De novo mutations in histone-modifying genes in congenital heart disease.
De novo mutations in histone-modifying genes in congenital heart disease.
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先天性心脏病（CHD）是最常见的出生缺陷，影响0.8%的活产婴儿。许多病例呈散发性发生，并损害生殖健康，这表明新生突变起作用。通过对亲子三联体的外显子组测序分析，我们比较了362例严重先天性心脏病病例和264例对照中新生突变的发生率。先天性心脏病病例在发育中的心脏所表达的基因中显示出蛋白质改变性新生突变显著过多，有害突变的优势比为7.5。在主要的严重先天性心脏病类别中也观察到了类似的优势比。我们发现，在参与H3K4甲基化（H3K4me）的产生、去除或读取，或H2BK120泛素化（H3K4甲基化所必需）的基因中，新生突变明显过多。在SMAD2中也有两个新生突变；胚胎左右组织者中的SMAD2信号传导诱导H3K27me的去甲基化。H3K4me和H3K27me标记调控关键发育基因表达的“预备”启动子和增强子。这些发现表明数百个基因中的新生点突变共同导致了约10%的严重先天性心脏病。
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. By analysis of exome sequencing of parent-offspring trios, we compared the incidence of de novo mutations in 362 severe CHD cases and 264 controls. CHD cases showed 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 mutations. Similar odds ratios were seen across major classes of severe CHD. We found a marked excess of de novo mutations in genes involved in production, removal or reading of H3K4 methylation (H3K4me), or ubiquitination of H2BK120, which is required for H3K4 methylation. There were also two de novo mutations in SMAD2; SMAD2 signaling in the embryonic left-right organizer induces demethylation of H3K27me. H3K4me and H3K27me mark `poised' promoters and enhancers that regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundred genes that collectively contribute to ~10% of severe CHD.