Rare Mutations and Autism Spectrum Disorders

摘要 散发性功能丧失突变、复发性错义突变和拷贝数变异（CNVs） 这对自闭症的病因学有重要意义，但大部分遗传结构尚未被理解。最 已知的致病性CNV很大，并且许多这些基因突变的意义仍然未知。的 这项提案的目标是通过关注自闭症基因， 从全基因组（n = 35，000个样本）和全外显子组中发现未充分研究的罕见变异类型 （n = 150，000个样本）从自闭症家庭产生的序列数据。该提案侧重于超- 罕见的基因破坏性突变，并利用全基因组鸟枪法提供的额外灵敏度 测序数据，新的CNV发现方法，以及超罕见遗传突变的传播，以增加 致病突变的产量。我们的目标将包括发现和验证更小更复杂的 结构变异（包括CNV）和私有基因破坏性突变，不富集从头突变，但 更容易传染给自闭症儿童我们将评估高保真长读序测序的实用性， 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个遗传风险可能性更高的悬案。此外，我们建议选出10名 具有从头突变证据的基因，用于进一步的临床评价、表型变异性和综合评估。 遗传特征这将包括五个基因，其中只有从头突变已被观察到 相比之下，有五个基因既有新生突变又有遗传突变， 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， 复发性突变和遗传模式，以发现致病变异，以开发一个更 复杂的模型来解释自闭症的遗传结构。作为这项工作的一部分，我们将量化和 比较自闭症不同类型突变的风险，并调查传播不平衡 差异这一分析的最终结果将是识别和表征新的类别， 高度外显的基因突变对自闭症的病因学有重要贡献，为临床治疗提供了靶点。 诊断和未来的治疗。

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.