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

Abstract

PurposeThe 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 non-syndromic individuals with AVSD.MethodsWhole 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.ResultsA significant enrichment of rare and rare/damaging variants was identified in the gene set, compared with controls (odds ratio 1.52, 95% confidence interval 1.35–1.71, p = 4.8 x 10-11). The enrichment was specific to AVSD probands compared with a non-AVSD cohort with tetralogy of Fallot (odds ratio 2.25, 95% confidence interval 1.84-2.76, p = 2.2 x 10-16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2 and MDM4) were enriched for rare variants in AVSD compared to controls, including three syndrome-associated genes (NIPBL, CHD7, CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands.ConclusionMutations 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.

Genetic profile of isolated congenital diaphragmatic hernia revealed by targeted next‐generation sequencing

“…Four more VUS, of which the two first are new, have been identified: c.424A > C, p.(Thr142Pro), c.1933G > A, p.(Asp645Asn), c.2651G > A, p.(Arg884His) and c.G292G > A, p.(Asp98Asn). The last variant is known and has a conflicting interpretation: reported as likely causing CDH or heart defect and likely benign in CLINVAR with a benign in silico prediction.…”

The fitness cost of a congenital heart defect shapes its genetic architecture

“…Consistent with this model, a small study of non-syndromic AVSD found that among 34 persons who carried a mutation of one of six AVSD genes (NIPBL, CHD7, CEP152, BMPR1A, ZFPM2, MDM4), 8 persons carried two or more, rare or rare, damaging nonsynonymous variants of the six genes. 22 Larger human studies are necessary to validate an oligogenic model in which nonlinear effects may have an outsized role in severe CHD.…”

Clinical and molecular effects of CHD7 in the heart

“…In a cohort of 81 patients with AVSD, an enrichment of rare and rare potentially damaging CHD7 mutations was identified while screening 112 AVSD-related genes. These patients had syndromic as well as non-syndromic heart defects, and the authors suspected that the CHD7 variants contributed to the AVSD, but the pathogenic effect of the rare CHD7 variants they identified in this study has not been proven (D'Alessandro et al, 2016).…”