De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.

中文翻译：

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结合医疗保健和研究数据发现 28 种遗传性疾病的证据


蛋白质编码基因的从头突变是发育障碍的一个明确原因1。然而，已知与发育障碍相关的基因仅占观察到的此类新生突变中的一小部分1,2。在这里，为了识别以前未描述的与发育障碍相关的基因，我们整合了来自 31,058 个患有发育障碍的亲子三人组的医疗保健和研究外显子组序列数据，并开发了基于模拟的统计测试，以从头识别基因特异性富集。突变。我们鉴定了 285 个与发育障碍显着相关的基因，其中 28 个基因此前并未与发育障碍密切相关。尽管我们检测到了更多与发育障碍相关的基因，但蛋白质编码基因中大量的从头突变仍未得到解释。模型表明，还有超过 1,000 个与发育障碍相关的基因尚未被描述，其中许多基因的渗透性可能不如目前已知的基因。研究获取临床诊断数据集对于完成与发育障碍相关的基因图谱至关重要。