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Abstract

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

Figures

Figure 1
Figure 1. Enrichment of non-synonymous de novo mutations in heart-expressed genes
a, Odds ratios (ORs), standard errors and P-values (two-tailed binomial exact test) are shown comparing incidence of classes of de novo mutations in CHD cases versus controls for genes in top 25% (red bars) and bottom 75% (blue bars) of expression at e14.5 in developing heart. b, ORs for incidence of mutations in genes in top 25% versus bottom 75% of expression in CHD cases (red bars) and controls (blue bars). `Damaging' denotes premature termination, frameshift or splice site mutations; `Conserved MS' and `Noncons MS' denote mutations at highly or poorly conserved positions, respectively. NS, not significant.
Figure 2
Figure 2. De novo mutations in the H3K4 and H3K27 methylation pathways
Nucleosome with histone octamer and DNA, with H3K4 methylation bound by CHD7, H3K27 methylation and H2bK120 ubiquitination is shown. Genes mutated in CHD that affect the production, removal and reading of these histone modifications are shown; genes with damaging mutations are shown in red, those with missense mutations are shown in blue. SMAD2 (2) indicates there are two patients with mutation in this gene. Genes whose products are found together in a complex are enclosed in a box.

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