UW Center for Mendelian Genomics

威斯康星大学孟德尔基因组学中心

• 批准号: 9419473
• 负责人: MICHAEL Joseph BAMSHAD
• 金额: $ 30万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-05 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9419473
• 关键词: Affect; Candidate Disease Gene; Clinical; Collaborations; Communities; Congenital Abnormality; Country; Coupled; Coupling; DNA; Data; Data Set; Deposition; Development; Diagnostic; Disease; Eligibility Determination; Equilibrium; Family; Genes; Genetic; Genome; Genomics; Genotype; Human; Individual; Institution; Leadership; Link; Massive Parallel Sequencing; Medical; Methodology; Methods; Mutation; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Ontology; Open Reading Frames; Patients; Phase; Phenotype; Process; Production; Productivity; Reporting; Research Design; Research Personnel; Role; Sampling; Structure; Technology; Time; Translations; Universities; Variant; Washington; Work; analytical tool; base; clinical care; clinical diagnostics; clinical phenotype; cohort; cost; data sharing; database of Genotypes and Phenotypes; exome; exome sequencing; gene complementation; gene discovery; genetic analysis; genome sequencing; improved; innovation; next generation sequencing; novel; novel strategies; open data; programs; public health relevance; repository; scale up; success; technological innovation; whole genome

 DESCRIPTION (provided by applicant): To date, 2,937 genes underlying 4,163 Mendelian conditions (MCs) has been discovered. However, the genetic basis of over 3,000 MCs remains unknown, and hundreds of novel MCs are described each year. In 2011, the NHGRI and NHLBI established the Centers for Mendelian Genomics (CMG) to facilitate large-scale discovery of genes responsible for MCs. In Phase-1 of the CMG program, and in partnership with 182 investigators from 117 institutions in 27 countries, the University of Washington CMG (UW-CMG) assessed 6,598 samples from 2,404 families and has, to date, produced 4,116 exome and 97 whole genome sequences. This extensive collaborative effort resulted in an unparalleled pace of discovery with the identification of genes for 237 MCs, including 123 novel discoveries. The translation and impact of these discoveries on diagnostics and clinical care has been immediate and substantial-when combined with discoveries made by the genetics community at-large, variants in genes identified as underlying MCs since 2012 represent ~25% of positive results in clinical diagnostic efforts. Additionally, the UW-CMG has developed multiple new analytical tools including CADD, PRIMUS, SimRare, STAR, RV-TDT, CHP, VAT and Spliceosaurus as well as methodological innovations including MIPs, smMIPs and approaches for low input exome and genome sequencing. The UW-CMG remains deeply committed to open data sharing with rolling submission of eligible exome and genome data to dbGaP (614 deposited and 1,748 pending deposition) and development of a new data browser (http://geno2mp.gs.washington.edu) that, for the first time, publicly provides anonymized links between individual-level genotypes, from over 3,000 exomes, to individual clinical phenotypes, defined by Human Phenotype Ontology terms. In this renewal application, we build from these successes to maximize novel gene discovery for MCs, capitalizing on immediate access to >22,000 sequence-ready samples from >16,500 families and 163 MCs, access to several large cohorts of birth defects totaling more than 24,000 trios (>94,000 samples total) and an aggressive sample solicitation plan including case aggregation and case matching of undiagnosed patients who have undergone clinical exome sequencing. We propose four specific aims: (1) Solicit, organize, and curate phenotypic information and DNA samples from families with unexplained (i.e., no known underlying gene) MCs from sample custodians around the world, by submission to our center of either samples for sequencing or sequence data for further analysis; (2) Apply our established production pipeline for exome and genome sequencing to samples corresponding to unexplained MCs and to improve this process through ongoing technology innovation; (3) Determine the genetic basis of as many unexplained MCs as is possible, maximizing novel discovery, by use of efficient study design and effective, innovative analysis; (4) Take a leadership role to disseminate and openly share methods and data to promote worldwide efforts to discover the full complement of genes underlying MCs.

 描述（由申请人提供）：迄今为止，已发现 4,163 种孟德尔条件 (MC) 背后的 2,937 个基因。然而，超过 3,000 种 MC 的遗传基础仍然未知，并且每年有数百种新的 MC 被描述。 2011 年，NHGRI 和 NHLBI 建立了孟德尔基因组中心 (CMG)，以促进大规模发现负责 MC 的基因。在 CMG 项目的第一阶段，华盛顿大学 CMG (UW-CMG) 与来自 27 个国家 117 个机构的 182 名研究人员合作，评估了来自 2,404 个家庭的 6,598 个样本，迄今为止，已产生 4,116 个外显子组和 97 个全基因组序列。这种广泛的合作努力带来了无与伦比的发现速度，鉴定了 237 个 MC 的基因，其中包括 123 个新发现。这些发现对诊断和临床护理的转化和影响是立竿见影和实质性的——与整个遗传学界的发现相结合，自 2012 年以来被确定为潜在 MC 的基因变异占临床诊断工作积极结果的约 25%。此外，UW-CMG 还开发了多种新的分析工具，包括 CADD、PRIMUS、SimRare、STAR、RV-TDT、CHP、VAT 和 Spliceosaurus，以及方法创新，包括 MIP、smMIP 以及低输入外显子组和基因组测序方法。 UW-CMG 仍然坚定地致力于开放数据共享，滚动向 dbGaP 提交合格的外显子组和基因组数据（614 个已提交，1,748 个待提交），并开发了一个新的数据浏览器 (http://geno2mp.gs.washington.edu)，该浏览器首次公开提供来自 3,000 多个个体水平基因型之间的匿名链接 外显子组，到个体临床表型，由人类表型本体论术语定义。在此更新应用中，我们以这些成功为基础，最大限度地发现 MC 的新基因，利用立即访问来自超过 16,500 个家庭和 163 个 MC 的超过 22,000 个已准备好测序的样本，访问总计超过 24,000 个三重组（总共超过 94,000 个样本）的几个出生缺陷大队列，以及积极的样本征集计划，包括病例汇总和已接受临床治疗的未确诊患者的病例匹配外显子组 测序。我们提出了四个具体目标：（1）通过向我们的中心提交样本进行测序或序列数据进行进一步分析，从世界各地的样本保管人处收集、组织和整理具有不明原因（即没有已知潜在基因）MC的家庭的表型信息和DNA样本； （2）将我们已建立的外显子组和基因组测序生产流程应用于不明MCs对应的样本，并通过持续的技术创新改进这一流程； (3) 通过高效的研究设计和有效的创新分析，确定尽可能多的无法解释的 MC 的遗传基础，最大限度地增加新发现； (4) 发挥领导作用，传播和公开分享方法和数据，以促进全世界努力发现 MC 的完整基因。