University of Washington Mendelian Genomics Research Center (UW-MGRC)

项目总结/摘要 超过2，920种孟德尔病症（MC）的遗传基础仍然未知，数百种新的MC正在研究中。 每年描述。我们的团队与来自55个国家656个机构的2,379名研究人员合作， 评估了来自5,675个家庭的15,387个样本，在过去的十年中，确定了1379个MC的基因， 包括915项新发现。这些发现对诊断和临床护理的转化和影响 是即时的和实质性的。此外，我们还开发了多种新的分析工具，包括 CADD、PRIMUS、CoNIFER、SMRT-SV、RV-TDT以及包括MIP、smMIP、 以及用于低输入外显子组和基因组测序（ES/WGS）的方法。我们也致力于开放 通过向AnVIL滚动提交外显子组和基因组数据（1，439个已保存）实现数据共享; 一个MatchMaker Exchange节点（http：MyGene2.org），用于公开共享基因型和表型 家庭、研究人员和临床医生之间的数据;以及创建公共数据浏览器 (http：geno2mp.gs.washington.edu），该网站将来自18，000多个国家的去识别化的个人基因型联系起来， 外显子组/基因组与个体表型的关系。在这个应用程序中，我们建立在这些成功的基础上， 华盛顿大学孟德尔基因组学研究中心（UW-MGRC）的总体目标是 最大限度地为MC发现新的基因，重点是使用未解决的典型MC ES/WGS和MC基础的非编码变体。为此，我们将开发新的方法， 为人类遗传学界提供变异解释和功能验证， 结果、数据和工具。我们将利用从约300个样本中立即获得测序样本的机会， MC（> 26，000个样品），1，500个怀疑携带MC的因果非编码变体的样品，和1，500个怀疑携带MC的因果非编码变体的样品。 与行业、学术中心和其他NIH项目合作制定积极的样本征集计划。我们 提出了三个具体目标：（1）通过征集、测序和分析，最大限度地发现MC的新基因 无法解释的家庭（即，没有已知的潜在基因）MC;经典MC被认为是高优先级的 临床遗传学界和已被拒绝的基因发现的努力;和案件仍然存在 在先前的外显子组或基因组测序之后未解决。(2)为未解决的基因发现开发新策略 由难以检测的变体或未知功能效应（例如，结构变体， 重复扩增、隐蔽剪接、调节等），和/或不寻常的遗传方式，这样做， 表征致病性非编码变异体的遗传结构的MC。实施高- 通量筛选和有针对性的后续功能研究，以优先考虑和验证以下断言： 候选非编码变体的致病性。(3)在可行的情况下，发挥领导作用， 共享测序和丰富的表型元数据、方法和知识，以增强全球研究者的能力 并加快基因发现的步伐。

PROJECT SUMMARY/ABSTRACT The genetic basis of >2,920 Mendelian conditions (MCs) remains unknown, and hundreds of novel MCs are described each year. Our group has, in partnership with 2,379 investigators from 656 institutions in 55 countries, assessed 15,387 samples from 5,675 families and has, over the past decade, identified genes for 1379 MCs, including 915 novel discoveries. The translation and impact of these discoveries on diagnostics and clinical care has been immediate and substantial. Additionally, we have developed multiple new analytical tools including CADD, PRIMUS, CoNIFER, SMRT-SV, RV-TDT, as well as methodological innovations including MIPs, smMIPs, and approaches for low input exome and genome sequencing (ES/WGS). We are also deeply committed to open data sharing with rolling submission of exome and genome data to the AnVIL (1,439 deposited); development of a MatchMaker Exchange node (http://MyGene2.org) that enables public sharing of genotype and phenotypic data among families, researchers, and clinicians; and creation of a public data browser (http://geno2mp.gs.washington.edu) that links de-identified, individual-level genotypes from over 18,000 exomes/genomes to individual phenotypes. In this application, we build upon these successes to establish the University of Washington Mendelian Genomics Research Center (UW-MGRC) with the overarching goal to maximize novel gene discovery for MCs, with an emphasis on canonical MCs that have gone unsolved using ES/WGS, and noncoding variants underlying MCs. To this end, we will develop novel approaches to inform variant interpretation and functional validation for the human genetics community at-large and disseminate results, data, and tools openly. We will capitalize on immediate access to sequence-ready samples from ~300 MCs (>26,000 samples), 1,500 samples suspected of harboring a causal noncoding variant for a MC, and an aggressive sample solicitation plan in partnership with industry, academic centers, and other NIH programs. We propose three specific aims: (1) maximize novel gene discovery for MCs by solicitation, sequencing, and analysis of families with unexplained (i.e., no known underlying gene) MCs; classic MCs considered high priority by the clinical genetics community and that have been recalcitrant to gene discovery efforts; and cases that remain unsolved after prior exome or genome sequencing. (2) Develop new strategies for gene discovery for unsolved MCs caused by variants that are difficult to detect or of unknown functional effects (e.g., structural variants, repeat expansions, cryptic splice, regulatory, etc.), and/or unusual modes of inheritance, and, in doing so, characterize the genetic architecture of pathogenic noncoding variants underlying MCs. Implement high- throughput screening and targeted follow-up functional studies to prioritize and validate assertions of pathogenicity of candidate noncoding variants. (3) Take a leadership role to openly and publicly, when feasible, share sequencing and rich phenotypic metadata, methods, and knowledge, to empower investigators worldwide and accelerate the pace of gene discovery.