Molecular Genetics of Autism

自闭症的分子遗传学

• 批准号: 6624386
• 负责人: Thomas H. Wassink
• 金额: $ 33.7万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624386
• 关键词: autism; chromosome disorders; cytogenetics; family genetics; fluorescent in situ hybridization; genetic polymorphism; genetic screening; genetic susceptibility; human subject; language disorders; linkage disequilibriums; linkage mapping; molecular genetics; patient oriented research; polymerase chain reaction; siblings; speech disorders; statistics /biometry

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.

自闭症是一种神经发育障碍，其特征是严重的重复仪式行为，社交活动受损，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经历了几乎完全的社会隔离，持续性的障碍，因此需要终身监护。家庭研究表明，自闭症具有高度的遗传性，我们小组和其他人的连锁研究已经确定了一些可能的遗传易感基因。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人对患有严重语言障碍的自闭症家庭亚群的联系研究，以及从分离各种语言和语言障碍的家庭的重叠联系研究中得到了证明。基于此，我们研究小组的成员最近报告了一项证据，表明WNT2是一种发育表达的大脑模式基因，是自闭症的易感基因。在这项申请中，我们建议在现有工作的基础上，进一步追求识别自闭症疾病基因的主要目标。这将通过：1)检查来自三个染色体感兴趣区域(ROI)的候选疾病基因，2)对500名自闭症患者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。基因筛查将使用与每个ROI重叠的表型互补的多个患者样本进行，并将使用各种方法对每个基因进行全面检查。这项分子工作将得到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，纳入了检测以前无法检测到的染色体异常的最新方法，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。WNT2的发现将在两个独立的患者样本中进一步检查。