al., 2009; Van Bon et al., 2009). Among these, only CHRNA7 has been associated nominally with ADHD in common variant studies (Stergiakouli et al., 2012; Williams et al., 2012). "
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    ABSTRACT: Objectives Evidence has supported a role for rare copy number variants in the etiology of attention-deficit hyperactivity disorder (ADHD), in particular, the region 15q13, which is also a hot spot for several neuropsychiatric disorders. This region spans several genes, but their role and the biological implications remain unclear.Methods We carried out, for the first time, an analysis of the 15q13 region in an Italian cohort of 117 ADHD patients and 77 controls using the MLPA method, confirmed by a genome single-nucleotide polymorphism array. In addition, we probed for downstream effects of the 15q13 deletions on gene expression by carrying out a transcriptomic analysis in blood.ResultsWe found 15q13 deletions in two ADHD patients and identified 129 genes as significantly dysregulated in the blood of the two ADHD patients carrying 15q13 deletions compared with ADHD patients without 15q13 deletions. As expected, genes in the deleted region (KLF13, MTMR10) were downregulated in the two patients with deletions. Moreover, a pathway analysis identified apoptosis, oxidation reduction, and immune response as the mechanisms that were altered most significantly in the ADHD patients with 15q13 deletions. Interestingly, we showed that deletions in KLF13 and CHRNA7 influenced the expression of genes belonging to the same immune/inflammatory and oxidative stress signaling pathways.Conclusion Our findings are consistent with the presence of 15q13 deletions in Italian ADHD patients. More interestingly, we show that pathways related to immune/inflammatory response and oxidative stress signaling are affected by the deletion of KFL13 and CHRNA7. Because the phenotypic effects of 15q13 are pleiotropic, our findings suggest that there are shared biologic pathways among multiple neuropsychiatric conditions.
    Psychiatric Genetics 11/2014; 25(2). DOI:10.1097/YPG.0000000000000056 · 1.94 Impact Factor
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    • "deletions in patients with generalized epilepsy [45••]. The 15q13.3 microdeletion (chr15: 31,000,000–32,500,000, hg19) was first described in patients with ID, but it was noted that most patients also suffered from seizures [46]. This observation led to a collaborative effort to determine the frequency of the deletion in a cohort of 1,223 patients with generalized epilepsy, most of whom did not have ID or other neurodevelopmental abnormalities. "
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    ABSTRACT: Copy number variants (CNVs) are deletions or duplications of DNA. CNVs have been increasingly recognized as an important source of both normal genetic variation and pathogenic mutation. Technologies for genome-wide discovery of CNVs facilitate studies of large cohorts of patients and controls to identify CNVs that cause increased risk for disease. Over the past 5 years, studies of patients with epilepsy confirm that both recurrent and non-recurrent CNVs are an important source of mutation for patients with various forms of epilepsy. Here, we will review the latest findings and explore the clinical implications.
    09/2014; 2(3):162-167. DOI:10.1007/s40142-014-0046-6
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