Autism spectrum disorder (ASD) is an early-onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviours^1,2. Family studies demonstrate that ASD has a substantial genetic basis with contributions both from inherited and de novo variants^3,4. It has been estimated that de novo mutations may contribute to 30% of all simplex cases, in which only a single child is affected per family⁵. Tandem repeats (TRs), defined here as sequences of 1 to 20 base pairs in size repeated consecutively, comprise one of the major sources of de novo mutations in humans⁶. TR expansions are implicated in dozens of neurological and psychiatric disorders⁷. Yet, de novo TR mutations have not been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here we develop new bioinformatics methods for identifying and prioritizing de novo TR mutations from sequencing data and perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. We infer specific mutation events and their precise changes in repeat number, and primarily focus on more prevalent stepwise copy number changes rather than large expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. Mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and are predicted to be more evolutionarily deleterious. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations.

自闭症谱系障碍 (ASD) 是一种早发性发育障碍，其特点是缺乏沟通和社交互动以及限制性或重复性行为^1,2。家庭研究表明，ASD 具有重要的遗传基础，遗传和新生变异^3,4都有贡献。据估计，新发突变可能导致所有单纯性病例的 30%，其中每个家庭只有一个孩子受到影响⁵。^{串联重复序列 (TRs)，此处定义为大小为 1 到 20 个碱基对的序列连续重复，是人类6}从头突变的主要来源之一。TR 扩展与数十种神经和精神疾病有关⁷. 然而，尚未在全基因组范围内表征从头 TR 突变，并且它们对 ASD 的贡献仍未探索。在这里，我们开发了新的生物信息学方法，用于从测序数据中识别和优先考虑从头 TR 突变，并对受 ASD 影响的先证者和未受影响的兄弟姐妹中的从头 TR 突变进行全基因组表征。我们推断出特定的突变事件及其重复数的精确变化，主要关注更普遍的逐步拷贝数变化，而不是大的扩展。我们的结果表明，ASD 先证者的全基因组 TR 突变显着过量。先证者的突变往往更大，富含胎儿大脑调节区域，并且预计对进化更有害。全面的，