2/3 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)家系资源将使我们能够为自闭症谱系障碍的遗传学研究做出重要贡献。我们将从信息最丰富的家系中对家族成员进行测序，以研究导致ASD和相关表型的遗传变异。我们将致力于发现新的变异，并利用资源与现有的通过我们的合作获得的整个外显子组数据来表征变异。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，为正在进行的单性和小多发性家庭的研究提供了补充方法。目前收集的家系代表了世界上一些最大的自闭症家系。我们已经在其中一些家系中发现了与临床诊断和相关表型相关的显著关联证据，包括性别、全量表智商、语言智商和非语言智商之间的差异、语言延迟、坚持相同、重复的感觉-运动动作(RSMA)、总体临床严重性和倒退发病(所有这些都来自ADI)、头围以及更广泛的自闭症表型。这些大家族中的序列数据将产生高度准确和广泛的遗传信息。我们将识别这些数据中的家族变异，并使用新的信息学方法预测潜在的有害变异。我们将通过与正在进行的序列项目进行比较来提炼有关风险的信息。我们还将利用正在进行的测序项目来帮助确定家族性变异发现的优先顺序，并选择最适合在其他AGP家族中进行复制的基因。最后，我们将调查通过单链/小家族测序发现的序列变异，以确定在我们的大家族中的特异性和外显性。我们提议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，以使这一独特资源能够得到最有效的利用。 公共卫生相关性：自闭症谱系障碍(ASD)对受影响的个人、他们的家庭和社会施加了巨大的心理和经济负担。我们将在多达40个世界上最大的ASD家族的独特资源中对家庭成员进行排序，以研究导致ASD的遗传变异。计划中的研究是理想的时机，以补充和加强正在进行的ASD病例和小家庭序列研究的结果。

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. PUBLIC HEALTH RELEVANCE: Autism Spectrum Disorder (ASD) imposes an enormous psychological and economic burden on affected individuals, their families, and society. We will sequence family members in a unique resource of up to 40 of the world's largest extended ASD families to study genetic variation contributing to ASD. The planned studies are ideally timed to complement and enhance findings from ongoing sequence studies of ASD in cases and small families.