Refining Mendelian disease analysis via detection of clinically relevant repeat variants

项目摘要 下一代测序（NGS）有可能同时分析所有临床相关的遗传变异- 在一次基因测试中。然而，临床变异发现管道大多集中在编码单个 核苷酸变体（SNV）、调节SNV和小插入缺失。该建议旨在使重复分析 现有管道的标准组成部分，特别侧重于短串联重复序列（STR），可变数目 串联重复（VNTR）和低拷贝重复或片段重复。总之，这些重复解释了 8%的人类基因组，但与不成比例的大量孟德尔疾病有关。的 所提出的方法主要针对Illumina测序，其形成了当前孟德尔遗传学的绝大多数。 测序管道，但也包括替代技术，如太平洋生物科学和10 X基因组学。的 First aim开发了用于发现目前NGS无法访问的重复变体的算法。第二个目标， PI建议使用多种技术生成孟德尔重复的金标准验证数据。在 第三个目标是，PI将把提出的方法整合到现有的NGS管道中，以发现临床变异。 ery，并将其应用于大型现有数据集，以获得大型对照人群的基因型频率。 该项目通过扩大孟德尔变异管道以包括高度相关的疾病来满足未满足的需求 变体。

Project Summary Next-generation sequencing (NGS) has the potential to profile all clinically relevant genetic variants simultane- ously in a single genetic test. However, clinical variant discovery pipelines have mostly focused on coding single nucleotide variants (SNVs), regulatory SNVs and small indels. This proposal aims to make repeat analysis a standard component of existing pipelines, focusing in particular on short tandem repeats (STRs), variable number tandem repeats (VNTRs), and low-copy repeats or segmental duplications. Together, these repeats account for 8% of the human genome, but are implicated in a disproportionately large number of Mendelian diseases. The proposed methods are primarily aimed at Illumina sequencing, which forms the vast majority of current Mendelian sequencing pipelines, but also includes alternative technologies such as Pacific Biosciences and 10X Genomics. The first aim develops algorithms for discovery of repeat variants currently inaccessible from NGS. In the second aim, the PIs propose to generate gold-standard validation data for Mendelian repeats using multiple technologies. In the third aim, the PIs will integrate the proposed methods into existing NGS pipelines for clinical variant discov- ery, and also apply them to large existing data-sets to obtain genotype frequencies of large control populations. The project serves an unmet need by augmenting Mendelian variant pipelines to include highly relevant disease variants.