孤独症是一种典型的脑发育障碍，可能具有独特的遗传基础及相应的脑发育缺陷表型。既往文献及项目组前期均发现孤独症神经发育相关易感基因参与神经干细胞增殖与分化、神经细胞迁移、轴树突生长和突触形成等过程，但因遗传及临床异质性导致致病基因难以得到重复验证，且脑发育异常的机理至今尚未完全阐明。本项目将在前期工作基础上开展以下研究：1)基于已完成的孤独症全基因组关联研究和外显子组测序结果，结合国内外现有数据进行生物信息学分析，采用独立样本重复验证，筛选和鉴定与神经发育高度关联的易感基因及功能变异；2)根据易感基因及功能变异线索建立基因工程小鼠模型，开展疾病模型病因学及行为表型与孤独症一致性的系统评价；3)对具有孤独症样行为表型的小鼠品系，分析其神经发育过程各个环节的异常改变，详细阐释相关信号通路及分子机理。本项目预期结果将有助于阐明孤独症的发病机理，并为该病的生物学诊断和发展治疗方法提供理论依据。

Autism is a typical developmental neurological disorder, which might has the unique genetic basis responsible for the abnormal phenotypes of brain development. Both of previous studies and our research found that the autism related neurodevelopmental susceptibility genes were involved in the processes such as neural stem cell proliferation and differentiation, nerve cell migration, axon and dendritic outgrowth and synaptic formation. However, due to the genetic and clinical heterogeneity, the pathogenic genes were difficult to be replicated and verified, and the mechanism of abnormal brain development of autistic patients has not yet been fully understood. Based on previous work, this project is proposed to carry out the following research: 1) To screen and identify the neural development related susceptibility genes. We will carry out bioinformatics analysis on the results of previous typical autism genome-wide association studies and the existing data from the domestic and foreign, by applying independent sample repeated verification, and combining with the expression pattern of genes.2) Establish the mice model of these susceptibility genes by genetic engineering, then systematically screen the consistency between the etiology and behavioral phenotypes of these mice models and autism spectrum disorder, to explore the potential intervention methods. 3) For the strains of mice with autism-like phenotypes, we could analyze the abnormal changes in all aspects of neural development, and explain the related signaling pathways and molecular mechanisms in detail. The expected results of this project will help to elucidate the pathogenesis of autism, and provide a theoretical basis for the biological diagnosis and treatment of the disease.