De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

“…Unlike prior studies 8 , 9 , 13 , we found that damaging DNMs were enriched in isolated CHD cases (CHD without extracardiac congenital anomaly, clinically diagnosed syndrome or neurodevelopmental abnormality, and limited to patients over age 1 at enrollment); these mutations contributed to ~3.1% of cases (1.5-fold enrichment, P = 8.5×10 −4 ; Supplementary Table 22a ). Damaging DNMs in known CHD genes accounted for ~50% (13/26) of the excess mutation burden in isolated CHD.…”

“…We analyzed the burden of de novo variants in CDH cases by comparing the observed number of variants to the expected number based on the background mutation rate. Consistent with previous studies on CDH 9 and other developmental disorders 50-52 , both de novo LGD (0.15 per case) and D-mis variants (0.35 per case) were significantly enriched in cases (relative risk [RR]=1.5, P=3.6×10 −5 for LGD; RR=1.3, P=3.1×10 −6 ; Figures 1A and B; Table S3) while the frequency of synonymous variants (0.30 per case) closely matches the expectation (RR=0.9, P=0.12; Table S3). The burden of LGD variants is mostly located in constrained (ExAC 39 pLI >0.5) genes (RR=2.2, P=1.8×10 −8 ).…”

“…Furthermore, among the 17 genes with at least one de novo mutation in CHD and autism cohorts, 5 genes ( KMT2D, NSD1, POGZ, SMAD2, KDM5B ) play a role in chromatin modeling. Such high proportion is consistent with previous studies that chromatin modeling-related transcriptional regulations are essential for both cardiac and neuro-development, and genes with critical regulatory roles in the process may be pleotropic 9 .…”