Integrating the genomics of Autism Spectrum Disorders(ASD) in consanguineous and "idiopathic" families

将自闭症谱系障碍 (ASD) 的基因组学整合到近亲和“特发性”家庭中

• 批准号: 9064857
• 负责人: MURAT GUNEL
• 金额: $ 58.73万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-08 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064857
• 关键词: Affect; Architecture; Autistic Disorder; Award; Behavioral; Biological; Biology; Chromosome Mapping; Cloning; Code; Collaborations; Collection; Complex; Copy Number Polymorphism; DSM-IV; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Egypt; Evaluation; Family; Family member; Foundations; Generations; Genes; Genetic; Genetic Risk; Genomic Segment; Genomics; Genotype; Goals; Health; Heterogeneity; Heterozygote; Human; Inbreeding; Individual; International; Laboratories; Lead; Maps; Meleagris gallopavo; Methods; Missense Mutation; Mission; Molecular; Mutation; Overlapping Genes; Parents; Pharmacotherapy; Physicians; Point Mutation; Population; Prevention; Productivity; Public Health; Recommendation; Recording of previous events; Research; Research Infrastructure; Risk; Running; Sampling; Series; Splice-Site Mutation; Syndrome; Translating; United States National Institutes of Health; Variant; autism spectrum disorder; bead chip; clinical practice; cohort; consanguineous family; cost; cost effective; data exchange; developmental disease; effective therapy; exome; exome sequencing; gene discovery; genetic pedigree; genetic variant; improved; interest; kindred; loss of function; novel; novel strategies; proband; repetitive behavior; risk variant; social communication; success; therapeutic development; therapeutic target

 DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASDs) are a group of related neurodevelopmental syndromes defined by social communication deficits and by restricted and repetitive behaviors. The public health burden is enormous, with an estimated cost of $35 billion in the U.S alone. Behavioral approaches are currently the mainstay of treatment; options for somatic therapies remain extremely limited. A new generation of more effective treatments will require a far deeper understanding of the pathobiology of ASD. In addition, while there has been significant recent progress in clarifying the genomic architecture of autism, only a small number of the hundreds of genes and genomic regions thought to be involved in ASD have so far been identified. The current proposal focuses on discovering additional rare recessive mutations leading to autism via the study of consanguineous families from Egypt and Turkey. The project leverages a long-standing collaboration between the Gunel and State labs, which have independently and collectively demonstrated the productivity of homozygosity mapping and whole exome sequencing for a range of developmental disorders including autism. Our long-term goal is to make use of genetics to identify therapeutic targets in ASD while contributing to translating such findings to clinical practice. Our hypothesis is that th discovery of additional rare recessive, highly penetrant ASD mutations in consanguineous families will advance the understanding of molecular mechanisms; that these will show overlap with the emerging picture of the genetic architecture and biology of idiopathic ASD in outbred populations, and that, combined, these advances will lay the foundation for the development of novel, rational, and more efficacious treatments. Therefore, we focused on 3 specific aims: 1) To expand our current cohort of consanguineous ASD families with an additional 250 carefully diagnosed ASD kindreds from Egypt and Turkey, 2) To identify novel, rare, highly penetrant genetic variants that contribute to ASD by employing homozygosity mapping and whole-exome sequencing in 384 ASD subjects and parents; and 3) To search for clustering of these variants among unrelated families as well as to evaluate the overlap in risk loci for inbred versus outbred ASD populations, cross- referencing findings from these Middle Eastern families with data from the Simons Simplex Collection (SSC), which we have been studying for the past 5 years and to evaluate the identified homozygous variants with reference to ASD-associated developmental co-expression networks using high confidence ASD genes discovered in outbred families. Overall this proposal is aimed at advancing the understanding of the genetics and biology of ASD in the interests of identifying novel approaches to diagnosis, and therapeutic development.

 描述(由申请人提供)：自闭症谱系障碍(ASD)是一组相关的神经发育综合征，由社交沟通障碍和限制和重复行为定义。公共卫生负担是巨大的，仅在美国就估计要花费350亿美元。行为疗法目前是治疗的主流；躯体疗法的选择仍然极其有限。新一代更有效的治疗方法将需要对ASD的病理生物学有更深入的了解。此外，尽管最近在阐明自闭症的基因组结构方面取得了重大进展，但到目前为止，被认为与自闭症相关的数百个基因和基因组区域中只有一小部分被识别出来。目前的建议侧重于通过对埃及和土耳其血亲家庭的研究，发现更多导致自闭症的罕见隐性突变。该项目利用Gunel和国家实验室之间的长期合作，这两个实验室已经独立和共同地展示了纯合子图谱和整个外显子组测序对包括自闭症在内的一系列发育障碍的生产力。我们的长期目标是利用遗传学来确定ASD的治疗靶点，同时为将这些发现转化为临床实践做出贡献。我们的假设是，在近亲家庭中发现额外的罕见的隐性、高穿透性ASD突变将促进对分子机制的理解；这些将与近交系人群中特发性ASD的遗传结构和生物学的新兴图景显示重叠，并且这些进展将为开发新的、合理的和更有效的治疗方法奠定基础。因此，我们专注于3个具体目标：1)扩大我们现有的近亲ASD家系队列，增加来自埃及和土耳其的250个精心诊断的ASD家系；2)通过对384名ASD受试者和父母进行纯合性作图和全外显子测序，寻找与ASD有关的新的、罕见的、高渗透性的遗传变异；3)寻找这些变异在不相关家系中的聚集性，以及评估近交系和近交系ASD人群风险基因座的重叠，交叉参考这些中东家庭的研究结果与我们过去5年来一直研究的Simons Simplex Collection(SSC)的数据，并参考在近交系中发现的高度可信的ASD基因的发育共表达网络来评估已识别的纯合变体。总体而言，这项建议旨在促进对ASD遗传学和生物学的理解，以确定诊断和治疗开发的新方法。