Genomic analyses implicate noncoding de novo variants in congenital heart disease

A genetic etiology is identified for one third of congenital heart disease (CHD) patients, including 8% attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10(−4)). Independent analyses of enhancers showed excess DNVs in associated genes (27 genes vs. 3.7 expected, P = 1 × 10(−5)). We observed significant overlap between these transcription-based approaches (OR = 2.5, 95% CI 1.1–5.0, P = 5.4 × 10(−3)). CHD DNVs altered transcription levels in five of 31 enhancers assayed. Finally, we observed DNV burden in RNA-binding protein regulatory sites (OR = 1.13, 95% CI 1.1–1.2, P = 8.8 × 10(−5)). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as observed for damaging coding DNVs.