Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin–protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.

自闭症是一种高度可遗传的复杂疾病，其中从头突变 (DNM) 变异显着增加了风险。使用来自 3,474 个家族的全基因组测序数据，我们调查了另一个大效应风险变异的来源，即超罕见变异。我们报告并复制了先证者中私人的、可能的基因破坏性 (LGD) 变异的传播不平衡，但发现这种负担的 95% 存在于已知的富含 DNM 的基因之外。这种变体类别对多重家庭先证者的影响更大，并支持自闭症的多重打击模型。优先传递给先证者的具有私有 LGD 变体的候选基因聚集在 E3 泛素-蛋白连接酶复合物、细胞内转运和 Erb 信号蛋白网络上。我们估计这些变体约为 2。比兄弟姐妹中类似类型和频率的其他变体老 5 代且显着年轻。总体而言，私人 LGD 变体处于强烈的净化选择之下，并且似乎作用于一组尚未与自闭症相关的独特基因。