Whole‐genome or whole‐exome sequencing (WGS/WES) of the affected proband together with normal parents (trio) is commonly adopted to identify de novo germline mutations (DNMs) underlying sporadic cases of various genetic disorders. However, our current knowledge of the occurrence and functional effects of DNMs remains limited and accurately identifying the disease‐causing DNM from a group of irrelevant DNMs is complicated. Herein, we provide a general‐purpose discussion of important issues related to pathogenic gene identification based on trio‐based WGS/WES data. Specifically, the relevance of DNMs to human sporadic diseases, current knowledge of DNM biogenesis mechanisms, and common strategies or software tools used for DNM detection are reviewed, followed by a discussion of pathogenic gene prioritization. In addition, several key factors that may affect DNM identification accuracy and causal gene prioritization are reviewed. Based on recent major advances, this review both sheds light on how trio‐based WGS/WES technologies can play a significant role in the identification of DNMs and causal genes for sporadic diseases, and also discusses existing challenges.

中文翻译：

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使用基于三重组的全外显子组/基因组测序鉴定散发性疾病的从头生殖系突变和致病基因

受累先证者与正常父母（三人）的全基因组或全外显子组测序（WGS/WES）通常用于鉴定各种遗传疾病零星病例的新发生殖系突变（DNM）。然而，我们目前对 DNM 的发生和功能影响的了解仍然有限，并且从一组不相关的 DNM 中准确识别引起疾病的 DNM 很复杂。在此，我们提供了基于三重 WGS/WES 数据的与致病基因鉴定相关的重要问题的通用讨论。具体而言，综述了 DNM 与人类散发性疾病的相关性、DNM 生物发生机制的当前知识以及用于 DNM 检测的常用策略或软件工具，然后讨论了致病基因的优先排序。此外，回顾了可能影响 DNM 识别准确性和因果基因优先级的几个关键因素。基于最近的重大进展，这篇综述既阐明了基于三重奏的 WGS/WES 技术如何在鉴定散发性疾病的 DNM 和致病基因方面发挥重要作用，也讨论了现有的挑战。