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：
10612917
负责人：
MICHAEL Joseph BAMSHAD
金额：
$ 269.07万
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/10612917
关键词：
Acceleration CRISPR interference ClinVar Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Collaborations 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 Institution Knowledge Leadership Link Medical Medical Genetics Metadata Methodology Methods Mutation National Heart, Lung, and Blood Institute National Human Genome Research Institute Oncogenes Open Reading Frames Pathogenicity Phenotype Publishing RNA Splicing Rare Diseases Reporting Research Research Personnel Resources Role Sampling Technology Testing Translations United States National Institutes of Health Universities Untranslated RNA Validation Variant Washington Work advocacy organizations analytical tool clinical care cohort cost effective data sharing database of Genotypes and Phenotypes design empowerment exome exome sequencing follow-up gene discovery genetic architecture 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 variant detection web platform whole genome

Acceleration CRISPR interference ClinVar Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Collaborations 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 Institution Knowledge Leadership Link Medical Medical Genetics Metadata Methodology Methods Mutation National Heart, Lung, and Blood Institute National Human Genome Research Institute Oncogenes Open Reading Frames Pathogenicity Phenotype Publishing RNA Splicing Rare Diseases Reporting Research Research Personnel Resources Role Sampling Technology Testing Translations United States National Institutes of Health Universities Untranslated RNA Validation Variant Washington Work advocacy organizations analytical tool clinical care cohort cost effective data sharing database of Genotypes and Phenotypes design empowerment exome exome sequencing follow-up gene discovery genetic architecture 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 variant detection web platform whole genome

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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。 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);发展 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.我们 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 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。