3/3-Sequencing Autism Spectrum Disorder Extended Pedigrees

3/3 测序自闭症谱系障碍扩展谱系

• 批准号: 8659502
• 负责人: GERARD DAVID SCHELLENBERG
• 金额: $ 16万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659502
• 关键词: Affect; Agreement; Autistic Disorder; Clinical; Collaborations; Collection; Communities; Complement; DNA; Data; Development; Economic Burden; Extended Family; Family; Family member; Foundations; Frequencies; Funding; Gender; Genetic; Genetic Risk; Genetic Variation; Genome; Genotype; Head circumference; Individual; Informatics; Institutes; Language Delays; Measures; Medical center; Molecular; Motor; Penetrance; Pennsylvania; Phenotype; Relative (related person); Research Personnel; Resources; Risk; Sampling; Sensory; Sequence Analysis; Severities; Site; Societies; Specificity; Statistical Methods; Testing; Time; Universities; Utah; Variant; Washington; Work; autism spectrum disorder; case control; clinical Diagnosis; exome; exome sequencing; follow-up; genetic pedigree; interest; psychologic; risk variant

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.

描述（由申请人提供）：我们对自闭症谱系障碍（ASD）的扩展血统的独特资源将使我们能够为ASD的遗传研究做出重要贡献。我们将从最有用的谱系中序列家庭成员，以研究有助于ASD和相关表型的遗传变异。我们将努力发现新的变化，并使用资源与通过我们的协作可用的现有整个外显子数据一起表征变体。我们将测试自闭症基因组项目（AGP）合作者网络中多达10个家庭的发现。我们还将向更广泛的科学界提供资源。大家庭提供了一个绝佳的机会来识别和研究遗传变异，从而为正在进行的单纯形和小型多重家庭提供了互补的方法。目前的家庭集合代表了一些最大的血统，其中包括世界上的ASD。我们已经在其中一些患有临床诊断的家庭以及包括性别在内的相关表型中检测到了重要的联系证据。全尺度智商；言语和非语言智商之间的差异；语言延迟，坚持相同性，重复的感觉运动动作（RSMA），整体临床严重程度和回归发作（全部源自ADI）；头围；以及更广泛的自闭症表型。这些扩展家庭中的序列数据将导致高度准确和广泛的遗传信息。我们将确定这些数据中的家族差异，并使用新的信息学方法来预测潜在的有害变体。我们将通过与正在进行的序列项目进行比较来完善有关风险的信息。我们还将使用正在进行的序列项目来帮助优先考虑家庭变体发现，并为其他AGP家庭选择最佳的复制工作。最后，我们将研究通过单纯形/小型家族测序发现的序列变体，以确定我们大家庭的特异性和渗透性。我们提出的项目将受益于自闭症基因组项目中出色的分子，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。