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: 6.68). 08/2009; 18(19):3626-31. DOI: 10.1093/hmg/ddp311
Source: PubMed

ABSTRACT 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, Jul 28, 2015
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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 · 2.05 Impact Factor
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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.
    Psychiatric Genetics 11/2014; 25(2). DOI:10.1097/YPG.0000000000000056 · 2.27 Impact Factor
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    • "Recent genome-wide scans for CNVs showed that a much rarer CNV at 15q13.3 is overrepresented in the common IGEs. In a population-based cohort study, Helbig et al. (2009) identified a 1.5-Mb microdeletion in the region encompassing CHRNA7 in 12 out of 1,223 individuals with IGE, but not in 3,699 controls, and this association was confirmed in several independent IGE samples (Dibbens et al., 2009; Mefford et al., 2010; Muhle et al., 2011). The 1.5-Mb deletion, which has previously been associated with mental retardation and seizures (Sharp et al., 2008), contains at least seven genes, including CHRNA7 as a candidate gene for epilepsy. "
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    ABSTRACT: There is evidence of linkage between the 15q13–q14 locus, containing the gene encoding the a7 subunit (CHRNA7) of the neuronal nicotinic acetylcholine receptor (nAChR) and its partially duplicated isoform (CHRFAM7A), and epilepsy. Additionally, a 2-bp deletion polymorphism (c.497–498delTG; rs67158670) in CHRFAM7A, resulting in a frame shift and truncation of the protein product, is associated with some neuro-logical diseases. This study was designed to explore the possibility of an association of the c.497–498delTG polymorphism of CHRFAM7A with idiopathic generalized epilepsies (IGEs) in Polish children and young pa-tients. The study included 197 IGE patients and 258 unrelated healthy individuals. The frequency of the CHRFAM7A c.497–498delTG polymorphism was determined in each group using heteroduplex analysis. An association between the c.497–498delTG polymorphism of CHRFAM7A and IGE was evidenced. It was dem-onstrated that the frequency of the CHRFAM7A 2-bp deletion carriers was significantly lower in the IGE patients than in the control group. The observed frequency of 2-bp deletion carriers was high in IGE subjects (64%), but significantly higher in control subjects (76%). Carriers of at least one copy of the -2 bp allele had halved their risk of IGE susceptibility (delTG/delTG and delTG/wild-type versus wild-type/wild-type: odds ratio = 0.55; 95% confidence intervals = 0.365–0.827; p = 0.004). Moreover, it has been demonstrated that this polymorphic variant is associated with the c.524-12_524-11insGTT variation (rs10649395) in intron 7 of CHRFAM7A. Our study substantiates the involvement of the a7 subunit of nAChR in the pathophysiology of IGEs and indicates that the CHRFAM7A c.497–498TG deletion or a nearby polymorphism may play a role in the pathogenesis of IGE. Further work should concentrate on ascertaining the exact mechanism of this polymorphism's effect and its relationship with IGE.
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