Exome Sequencing to identify novel candidate genes for autism

新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，该方法具有更大的潜力来揭示与ASD相关的单基因。我们对20名散发性自闭症患者及其父母(总共60人)的外显子组进行了测序，推测这些家庭将因新生的严重影响的突变而变得更加丰富。在没有ASD病史或相关表型的散发性或单纯性家庭中，从头突变是发生ASD风险的相当大一部分基础。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/超罕见的从头突变，其中许多是潜在的有害的，进一步突出了这种疾病的遗传异质性。估计罕见突变的确切功能后果，并将这一知识转化为个性化药理学干预的临床决策是一个真正的未来挑战。

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.