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

 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性和重复性行为定义。公共卫生负担是巨大的，仅在美国就估计花费350亿美元。行为疗法是目前治疗的主流;躯体疗法的选择仍然非常有限。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，虽然最近在澄清自闭症的基因组结构方面取得了重大进展，但迄今为止，被认为与ASD有关的数百个基因和基因组区域中只有一小部分被确定。目前的建议侧重于通过研究埃及和土耳其的近亲家庭发现导致自闭症的其他罕见隐性突变。该项目利用了Gunel和State实验室之间的长期合作，这些实验室已经独立和共同证明了纯合性映射和全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，同时将这些发现转化为临床实践。我们的假设是，在近亲家庭中发现额外的罕见隐性、高度外显的ASD突变将促进对分子机制的理解;这些突变将与远交人群中特发性ASD的遗传结构和生物学的新图像重叠，并且，结合起来，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）用来自埃及和土耳其的另外250个仔细诊断的ASD激酶扩展我们目前的近亲ASD家族的队列，2）通过在384个ASD受试者和父母中采用纯合性作图和全外显子组测序来鉴定促成ASD的新的、罕见的、高度外显的遗传变异;和3）为了在不相关的家族中寻找这些变体的聚类，以及为了评估近交与远交ASD群体的风险基因座的重叠，将来自这些中东家族的发现与来自Simons Simplex Collection（SSC）的数据进行交叉参考，我们已经研究了过去5年，并使用在远交家族中发现的高置信度ASD基因，参照ASD相关的发育共表达网络来评估所鉴定的纯合变体。总的来说，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。

 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.