Refining Mendelian disease analysis via detection of clinically relevant repeat variants

项目摘要 下一代测序技术有可能对所有临床相关的遗传变异进行fi。 在单一的基因测试中表现出色。然而，临床变异发现流水线主要集中在单个编码上 核苷酸变异体(SNV)、调节性SNV和小INDELs。这项建议旨在使重复分析成为一种 现有管道的标准组件，特别关注短串联重复(STR)，数量可变 串联重复序列(VNTRs)和低拷贝重复序列或节段性复制。加在一起，这些重复解释了 占人类基因组的8%，但与孟德尔疾病的数量不成比例地有关。这个 所提出的方法主要是针对Illumina测序，它构成了当前孟德尔人的绝大多数 测序管道，但也包括替代技术，如PACIfic生物科学和10X基因组学。这个 fiRst Aim开发了发现目前无法从NGS获得的重复变异的算法。在第二个目标中， PI建议使用多种技术生成孟德尔重复的黄金标准验证数据。在……里面 第三个目标是，PIS将把建议的方法整合到现有的NGS管道中，用于临床变异发现- Ery，并将它们应用于现有的大型数据集，以获得大型对照人群的基因频率。 该项目通过扩大孟德尔变种管道以包括高度相关的疾病来满足未得到满足的需求 变种。

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.