孤独症是一种严重的神经发育障碍，多在婴幼儿期起病。遗传因素是孤独症的重要病因。基因外显子区的突变可能改变所编码的氨基酸，影响蛋白质功能而具有致病性，在孤独症病因中发挥重要作用。基因表达具有时间-空间特异性的模式，因此以遗传发现为线索，探讨脑内高表达基因对孤独症的致病作用更为重要。本课题拟进行200例孤独症患者的全外显子组测序，结合课题组前期已完成的14个孤独症双生子家系及10个孤独症同胞对家系的全外显子组测序结果、96例孤独症患者靶向测序的结果，初步筛选脑内高表达易感基因的突变位点。继而在课题组收集的独立大样本1000个孤独症核心家系和1000例正常对照中进行靶向测序验证，筛选出脑内高表达的孤独症易感基因突变位点。在细胞和动物水平探讨这些突变位点对神经发育及小鼠孤独症相关行为的影响及可能的致病机制。本项目预期结果有助于发现影响脑发育的孤独症易感基因，为深入研究孤独症病因及发病机制提供线索。

Autism is a severe neurodevelopmental disorder. The core symptoms were onset in infants and young children. The genetic etiology might play important roles in autism. Mutations in exons of genes could change the encoded amino acid, and might cause the abnormalities of protein, which might be involved in the etiology of autism. Since genes have a specific pattern of spatiotemporal expression, it is important to explore the pathogenesis of highly brain-expressed genes in autism. In this study, we plan to perform whole exome sequencing of 200 autism patients. Combined with the results of whole exome sequencing of 14 autism families with twins, 10 families with autistic children and unaffected siblings, and targeted sequencing of 96 autism children, we will screen highly brain-expressed susceptibility genes. Then we will perform targeted sequencing of these mutations in 1000 autism trios and 1000 healthy controls. We try to detect the mutations in autism susceptibility genes which are highly expressed in the brain. Finally, we will explore the effects of these mutations on neurodevelopment in neurons and mice model. This study will contribute to the detection of autism susceptibility genes which affect brain development, and provide clues for the pathogenesis of autism.