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

华盛顿大学孟德尔基因组学研究中心 (UW-MGRC)

• 批准号: 10215884
• 负责人: MICHAEL Joseph BAMSHAD
• 金额: $ 270.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10215884
• 关键词: CRISPR interference; ClinVar; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Communities; Congenital Abnormality; Coniferophyta; Country; Coupled; Data; Data Coordinating Center; Deposition; Development; Diagnostic; Diagnostic tests; Disease; FURIN gene; Family; Gene Expression; Genes; Genetic; Genome; Genomics; Genotype; Goals; Human Genetics; Individual; Industry; Institutes; Institution; Knowledge; Leadership; Link; Medical; Medical Genetics; Metadata; Methodology; Methods; Mutation; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Oncogenes; Online Systems; Open Reading Frames; Pathogenicity; Phenotype; Publishing; RNA Splicing; Rare Diseases; Reporting; Research; Research Personnel; Role; Sampling; Structure; Technology; Testing; Translations; United States National Institutes of Health; Universities; Untranslated RNA; Validation; Variant; Washington; Work; advocacy organizations; analytical tool; base; clinical care; cohort; cost effective; data resource; data sharing; data tools; database of Genotypes and Phenotypes; design; exome; exome sequencing; follow-up; gene discovery; genetic architecture; genome analysis; genome editing; genome sequencing; genome wide methylation; high throughput screening; innovation; next generation sequencing; novel; novel strategies; open data; phenotypic data; programs; rare condition; repository; success; technological innovation; tool; transcriptome sequencing; whole genome

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.

项目概要/摘要 > 2,920 种孟德尔病症 (MC) 的遗传基础仍然未知，并且数百种新的 MC 每年都有描述。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， 在过去的十年中，评估了来自 5,675 个家族的 15,387 个样本，并鉴定了 1379 个 MC 的基因， 其中包括 915 项新发现。这些发现对诊断和临床护理的转化和影响 是直接且实质性的。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 以及方法创新，包括 MIPs、smMIPs、 以及低输入外显子组和基因组测序（ES/WGS）的方法。我们也坚定地致力于开放 数据共享，滚动向 AnVIL 提交外显子组和基因组数据（已保存 1,439 个）；发展 MatchMaker Exchange 节点 (http://MyGene2.org)，可实现基因型和表型的公共共享 家庭、研究人员和临床医生之间的数据；并创建公共数据浏览器 (http://geno2mp.gs.washington.edu) 链接超过 18,000 个去识别化的个体级基因型 外显子组/基因组到个体表型。在此应用程序中，我们在这些成功的基础上建立了 华盛顿大学孟德尔基因组学研究中心 (UW-MGRC) 的总体目标 最大限度地发现 MC 的新基因，重点是使用尚未解决的典型 MC ES/WGS 和 MC 底层的非编码变体。为此，我们将开发新颖的方法来告知 对整个人类遗传学界进行变异解释和功能验证并传播 公开结果、数据和工具。我们将利用立即获取约 300 个序列就绪样本的机会 MC（>26,000 个样本）、1,500 个疑似含有 MC 因果非编码变体的样本，以及 与工业界、学术中心和其他 NIH 项目合作的积极样本征集计划。我们 提出三个具体目标：（1）通过征集、测序和分析最大限度地发现 MC 的新基因 具有无法解释的（即没有已知潜在基因）MC 的家庭；被视为高度优先的经典MC 临床遗传学界和一直抵制基因发现工作的人；以及剩余的案件 在之前的外显子组或基因组测序后仍未解决。 (2) 为未解决的基因发现制定新策略 由难以检测或未知功能影响的变异引起的 MC（例如结构变异、 重复扩展、神秘剪接、调节等）和/或不寻常的继承模式，并且在此过程中， 描述 MC 致病性非编码变异的遗传结构。实施高 通量筛选和有针对性的后续功能研究，以确定优先顺序并验证 候选非编码变异的致病性。 (3) 在可行的情况下发挥领导作用，以公开和公开的方式， 共享测序和丰富的表型元数据、方法和知识，为全世界的研究人员提供支持 并加快基因发现的步伐。