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，沟通/语言受损。 自闭症通常在婴儿期表现出来，大多数受影响的儿童经历几乎完全的社会分离，持续性障碍，因此需要终身监护。家族研究已经证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。 语言障碍相互作用显着与这些研究结果，证明了连锁研究，从我们的样本和其他人，自闭症家庭的亚组严重的语言障碍，并通过重叠的连锁研究结果，从家庭分离各种言语和语言障碍。 基于此，我们研究小组的成员最近报告了证据表明，WNT 2，一个发育表达的大脑模式基因，是自闭症易感基因。 我们建议在这个应用程序中建立在我们现有的工作基础上，进一步追求我们识别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的染色体区域（ROI）的候选疾病基因，2）对500名自闭症个体的队列进行复杂的细胞遗传学分析，以及3）进一步检查WNT 2作为自闭症易感基因。 将使用具有互补表型的多个患者样本进行基因筛选，这些表型显示与每个ROI的重叠连锁，并且将使用各种方法全面检查每个基因。 这项分子工作将得到我们高通量测序和筛选能力、最先进的生物信息学实验室以及我们最近成立的统计遗传学研究中心的支持。 细胞遗传学检查也将是全面的，采用最新的方法来检测以前无法检测到的染色体异常，并得到广泛的临床网络和完善的区域细胞遗传学实验室的支持。 WNT 2结果将在两个独立的患者样本中进一步检查。

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.