Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

中文翻译：

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错义突变热点确定神经发育障碍基因和功能域

尽管已经预测从头错义突变比基因截断突变占更多的自闭症病例，但是大多数研究都集中在后者上。我们确定了de novo的性质神经发育障碍（NDDs）患者的错义突变，并突出显示35个错义突变过多的基因。此外，在36个基因中对40个氨基酸位点进行了重复突变，对17688名NDD患者的20个位点进行了靶向测序，确定了21名具有相同错义突变的新患者。谷氨酸受体亚基GRIA1中发生一个重复位点替换（p.A636T）。同源但不同的小鼠谷氨酸受体亚基Grid2中的相同氨基酸取代与Lurcher共济失调相关。对5名具有GRIA1突变的个体进行的表型随访显示了特定学习障碍和自闭症的证据。总体而言，我们发现从头开始存在明显的集群 200个基因的突变，突出了NDD病理学中重要的特定功能域和突触候选基因。