Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

中文翻译：

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在新发变异的情况下，常见变异会增加先天性膈疝的风险


先天性膈疝 （CDH） 是一种严重的先天性异常，通常伴有其他结构异常和/或神经行为表现。罕见的从头蛋白质编码变异和拷贝数变异有助于人群中的 CDH。然而，大多数 CDH 患者在遗传学上仍未被诊断。在这里，我们使用 1,469 个 CDH 个体进行了综合的从头和共同变异分析，其中包括 1,064 个父子三胞胎和 6,133 个祖先匹配、未受影响的对照，用于全基因组关联研究。我们通过有害的 de novo 变体在 15 个基因中鉴定候选 CDH 变体，包括 8 个新基因。我们进一步确定了两个导致 CDH 风险的基因组位点，这些基因位点通过欧洲人和拉丁裔中具有相似效应量的常见变异。这两个位点都位于发育模式基因的推定转录调控区域。常见变异的估计遗传力约为 19%。引人注目的是，孤立和复杂的 CDH 之间或携带有害新发变异的个体与没有这些变异的个体之间的估计多基因风险评分没有显著差异。数据支持多基因模型作为 CDH 遗传结构的一部分。