Deep sequencing of autism candidate genes in 2000 families from the Simons Simple

描述(由申请人提供)：自闭症谱系障碍(ASD)的特征是语言习得延迟或缺失，社交障碍和重复行为。ASD在很大程度上是遗传的，既可以零星发生(单发)，也可以家族性(多发)发生，男性更常见(女性为4：1)，总发病率为每150名新生儿中约1名。由于许多因素，导致ASD的基因鉴定变得复杂，例如自闭症家系数量很少--这可能反映了零星的发病率--以及现有样本中缺乏一致的临床数据，特别是关于自闭症谱系中不太严重(和更具表型异质性)的部分。该项目旨在通过高通量的候选基因测序方法解决ASD的遗传基础问题。建议的方法旨在补充现有的比较基因组杂交(CGH)分析。通过正在进行的CGH研究确定新的ASD候选基因，并通过这项工作详细描述100个已知/预测和新的ASD候选基因的突变谱，将揭示ASD潜在遗传变异的主要部分。对于这些实验，将使用Simons Simplex Collection(SSC)作为样本总体。SSC是迄今为止组装的ASD家族中最大的高质量集合，它是专门设计的，通过确保全面和一致的临床分析来弥补现有ASD家族人群的缺点。更重要的是，它是单纯型家庭的集合，因此，由于自发突变而导致的自闭症病例的比例--而不是遗传--被最大化。这项工作的一个可能结果将是在幼儿ASD分子筛查方面取得重大进展。这种影响将从许多方面感受到：对ASD临床亚型的更准确诊断；基于遗传标记对ASD严重程度的评估；以及更具体地针对受影响个人的需求进行治疗。鉴于ASD的异质性和目前缺乏标记物，这项研究将在解卷与自闭症相关的复杂表型方面取得重大进展。这项工作还将为未来的研究提供新的途径，从新的小鼠模型到阐明语言习得、社会互动和行为所需的遗传途径。 与公共卫生相关：这项研究将对自闭症谱系障碍的分子基础产生重要的洞察，自闭症谱系障碍主要是遗传的，在所有人群中高度流行，很难诊断和分类。这项工作将导致在幼儿中进行ASD分子筛查的进展，这反过来将导致诊断的改善和更精确的靶向治疗制度。

DESCRIPTION (provided by applicant): Autistic Spectrum Disorders (ASD) are characterized by delay in or absence of language acquisition, deficits in social interactions and repetitive behaviors. ASD are largely genetic in origin, and occur either sporadically (simplex) or in a familial (multiplex) pattern, are far more commonly in males (4:1 ratio over females), and have an overall incidence of ~1 in 150 births. Identification of genes responsible for ASD has been complicated by many factors, such as the small number of autistic pedigrees-which may reflect the sporadic incidence-as well as the lack of consistent clinical data among existing samples, particularly with respect to the less severe (and more phenotypically heterogeneous) portion of the autistic spectrum. This project is intended to address the genetic basis of ASD through a high-throughput, candidate-gene sequencing approach. The proposed approach is designed to complement existing comparative genomic hybridization (CGH) analyses. The combination of identifying novel ASD candidate genes through the ongoing CGH study and detailing the mutational spectra of 100 known/predicted and novel ASD candidate genes through this work will reveal a major fraction of the genetic variation underlying ASD. For these experiments, the Simons Simplex Collection (SSC) will be utilized as the sample population. The SSC is the largest high- quality set of ASD families assembled so far, and it is specifically designed to compensate for the shortcomings of existing ASD family populations by ensuring comprehensive and consistent clinical analyses. More importantly, it is a collection of simplex families, and as a result the proportion of cases of autism due to spontaneous mutation-as opposed to inheritance-is maximized. A likely outcome of this work will be significant advances in molecular screening of ASD among young children. This impact would be felt in many ways: more precise diagnosis with respect to clinical subtypes of ASD; assessment of ASD severity based on genetic markers; and treatment more specifically tailored to the needs of affected individuals. Given the heterogeneity of ASD and current lack of markers, this study stands to provide significant progress in deconvoluting the complex phenotypes associated with autism. This work will also provide new avenues for future studies, from new mouse models to elucidation of genetic pathways required for language acquisition, social interactions and behavior. PUBLIC HEALTH RELEVANCE: This study will yield significant insight into the molecular basis of autistic spectrum disorders, which are largely genetic in origin, highly prevalent among all populations, and difficult to diagnose and classify. This work will lead to advances in molecular screening of ASD among young children, which will in turn result in improved diagnoses and more precisely targeted treatment regimes.