Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Nat Commun. 2021 Jan 27;12(1):627. doi: 10.1038/s41467-020-20852-3.
Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.
超过 130 个 X 连锁基因与发育障碍密切相关，并且假设 X 连锁病因是男性发育障碍率较高的原因。在这里，我们评估了 11044 名发育障碍患者的 X 连锁编码变异负担，发现男性和女性的 X 连锁病因发生率相似（分别为 6.0%和 6.9%），这表明此类变体不能解释男性的 1.4 倍偏倚。我们开发了一种改进的策略来检测 X 连锁发育障碍，并确定了 23 个重要基因，这些基因以前都是已知的，这与我们的推断一致，即 X 连锁负担的绝大多数都在已知的与发育障碍相关的基因中。重要的是，我们估计，在男性先证者中，已知与发育障碍相关的基因中遗传性罕见错义变异的 13%可能是致病性的。我们的研究结果表明，对大型数据集的统计分析可以深入了解个体 X 连锁疾病的遗传方式。
