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，已经发现了4，163种孟德尔条件（MC）的2，937个基因。然而，超过3，000个MC的遗传基础仍然未知，并且每年描述数百个新的MC。2011年，NHGRI和NHLBI建立了孟德尔基因组学中心（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，已经产生了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导致了前所未有的发现速度，鉴定了237个MC的基因，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直接和实质性的-当与遗传学界的发现相结合时，自2012年以来被确定为潜在MC的基因变异代表了临床诊断工作中约25%的阳性结果。此外，UW-CMG还开发了多种新的分析工具，包括CADD，PRIMUS，SimRare，星星，RV-TDT，CHP，VAT和Spliceosaurus，以及方法创新，包括MIP，smMIP和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，向dbGaP滚动提交符合条件的外显子组和基因组数据（614个已沉积，1，748个待沉积），并开发新的数据浏览器（http：geno2mp.gs.washington.edu），首次公开提供个体水平基因型之间的匿名链接，从3，000多个外显子组到个体临床表型，由人类表型本体论术语定义。在这次更新申请中，我们在这些成功的基础上，最大限度地发现MC的新基因，利用立即获得来自> 16，500个家庭和163个MC的> 22，000个序列就绪样本，获得几个大型出生缺陷队列，总计超过24，000个三胞胎，（总共> 94，000个样本）和积极的样本征集计划，包括病例聚集和已进行临床外显子组测序的未确诊患者的病例匹配。我们提出了四个具体的目标：（1）征求，组织和策划表型信息和DNA样本的家庭无法解释（即，（2）将我们已建立的外显子组和基因组测序生产线应用于对应于无法解释的MC的样品，并通过持续的技术创新来改进这一过程;（3）通过有效的研究设计和有效的创新分析，尽可能多地确定无法解释的MC的遗传基础，最大限度地增加新的发现;（4）发挥领导作用，传播和公开分享方法和数据，以促进全球努力发现MC背后的完整基因。