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: 8471782
• 负责人: GERARD DAVID SCHELLENBERG
• 金额: $ 15.36万
• 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/8471782
• 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）：我们独特的自闭症谱系障碍 (ASD) 谱系资源将使我们能够为 ASD 的遗传学研究做出重要贡献。我们将对信息最丰富的谱系中的家庭成员进行测序，以研究导致自闭症谱系障碍和相关表型的遗传变异。我们将努力发现新的变异，并利用该资源结合通过我们的合作获得的现有全外显子组数据来表征变异。我们将测试自闭症基因组计划 (AGP) 合作者网络中最多 10 个其他家庭的研究结果。我们还将向更广泛的科学界提供该资源。大家庭提供了识别和研究遗传变异的绝佳机会，为正在进行的单一家庭和小型多重家庭的研究提供了补充方法。目前的家族收藏代表了世界上一些最大的自闭症谱系谱系。我们已经在其中一些家族中发现了与临床诊断以及相关表型（包括性别）之间的显着关联证据；全面智商；语言智商和非语言智商之间的差异；语言延迟、坚持同一性、重复感觉运动动作 (RSMA)、总体临床严重程度和退化性发作（全部源自 ADI）；头围；和更广泛的自闭症表型。这些大家族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完善有关风险的信息。我们还将利用正在进行的序列项目来帮助确定家族变异发现的优先顺序，并选择在其他 AGP 家族中进行复制工作的最佳方案。最后，我们将研究通过单一/小家族测序发现的序列变异，以确定我们大家族中的特异性和外显率。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，从而能够最有效地利用这一独特的资源。