Sporadic Mutations and Autism Spectrum Disorders

描述（由申请人提供）：散发性点突变和大拷贝数变异（CNVs）对自闭症的病因有重要影响，但相对较少的基因被证明是致病的。该项目的目标是确定与自闭症谱系障碍（ASD）和发育迟缓有关的基因。我们将采用结合外显子组序列数据和详细从头算CNV分析的综合方法来确定可能的候选基因。我们将在病例组和对照组的三人组中测试这些候选者是否有过量的新生破坏性突变。有三个具体目标：1)扩展我们现有的CNV发病率图，包括来自40万例发育迟缓病例和2万例对照的数据，并将这些数据与新出现的外显子组数据整合，以识别可能的单倍不足基因；2)通过分子倒置探针（MIP）重测序，评估这些基因的破坏性新生突变负担是否在ASD家族中显著富集；3)选择10个从头突变负担最高的基因进行进一步的临床评估、表型变异和综合遗传表征。该分析的最终结果将是识别和表征对自闭症病因有重要贡献的高外显子基因突变，为临床提供靶点

DESCRIPTION (provided by applicant): Sporadic point mutations and large copy number variants (CNVs) contribute significantly to the etiology of autism but relatively few genes have been proven to be pathogenic. The goal of this project is to identify genes responsible for autism spectrum disorder (ASD) and developmental delay. We will apply an integrated approach combining exome sequence data and detailed ab initio CNV analysis to pinpoint likely candidate genes. We will test these candidates for an excess of de novo disruptive mutations in case versus control trios. There are three specific aims: 1) Expand our existing CNV morbidity map to include data from >40,000 cases of developmental delay versus 20,000 controls and integrate these data with emerging exome data to identify likely haploinsufficient genes; 2) Assess whether the burden of disruptive de novo mutations in these genes is significantly enriched in ASD families by molecular inversion probe (MIP) resequencing of approximately 6,200 cases and 6,200 controls; and 3) Select ten genes with the highest burden of de novo mutations for further clinical evaluation, phenotypic variability, and comprehensive genetic characterization. The end product of this analysis will be the identification and characterization of highly penetran genic mutations that contribute significantly to etiology of autism, providing targets for clinical diagnostics and future therapeutics.