UW Center for Mendelian Genomics

威斯康星大学孟德尔基因组学中心

• 批准号: 9634277
• 负责人: MICHAEL Joseph BAMSHAD
• 金额: $ 15万
• 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/9634277
• 关键词: Affect; Candidate Disease Gene; Clinical; Collaborations; Communities; Congenital Abnormality; Country; Coupled; Coupling; DNA; Data; Data Set; Deposition; Development; Diagnostic; Disease; 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（由适用提供）：迄今为止，已经发现了4,163个Mendelian条件（MCS）的2,937个基因。然而，超过3,000多种MC的遗传基础仍然未知，每年都描述了数百个新型MC。 2011年，NHGRI和NHLBI建立了Mendelian基因组学中心（CMG），以促进大规模发现负责MCS的基因。华盛顿大学CMG（UW-CMG）在CMG计划的第1阶段，并与来自117个机构的182家调查人员合作，评估了来自2,404个家庭的6,598个样本，并且迄今为止已经产生了4,116个Exome和97个整个基因组序列。这项广泛的协作努力导致了无与伦比的发现空间，并鉴定了237个MC的基因，其中包括123个新颖的发现。这些发现对诊断和临床护理的翻译和影响是直接而实质性的，当时遗传学界的发现很大，自2012年以来被鉴定为基因基础MC的变体代表了临床诊断努力的阳性结果的25％。此外，UW-CMG开发了多种新的分析工具，包括CADD，Primus，Simrare，Star，RV-TDT，RV-TDT，CHP，VAT和Spliceosaurus，以及方法论创新，包括MIPS，SMMIP和用于低输入外显子组和基因组测序的方法。 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 deposit) 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,由人类表型本体论项定义的个体临床表型。 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 solarization plan MCs from sample custodians around the world, by submission to our center of either samples for测序或序列数据以进行进一步分析； （2）将我们已建立的生产管道应用于与未知MC相对应的样品，并通过正在进行的技术创新来改善此过程； （3）通过使用有效的研究设计和有效的创新分析来确定尽可能多的未知MC的遗传基础； （4）扮演领导角色来传播并公开共享方法和数据，以促进全球范围内的努力，以发现MC的完全完成。