Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: Precedent for disorders with complex inheritance

Epilepsy Research Program, SA Pathology at Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia.
Human Molecular Genetics (Impact Factor: 6.39). 08/2009; 18(19):3626-31. DOI: 10.1093/hmg/ddp311
Source: PubMed


Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determine the relative occurrence of sporadic and familial cases and to examine the likelihood of having seizures for individuals with the microdeletion in familial cases. The 15q13.3 microdeletion was identified in 7 of 539 (1.3%) unrelated cases of IGE using quantitative PCR or SNP arrays and confirmed by array comparative genomic hybridization analysis using probes specific to the 15q13.3 region. The inheritance of this lesion was tracked using family studies. Of the seven microdeletions identified in probands, three were de novo, two were transmitted from an unaffected parent and in two cases the parents were unavailable. Non-penetrance of the microdeletion was identified in 4/7 pedigrees and three pedigrees included other family members with IGE who lacked the 15q13.3 deletion. The odds ratio is 68 (95% confidence interval 29-181), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families.

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Available from: Susannah T Bellows
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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.
    Full-text · Article · Feb 2015 · American Journal of Medical Genetics Part A
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    • "Several studies have found an increased burden of large, rare CNVs in ADHD, some of which overlap with findings in autism (Elia et al., 2010; Williams et al., 2010, 2012; Lionel et al., 2011). A CNV region of particular interest is 15q13, a hot spot for several neuropsychiatric disorders such as schizophrenia (Stefansson et al., 2008; Stone et al., 2008; Van Bon et al., 2009; Stephens et al., 2012), epilepsy (Dibbens et al., 2009; Helbig et al., 2009), autism (Pagnamenta et al., 2009), developmental delay (DD), intellectual disability (ID), and dysmorphic features (Sharp et al., 2008; Ben-Shachar et al., 2009; Miller et al., 2009), as well as ADHD (Lionel et al., 2011; Williams et al., 2012). The frequency of 15q11q13 CNVs was estimated by Williams et al. (2010) to be 1.91% in European cohorts. "
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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.
    Full-text · Article · Nov 2014 · Psychiatric Genetics
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    • "deletion compared to 0/3,699 control individuals [45••]. Several subsequent studies confirmed this finding [33, 47, 48], establishing the deletion as one of the most prevalent genetic risk factors for GGE with an estimated odds ratio of 68 (29–181) [47]. "
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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.
    Preview · Article · Sep 2014
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