2/3 Sequencing Autism Spectrum Disorder Extended Pedigrees

2/3 自闭症谱系障碍扩展谱系测序

• 批准号: 8291776
• 负责人: ELLEN M WIJSMAN
• 金额: $ 23.17万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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/8291776
• 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; follow-up; genetic pedigree; interest; psychologic

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.

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。我们将对来自信息量最大的家系的家庭成员进行测序，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，并利用该资源结合我们合作提供的现有全外显子组数据来表征变异。我们将测试来自自闭症基因组计划（AGP）合作者网络的多达10个其他家庭的发现。我们还将向更广泛的科学界提供资源。大家庭提供了一个很好的机会，以确定和研究遗传变异，提供了一个补充的方法，正在进行的研究的单一和小型多重家庭。目前收集的家庭代表了世界上一些最大的ASD谱系。我们已经在其中一些具有临床诊断和相关表型的家族中发现了重要的关联证据，包括性别;全量表智商;语言和非语言智商之间的差异;语言延迟，坚持相同性，重复感觉运动动作（RSMA），总体临床严重程度和退行性发作（均来自ADI）;头围;和广泛自闭症表型。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。我们将通过与正在进行的序列项目进行比较来细化有关风险的信息。我们还将使用正在进行的序列项目，以帮助优先考虑家族变异的发现，并选择最好的复制工作在其他AGP家庭。最后，我们将调查通过单纯/小家族测序发现的序列变异，以确定我们的大家族中的特异性和重复性。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。 公共卫生相关性：自闭症谱系障碍（ASD）给受影响的个人、他们的家庭和社会带来了巨大的心理和经济负担。我们将对多达40个世界上最大的ASD扩展家族的独特资源中的家族成员进行测序，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。