De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes involving errors of DNA repair/replication. These spontaneous errors play a significant role in the causation of genetic disorders, and their importance in the context of molecular diagnostic medicine has become steadily more apparent as more DNMs have been reported in the literature. In this study, we examined 46,489 disease-associated DNMs annotated by the Human Gene Mutation Database (HGMD) to ascertain their distribution across gene and disease categories. Most disease-associated DNMs reported to date are found to be associated with developmental and psychiatric disorders, a reflection of the focus of sequencing efforts over the last decade. Of the 13,277 human genes in which DNMs have so far been found, the top-10 genes with the highest proportions of DNM relative to gene size were H3-3 A, DDX3X, CSNK2B, PURA, ZC4H2, STXBP1, SCN1A, SATB2, H3-3B and TUBA1A. The distribution of CADD and REVEL scores for both disease-associated DNMs and those mutations not reported to be de novo revealed a trend towards higher deleteriousness for DNMs, consistent with the likely lower selection pressure impacting them. This contrasts with the non-DNMs, which are presumed to have been subject to continuous negative selection over multiple generations. This meta-analysis provides important information on the occurrence and distribution of disease-associated DNMs in association with heritable disease and should make a significant contribution to our understanding of this major type of mutation.

中文翻译：

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对 46,000 个与人类遗传病相关的种系新生突变的荟萃分析

新生突变（DNM）是在非携带者父母的后代中重新发生的变异。它们不是从父母任何一方继承的，而是由涉及 DNA 修复/复制错误的内源突变过程引起的。这些自发错误在遗传性疾病的病因中发挥着重要作用，并且随着文献中报道了更多的 DNM，它们在分子诊断医学背景下的重要性变得越来越明显。在这项研究中，我们检查了人类基因突变数据库 (HGMD) 注释的 46,489 个与疾病相关的 DNM，以确定它们在基因和疾病类别中的分布。迄今为止报道的大多数与疾病相关的 DNM 被发现与发育和精神疾病有关，这反映了过去十年测序工作的重点。迄今为止已发现 DNM 的 13,277 个人类基因中，相对于基因大小而言 DNM 比例最高的前 10 个基因是 H3-3 A、DDX3X、CSNK2B、PURA、ZC4H2、STXBP1、SCN1A、SATB2、H3 -3B 和 TUBA1A。与疾病相关的 DNM 和那些未报道的从头突变的 CADD 和 REVEL 评分的分布揭示了 DNM 的有害性更高的趋势，这与影响它们的选择压力可能较低是一致的。这与非 DNM 形成鲜明对比，非 DNM 被认为在多代中受到持续的负选择。这项荟萃分析提供了与遗传性疾病相关的疾病相关 DNM 的发生和分布的重要信息，并且应该对我们对这种主要突变类型的理解做出重大贡献。