Exome Sequencing Identifies Rare Variants in Multiple Genes in Atrioventricular Septal Defect

Purpose 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 non-syndromic individuals with AVSD. Methods: 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. Results: A 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. Conclusion: 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

Rare variants in NR2F2 cause congenital heart defects in humans

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10?7) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters