Tourette综合征（TS）是在儿童期发病的神经精神障碍性疾病，遗传因素在其发病中有重要作用。前期对100例TS核心家系进行全外显子测序发现5个患者携带ASH1L的5个罕见变异（传递和de novo），在Ash1l+/-小鼠观察到抽动等TS相关行为学改变及多巴胺水平升高，提示其可能是TS候选易感基因。依托已建立的TS遗传资源库，采用MiSeq高通量测序对500例TS核心家系进行ASH1L靶向测序，研究中国TS患者ASH1L罕见变异类型及特点，结合常见变异Tag SNP分型，鉴定TS新易感基因；构建多巴胺神经元特异性敲除Ash1l小鼠，评价其行为学改变并进行反向验证，探究其对纹状体内多巴胺代谢及神经元突触形态和兴奋性的影响；构建体外细胞突变体模型p.Y2077F和p.R2630T，结合体内和体外实验共同探讨ASH1L突变影响多巴胺代谢异常导致TS的致病机理，为开发TS精准医疗防治奠定基础。

Tourette syndrome (TS) is a polygenic childhood-onset neuropsychiatric disorder and the genetic factor has been reported to play an important role. We previously made a whole exome sequencing in 100 TS nuclear trios and the results showed that patients in five trios carried five rare mutations in ASH1L ( inherited and de novo), the tics-like behavior of TS and elevated dopamine-releasing events were observed in Ash1l+/- mouse model, which indicated that this gene might be a candidate susceptibility gene of TS. Based on previously established TS genetic resource database, we will select 500 TS nuclear trios and performed a target sequencing on ASH1L with the help of Miseq sequencing platform to explore the types and characteristics of rare variations of ASH1L in Chinese TS, and combined with the genotyping in Tag SNP loci to identify the new susceptibility genes of TS. We will build dopamine neuron-specific Ash1l conditional knockout mice, evaluate of their behavioral changes and perform reverse validation to explore their effects on striatum in vivo dopamine metabolism and the morphology and excitability of neuronal synaptic; we will also build cell mutant model p .Y2077F and p.R2630T in vitro, combined with in vivo and in vitro experiments to explore the pathogenesis of TS caused by abnormal ASH1L mutations affecting dopamine metabolism, laying a foundation for the development of precision medical prevention and treatment of TS.