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.

项目摘要/摘要 2,920例孟德尔条件(MC)的遗传基础尚不清楚，数百种新的MC是 每年都有描述。我们的小组与来自55个国家656个机构的2379名调查人员合作， 评估了来自5,675个家庭的15,387个样本，并在过去十年中确定了1379个MC的基因， 包括915项新发现。这些发现的翻译及其对诊断和临床护理的影响 是立竿见影的和实质性的。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， 以及低投入外显子组和基因组测序方法(ES/WGS)。我们也坚定地致力于开放 数据共享，滚动提交外显子组和基因组数据到砧板(1,439个已交存)；开发 一个媒人交换节点(http://MyGene2.org)，允许公开共享基因和表型 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)将18,000多个未识别的个人水平的基因类型链接起来 外显子体/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 华盛顿大学孟德尔基因组研究中心(UW-MGRC)的首要目标是 最大限度地发现MC的新基因，重点放在尚未使用 ES/WGS和基于MC的非编码变体。为此，我们将开发新的方法来告知 对整个人类遗传学社区的变体解释和功能验证 公开结果、数据和工具。我们将利用即时访问约300个可测序样本的机会 MCS(&gt；26,000个样本)，怀疑含有MC的因果非编码变体的1,500个样本，以及 积极的样本征集计划，与工业、学术中心和其他NIH项目合作。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 对于患有不明原因(即，未知的潜在基因)的MC的家庭；经典MC被认为是高度优先的 临床遗传学社区和顽固的基因发现努力；以及仍然存在的病例 在先前的外显子组或基因组测序后未解决的。(2)开发新的未解决的基因发现策略 由难以检测或具有未知功能效应的变体引起的MCS(例如，结构变体， 重复扩展、神秘拼接、调节等)和/或不寻常的继承模式，并且在这样做时， 描述MC下致病非编码变异的遗传结构。实施高- 吞吐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以下断言 候选非编码变异体的致病性。(3)发挥领导作用，在可行的情况下，公开和公开地， 共享测序和丰富的表型元数据、方法和知识，以增强全球研究人员的能力 加快基因发现的步伐。