孤独症疾病相关突变位点高通量筛选及致病机制研究

孤独症是一种高遗传度的广泛发育障碍，属于多基因复杂疾病。针对复杂疾病，罕见等位基因-重大效应(Rare Allele-Major Effects)理论认为，罕见突变是常见复杂疾病遗传病因的关键，功能性突变位点导致所编码氨基酸改变，可能是疾病潜在的病因。尽管国外已有外显子组测序的研究，但结果并不一致；由于不同种族遗传背景不同，也存在人群异质性差异。本研究将在中国汉族人群中进行高通量测序工作，对10个孤独症双生子家系(共40人)进行全外显子组测序；为减少假阳性结果，继而采用Sanger 和MiSeq测序方法，对全外显子组测序结果在另外的1000个孤独症核心家系和1000例正常对照中进一步验证，明确孤独症新发(de novo)且影响氨基酸改变的突变位点；最后通过在体及离体实验开展功能研究，探讨突变位点对疾病发生发展的影响。本项目预期结果将为深入研究易感基因在孤独症的致病机制提供实验线索。

Autism is a neurodevelopmental disorder. Early twin studies produced heritability estimated approaching 90%. However, it is a multigenic common disorder. The basis of this heritability remains largely unexplained. To data, genetic association studies have had limited success in identifying genetic risk for autism. The lack of common predisposition genes has led to the suggestion that rare variants constitute the majority of autism risk. The Rare Allele-Major Effects (RAME) model postulates that rare penetrant variants are the key to the genetic etiology of common disease. Functional mutations that lead to an altered amino acid are often deleterious and potentially disease causing. Although whole exome sequencing studies were performed in autism with Caucasine, the results of these studies were not consistent. As for the different genetic backgrouds between different ethnic popultiaons, the heterogeneity was obvious in different ethnic popultiaons. Therefore we will perform whole exome sequencing in autism with Han Chinese population. First, we will sequence 10 autism twin families (40 individuals). Second, to decrease the false postive results, we will sequence the mutations found in the autism twin families using Sanger sequencing and Miseq sequence platform in 1000 autism trios and 1000 health controls. The aim of this study is to seek the de novo mutations in patients with autism. Finally, the function of these de novo mutations and the effects of them on neurodevelopment will be explored in experiment in vivo and in vitro. The results of this study will provide the clues and evidence to investigate the pathogenesis of autism.