Sporadic Mutations and Autism Spectrum Disorders

描述(申请人提供)：零星的点突变和大拷贝数变异(CNV)对自闭症的病因有很大贡献，但相对较少的基因已被证明是致病的。该项目的目标是确定导致自闭症谱系障碍(ASD)和发育迟缓的基因。我们将应用一种结合外显子组序列数据和详细的从头算CNV分析的综合方法来精确定位可能的候选基因。我们将测试这些候选者在病例和对照三人组中是否存在过多的从头开始的破坏性突变。有三个具体目标：1)扩展我们现有的CNV发病率图谱，包括来自40,000例发育迟缓和20,000名对照的数据，并将这些数据与新兴的外显子组数据整合，以确定可能的单倍体不足基因；2)通过对大约6,200例病例和6,200名对照的分子倒置探针(MIP)重新测序，评估这些基因中破坏性从头突变的负担是否显著丰富在ASD家族中；以及3)挑选10个从头突变负担最高的基因用于进一步的临床评估、表型变异性和全面的基因特征。这项分析的最终结果将是鉴定和表征高度渗透性基因突变，这些突变对自闭症的病因有重要影响，为临床提供靶点。 诊断学和未来治疗学。

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.