BACKGROUND Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently. De novo variants are estimated to contribute to approximately 8% of sporadic CHD. METHODS CHD is genetically heterogeneous, making pathway enrichment analysis an effective approach to explore and statistically validate CHD-associated genes. In this study, we performed novel gene and pathway enrichment analyses of high-impact de novo variants in the recently published whole-exome sequencing (WES) data generated from a cohort of CHD 2645 parent-offspring trios to identify new CHD-causing candidate genes and mutations. We performed rigorous variant- and gene-level filtrations to identify potentially damaging variants, followed by enrichment analyses and gene prioritization. RESULTS Our analyses revealed 23 novel genes that are likely to cause CHD, including HSP90AA1, ROCK2, IQGAP1, and CHD4, and sharing biological functions, pathways, molecular interactions, and properties with known CHD-causing genes. CONCLUSIONS Ultimately, these findings suggest novel genes that are likely to be contributing to CHD pathogenesis.

中文翻译：

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先天性心脏病患者外显子组中的从头变异识别风险基因和途径。

背景先天性心脏病 (CHD) 影响约 1% 的活产儿，是最常见的出生缺陷。尽管长期以来一直怀疑对先天性心脏病的遗传贡献，但直到最近才得到充分证实。据估计，新发变异约占散发性 CHD 的 8%。方法 CHD 具有遗传异质性，使得通路富集分析成为探索和统计验证 CHD 相关基因的有效方法。在这项研究中，我们在最近发表的全外显子组测序 (WES) 数据中对高影响力的从头变异进行了新的基因和通路富集分析，这些数据是从一组 CHD 2645 亲代 - 后代三人组中生成的，以识别新的 CHD 致病候选基因和突变。我们进行了严格的变异和基因级过滤，以识别潜在的破坏性变异，其次是富集分析和基因优先排序。结果 我们的分析揭示了 23 个可能导致 CHD 的新基因，包括 HSP90AA1、ROCK2、IQGAP1 和 CHD4，并与已知的 CHD 致病基因共享生物学功能、途径、分子相互作用和特性。结论 最终，这些发现表明可能导致 CHD 发病机制的新基因。