Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect

Lisa C. A. D'Alessandro, Saeed Al Turki, Ashok Kumar Manickaraj, Dorin Manase, Barbara J. M. Mulder, Lynn Bergin, Herschel C. Rosenberg, Tapas Mondal, Elaine Gordon, Jane Lougheed, John Smythe, Koen Devriendt, Shoumo Bhattacharya, Hugh Watkins, Jamie Bentham, Sarah Bowdin, Matthew E. Hurles, Seema Mital

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30 Citations (Scopus)

Abstract

The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD. Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35-1.71; P = 4.8 × 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84-2.76; P = 2.2 × 10(-16)). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort
Original languageEnglish
Pages (from-to)189-198
JournalGenetics in medicine
Volume18
Issue number2
DOIs
Publication statusPublished - 2016

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