De Novo Gene Disruptions in Children on the Autistic Spectrum

Public Abstract:

Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.

Public Abstract:

对343个家庭（每个家庭均包含1名自闭症谱系儿童及至少1名未受影响的兄弟姐妹）开展外显子测序（exome sequencing），结果发现存在新生小插入缺失（de novo small indels）与点突变（point substitutions），这些突变主要来源于父系且呈现年龄依赖性。我们观察到，受影响儿童与未受影响儿童的新生错义突变（de novo missense mutations）数量无显著差异，但基因破坏性突变（gene-disrupting mutations，含无义突变（nonsense）、剪接位点突变（splice site）及移码突变（frame shifts））的频率为后者的两倍（59 vs 28）。基于这一差异，以及本研究与同类研究中发现的反复出现及全部基因破坏靶点数量，我们估计自闭症易感基因（autism susceptibility genes）数量介于350至400之间。这些研究中多数被破坏的基因与脆性X蛋白（fragile X protein，FMRP）相关，进一步强化了自闭症与突触可塑性（synaptic plasticity）的关联。我们发现，FMRP相关基因承受的纯化选择（purifying selection）强于其他基因，并推测它们是认知障碍（cognitive disorders）中尤其敏感的剂量依赖性靶点。