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（由应用程序提供）：自闭症谱系障碍（ASD）是由社会交流缺陷和限制和重复行为定义的一组相关神经发育综合症。公共卫生的烧伤是巨大的，仅在美国，估计成本为350亿美元。行为方法目前是治疗的主要手段。体细胞疗法的选择仍然非常有限。新一代更有效的治疗将需要更深入地了解ASD的病理学。此外，尽管在清晰的自闭症基因组结构方面取得了重大进展，但迄今为止，仅确定了被认为与ASD有关的数百个基因和基因组区域中的少数。当前的提案着重于通过研究埃及和土耳其的亲属家庭的研究发现其他罕见隐性突变，从而导致自闭症。该项目利用了枪支和国家实验室之间的长期合作，这些合作已独立并集体证明了纯合性映射和整个外显子组测序的生产力，用于包括自闭症在内的一系列发育障碍。我们的长期目标是利用遗传学来识别ASD中的治疗靶标，同时促进将这种发现转化为临床实践。我们的假设是，在近亲家族中发现其他罕见隐性，高度渗透的ASD突变将提高对分子机制的理解。这些将与近代种群中特发性ASD的遗传结构和生物学的新兴形象相重叠，并且结合在一起，这些进步将为发展，理性和更有效的治疗的发展奠定基础。因此，我们重点关注3个具体目标：1）扩大我们目前的近亲ASD家族队列的同类，另外有250个经过精心诊断为埃及和土耳其的ASD亲戚，2）确定新颖的，罕见的，高度渗透的遗传变异，这些变体通过在384 ASD ASD ASD和父母中雇用全合格映射和全身效果序列，从而对ASD产生了贡献。和3）在无关家庭中寻找这些变体的聚类，并评估近交和杂种ASD人群的风险重叠，从这些中东家族那里通过Simons Simplex Collection（SSC）的数据从这些中东家庭进行了交叉引用的发现（SSC），我们在过去的5年中一直在研究识别的网络，并介绍了识别的变量，这些网络涉及识别的变种，这些网络均可依次进行。利用在杂种家族中发现的高信心ASD基因。总体而言，该建议旨在推进对ASD的遗传学和生物学的理解，以识别新颖的诊断方法和治疗发展。