3/3-Sequencing Autism Spectrum Disorder Extended Pedigrees

描述（由申请人提供）：我们独特的自闭症谱系障碍（ASD）扩展谱系资源将使我们能够为ASD的遗传研究做出重要贡献。我们将从最有信息的谱系中对家庭成员进行测序，以研究导致ASD和相关表型的遗传变异。我们将努力发现新的变异，并利用资源结合现有的全外显子组数据来描述变异。我们将在自闭症基因组计划（AGP）合作者网络提供的多达10个其他家庭中测试研究结果。我们还将向更广泛的科学界提供这些资源。大家庭为识别和研究遗传变异提供了极好的机会，为正在进行的单一和小型多重家庭研究提供了补充方法。目前收集的家庭代表了世界上最大的ASD谱系。我们已经在其中一些家庭中发现了与临床诊断以及相关表型（包括性别）相关的显著关联证据；全面智商；语言和非语言智商差异；语言延迟、坚持同一性、重复性感觉运动动作（RSMA）、总体临床严重程度和退行性发病（均源于ADI）；头围;以及更广泛的自闭症表型。在这些大家庭序列数据将导致高度准确和广泛的遗传信息。我们将在这些数据中识别家族变异，并使用新的信息学方法预测潜在的有害变异。我们将通过比较正在进行的序列项目来细化关于风险的信息。我们还将使用正在进行的序列项目来帮助确定家族变异发现的优先级，并选择最佳的用于其他AGP家族的复制工作。最后，我们将研究通过单形/小家族测序发现的序列变异，以确定在我们的大家庭中的特异性和外显性。我们提出的项目将受益于自闭症基因组计划中优秀的分子、分析和临床专业知识的持续合作，以最有效地利用这一独特的资源。

DESCRIPTION (provided by applicant): Our unique resource of extended pedigrees with autism spectrum disorder (ASD) will allow us to make important contributions to genetic studies of ASD. We will sequence family members from the most informative pedigrees to study genetic variation contributing to ASD and related phenotypes. We will work to discover new variation, and also use the resource to characterize variants in conjunction with existing whole exome data available through our collaborations. We will test findings in up to 10 other families available from the Autism Genome Project (AGP) network of collaborators. We will also make the resource available to the broader scientific community. Extended families offer an excellent opportunity to identify and study genetic variation, giving a complementary approach to ongoing studies of simplex and small multiplex families. The current collection of families represents some of the largest pedigrees with ASD in the world. We have already detected significant linkage evidence in some of these families with clinical diagnosis and also with related phenotypes, including gender; Full Scale IQ; discrepancy between verbal and nonverbal IQ; language delay, Insistence on Sameness, Repetitive Sensory-Motor Actions (RSMA), overall clinical severity, and regressive onset (all derived from the ADI); head circumference; and the Broader Autism Phenotype. Sequence data in these extended families will result in highly accurate and extensive genetic information. We will identify familial variation in these data, and predict potentially deleterious variants using new informatics approaches. We will refine information about risk by comparing to ongoing sequence projects. We will also use the ongoing sequence projects to help prioritize the familial variant discovery, and choose the best for replication efforts in other AGP families. Finally, we will investigate sequence variants found by simplex/small family sequencing to determine specificity and penetrance in our extended families. Our proposed project will benefit from the continued collaboration of excellent molecular, analytic, and clinical expertise in the Autism Genome Project to enable the most effective use of this unique resource.