Rare Mutations and Autism Spectrum Disorders

摘要 零星的功能丧失突变、反复出现的错义突变和拷贝数变异(CNV)也是致病因素 这对自闭症的病因学意义重大，但其遗传结构的大部分还没有被理解。多数 已知的致病CNV很大，其中许多基因突变的意义尚不清楚。这个 这项提案的目标是通过关注高影响的自闭症突变 从全基因组(n=3.5万个样本)和全外显子组中发现未被研究的稀有变异类 (n=150,000个样本)来自自闭症家庭的序列数据。这项提案的重点是超 罕见的基因颠覆性突变，并利用全基因组猎枪提供的额外敏感性 测序数据，新的CNV发现方法，以及超罕见遗传突变的传播增加 致病突变的产率。我们的目标将包括发现和验证更小和更复杂的 结构变异(包括CNV)和私有基因干扰突变不会在从头突变中丰富，但 优先传播给自闭症儿童。我们将评估高保真长读测序对 发现标准短读测序遗漏的更复杂形式的结构变异 通过调查100个遗传风险较高的未破案。此外，我们建议选择10个 具有从头突变证据的基因可用于进一步的临床评估、表型可变性和综合性 基因特征。这将包括五个仅观察到从头突变的基因。 与五个基因相比，这些基因既有从头突变，也有遗传突变，目的是为了 了解携带者的表型。该提案特别关注新的基因组方法的应用， 反复突变，并发现致病变异的遗传模式，以便制定更多 解释自闭症遗传结构的复杂模型。作为这一努力的一部分，我们将量化和 比较自闭症不同类别突变的风险并调查传递不平衡 不同之处。这一分析的最终结果将是识别和表征新的类别 高度渗透性基因突变对自闭症的病因有显著贡献，为临床提供靶点 诊断学和未来治疗学。

ABSTRACT Sporadic loss-of-function mutations, recurrent missense mutations, and copy number variants (CNVs) contribute significantly to the etiology of autism, but much of the genetic architecture has not yet been understood. Most known pathogenic CNVs are large and the significance of many of these gene mutations is still not known. The goal of this proposal is to significantly increase the yield of high-impact autism mutations by focusing on the discovery of understudied classes of rare variants from whole-genome (n = 35,000 samples) and whole-exome (n = 150,000 samples) sequence data being generated from autism families. This proposal focuses on ultra- rare, gene-disruptive mutations and leverages the additional sensitivity afforded by whole-genome shotgun sequencing data, novel CNV discovery methods, and transmission of ultra-rare inherited mutations to increase yield of pathogenic mutations. Our target will include the discovery and validation of smaller and more complex structural variants (including CNVs) and private gene-disruptive mutations not enriched in de novo mutation but preferentially transmitted to autism children. We will assess the utility of high-fidelity long-read sequencing to discover more complex forms of structural variation that have been missed by standard short-read sequencing by investigating 100 unsolved cases with a higher likelihood of genetic risk. In addition, we propose to select 10 genes with evidence of de novo mutation for further clinical evaluation, phenotypic variability, and comprehensive genetic characterization. This will include five genes where only de novo mutations have been observed compared to five genes where both de novo and inherited mutations have been documented in order to understand carrier phenotypes. This proposal specifically focuses on the application of novel genomic methods, recurrent mutations, and inheritance patterns to discover pathogenic variants in order to develop a more sophisticated model to explain the genetic architecture of autism. As part of this effort, we will quantify and compare the risk of different classes of mutation for autism and investigate transmission disequilibrium differences. The end product of this analysis will be the identification and characterization of new classes of highly penetrant genic mutations that contribute significantly to etiology of autism, providing targets for clinical diagnostics and future therapeutics.