Molecular Genetics of Autism

自闭症是一种神经发育障碍，其特征是严重的仪式重复行为、社会互动受损和沟通/语言受损。自闭症通常表现在婴儿期，大多数受影响的儿童几乎完全脱离社会，持续受损，因此需要终身监护。家庭研究表明，自闭症是高度遗传的，我们小组和其他人的连锁研究已经确定了一些假定的遗传易感性位点。语言障碍与这些发现有显著的相互作用，从我们的样本和其他有严重语言障碍的自闭症家庭的亚组中进行的关联研究，以及从分离各种语言障碍的家庭中进行的重叠关联研究都证明了这一点。基于此，我们的研究小组成员最近报告的证据表明，WNT2，一个发育表达的大脑模式基因，是一个自闭症易感基因。我们建议在这个应用程序中建立我们现有的工作主体，进一步追求我们确定自闭症疾病基因的主要目标。这将通过以下方式实现：1)检查来自三个感兴趣染色体区域（ROI）的候选疾病基因，2)对500名自闭症个体进行复杂的细胞遗传学分析，以及3)进一步检查WNT2作为自闭症易感基因。基因筛选将使用具有互补表型的多个患者样本进行，显示与每个ROI的重叠联系，并且每个基因将使用各种方法进行全面检查。这项分子工作将由我们的高通量测序和筛选能力、最先进的生物信息学实验室和我们最近成立的统计遗传学研究中心提供支持。细胞遗传学检查也将是全面的，结合检测以前无法检测的染色体异常的最新方法，并由广泛的临床网络和完善的区域细胞遗传学实验室提供支持。将在两个独立的患者样本中进一步检查WNT2的发现。

Autism is a neurodevelopmental disorder characterized by severe ritualistic-repetitive behaviors, impaired social interaction, and impaired communication/language. Autism generally manifests in infancy, with most affected children experiencing nearly complete social detachment, persistent impairment, and therefore requiring life-long supervision. Family studies have demonstrated that autism is highly heritable, and linkage studies from our group and others have identified a number of putative genetic susceptibility loci. Language impairment interacts prominently with these findings, as evidenced by linkage studies, from our sample and others, of subgroups of autistic families with severe language impairment, and by overlapping linkage findings from families segregating various speech and language disorders. Based on this, members of our research group recently reported evidence suggesting that WNT2, a developmentally expressed brain patterning gene, is an autism susceptibility gene. We propose in this application to build on our existing body of work, further pursuing our primary goal of identifying autism disease genes. This will be accomplished by: 1) examining candidate disease genes from three chromosomal regions of interest (ROI), 2) performing sophisticated cytogenetic analyses on a cohort of 500 autistic individuals, and 3) further examination of WNT2 as an autism susceptibility gene. The gene screening will be performed using multiple patient samples with complementary phenotypes showing overlapping linkages to each ROI, and each gene will be comprehensively examined using a variety of approaches. This molecular work will be supported by our high-throughput sequencing and screening capabilities, state-of-the-art bioinformatics laboratory, and our recently formed Center for Statistical Genetics Research. The cytogenetic examination will also be comprehensive, incorporating the latest methods for detecting previously undetectable chromosomal abnormalities, and supported by an extensive clinical network and a well-established regional cytogenetics laboratory. The WNT2 findings will be further examined in two-independent patient samples.