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)

基本信息

批准号：
10415070
负责人：
MICHAEL Joseph BAMSHAD
金额：
$ 269.76万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10415070
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 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

项目摘要

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个孟德尔条件（MC）的遗传基础仍然未知，数百个新型MC是每年描述。我们的小组与来自55个国家的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 MC的基因，包括915个新颖的发现。这些发现对诊断和临床护理的翻译和影响直接和实质性。此外，我们开发了多种新的分析工具 CADD，Primus，针叶树，SMRT-SV，RV-TDT以及包括MIPS，SMMIP，以及低输入外显子组和基因组测序（ES/WGS）的方法。我们也非常致力于开放数据共享以滚动向砧座的外显子和基因组数据滚动（1,439个沉积）；发展媒人交换节点（http://mygene2.org），可公开共享基因型和表型家庭，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），该链接从18,000多个以上的个人级基因型链接外观/基因组对单个表型。在此应用程序中，我们以这些成功为基础华盛顿大学孟德尔大学基因组学研究中心（UW-MGRC）的总体目标最大化MC的新型基因发现，重点是使用使用的规范MC ES/WGS和MC的非编码变体。为此，我们将开发出新颖的方法来告知人类遗传学社区的变体解释和功能验证一般并传播结果，数据和工具公开。我们将利用〜300的即时访问序列就绪样品 MCS（> 26,000个样本），1,500个样本涉嫌携带MC的因果非编码变体，一个积极的样本招标计划与行业，学术中心和其他NIH计划合作。我们提出三个特定目的：（1）通过招标，测序和分析最大化MC的新基因发现。有无法解释的家庭（即没有已知的基本基因）MC的家庭；经典MC被认为是高度优先的临床遗传学界，一直是基因发现工作的顽固性；还有仍然存在的案件先前的外显子组或基因组测序后未解决。（2）为未解决的基因发现制定新的策略由难以检测或未知功能效应的变体引起的MC（例如结构变体，重复扩展，隐秘的剪接，调节等）和/或不寻常的继承模式，然后，这样做，表征了MC的致病性非编码变体的遗传结构。高级实施吞吐量筛查和针对性的随访功能研究，以优先考虑和验证主张候选非编码变体的致病性。（3）在可行的情况下扮演领导角色共享测序和丰富的表型元数据，方法和知识，以增强全球调查人员的能力并加速基因发现的速度。