Exome Sequencing to identify novel candidate genes for autism

下一代测序技术的最新进展使大规模分析人类基因组成为可能。与基于阵列的大CNV分析相比，这种方法具有更大的潜力来揭示与ASD相关的单个基因。我们对20名散发性自闭症患者及其父母（共60人）的外显子组进行了测序，推断这些家庭将富含严重影响的新生突变。在没有ASD或相关表型病史的散发或单纯型家族中，新生突变是发展ASD风险的重要组成部分。因此，我们在日本自闭症受试者的首次外显子组测序研究中发现了几种新的/超罕见的新生变异，其中许多是潜在有害的;进一步强调了该疾病的遗传异质性。估计罕见突变的确切功能后果，并将这些知识转化为支持个性化药理学干预的临床决策，是未来真实的挑战。

Recent advances in next-generation sequencing techniques have made the large-scale analysis of human genomes possible. In contrast with the array-based analysis of large CNVs, this approach has a greater potential to reveal single genes associated with ASDs. We sequenced the exome of 20 patients with sporadic autism and their parents (60 individuals in total), reasoning that these families would be enriched for de novo mutations of severe impact. In the sporadic or simplex families with no previous history of ASD or related phenotypes, de novo mutations underlie a substantial fraction of the risk to develop ASD.As a result, we discovered several novel/ultra-rare de novo variations, many of them are potentially deleterious, in the first ever exome sequencing study in Japanese autism subjects; further highlighting the genetic heterogeneity of the disorder. Estimation of the exact functional consequences of rare mutations, and the translation of this knowledge to support clinical decisions towards personalized pharmacological interventions is a real future challenge.