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

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.

SUBMITTER: D'Alessandro LC

PROVIDER: S-EPMC5988035 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

D'Alessandro Lisa C A LC Al Turki Saeed S Manickaraj Ashok Kumar AK Manase Dorin D Mulder Barbara J M BJ Bergin Lynn L Rosenberg Herschel C HC Mondal Tapas T Gordon Elaine E Lougheed Jane J Smythe John J Devriendt Koen K Bhattacharya Shoumo S Watkins Hugh H Bentham Jamie J Bowdin Sarah S Hurles Matthew E ME Mital Seema S

Genetics in medicine : official journal of the American College of Medical Genetics 20150521 2

<h4>Purpose</h4>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.<h4>Methods</h4>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.<h4>Results</h4>A significant enrichment of rare and rare damaging vari ...[more]

PMID: 25996639

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Project description:BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.

Dataset Information

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

Publications

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

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