UW Center for Mendelian Genomics

威斯康星大学孟德尔基因组学中心

基本信息

批准号：
9922590
负责人：
MICHAEL Joseph BAMSHAD
金额：
$ 233.67万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-29 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922590
关键词：
Adoption Adult Architecture Award Biological Assay Biological Models Childhood ClinVar Clinical Clinical Management Communities Complex Computing Methodologies Congenital Abnormality Congenital Heart Defects Copy Number Polymorphism Country Coupled Cystic Fibrosis Transmembrane Conductance Regulator DNA Data Deposition Development Diagnostic Diagnostic tests Disease Economic Burden England Epilepsy Evolution FURIN gene Family Funding Genes Genetic Genetic Medicine Genome Genomics Genotype Goals Gold Human Human Genetics Human Genome Individual Industry Infrastructure Institution Investigation Knowledge Leadership Link Methodology Methods Modeling Morbidity - disease rate Mutation National Heart, Lung, and Blood Institute National Human Genome Research Institute Ontology Open Reading Frames Parents Patients Penetrance Phase Phenotype Population Preventive Private Sector Process Production Public Sector RNA Splicing Rare Diseases Research Design Research Personnel Resources Risk Role Sampling Structure Sum Syndrome Technology Test Result Testing Therapeutic Time Translations Universities Untranslated RNA Variant Washington adjudicate analytical tool autism spectrum disorder base candidate validation causal variant clinical care clinical diagnostics clinical phenotype clinical practice cohort computerized tools cost cost effective data sharing database of Genotypes and Phenotypes developmental disease exome exome sequencing gene complementation gene discovery genome sequencing genomic data heuristics human disease improved industry partner innovation insertion/deletion mutation mortality new technology next generation sequencing novel novel strategies open data programs reproductive success technological innovation tool transcriptome sequencing treatment strategy variant of unknown significance whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT (FROM FUNDED PARENT AWARD) To date, 2,937 genes underlying 4,163 Mendelian conditions (MCs) have 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.

项目摘要/摘要（来自资助的家长奖）迄今为止，已发现 4,163 种孟德尔条件 (MC) 背后的 2,937 个基因。超过 3,000 种 MC 的遗传基础仍然未知，每年都有数百种新的 MC 被描述。 2011 年，NHGRI 和 NHLBI 建立了孟德尔基因组学中心 (CMG)，以促进大规模研究在 CMG 计划的第一阶段，与 182 合作发现了负责 MC 的基因。华盛顿大学 CMG (UW-CMG) 评估了来自 27 个国家 117 个机构的研究人员来自 2,404 个家族的 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基因鉴定方面无与伦比的发现速度 237 个 MC，包括 123 个新发现这些发现对诊断的转化和影响。结合遗传学的发现，临床护理得到了立即且实质性的帮助自 2012 年以来，在整个社区中，被确定为潜在 MC 的基因变异占阳性的约 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 以及方法论创新包括 MIP、smMIP 以及低输入外显子组和基因组测序方法。 CMG 仍然坚定地致力于开放数据共享，滚动提交合格的外显子组和基因组数据传输至 dbGaP（614 项已提交，1,748 项待提交）并开发新的数据浏览器 (http://geno2mp.gs.washington.edu) 首次公开提供匿名链接个体水平的基因型，从 3,000 多个外显子组到个体临床表型，由 Human 定义在这个更新应用程序中，我们以这些成功为基础，最大限度地利用新基因。 MC 的发现，利用立即访问超过 16,500 个序列就绪的超过 22,000 个样本家庭和 163 个 MC，获得了几个出生缺陷的大群体，总计超过 24,000 个三人组（>94,000 样本总数）和积极的样本征集计划，包括案例聚合和案例匹配我们提出了四个具体目标：（1）征求、组织和整理来自不明原因家庭（即无症状）的表型信息和 DNA 样本。已知的潜在基因）来自世界各地样本保管人的 MC，通过提交给我们的中心用于测序的样品或用于进一步分析的序列数据；（2）应用我们已建立的生产流程对与无法解释的 MC 相对应的样本进行外显子组和基因组测序，并改进这一过程通过持续的技术创新；（3）确定尽可能多的无法解释的MC的遗传基础 (4) 通过高效的研究设计和有效的创新分析，尽可能地最大化新发现；发挥领导作用，传播并公开分享方法和数据，以促进全世界的努力发现 MC 背后的完整基因。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A new NBIA patient from Turkey with homozygous C19ORF12 mutation.

一名来自土耳其的新 NBIA 患者，具有 C19ORF12 纯合突变。

DOI：
10.1007/s13760-018-1026-5
发表时间：
2019
期刊：
Acta neurologica Belgica
影响因子：
2.7
作者：
Kasapkara,ÇiğdemSeher;Tümer,Leyla;Gregory,Allison;Ezgü,Fatih;İnci,Aslı;Derinkuyu,BetülEmine;Fox,Rachel;Rogers,Caleb;Hayflick,Susan
通讯作者：
Hayflick,Susan

Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia.

DOI：
10.1186/s13630-017-0051-y
发表时间：
2017-01-01
期刊：
Cilia
影响因子：
0
作者：
Duran, Ivan;Taylor, S Paige;Krakow, Deborah
通讯作者：
Krakow, Deborah

A novel homozygous variant in BMPR1B underlies acromesomelic dysplasia Hunter-Thompson type.

DOI：
10.1111/ahg.12233
发表时间：
2018-05
期刊：
Annals of human genetics
影响因子：
1.9
作者：
Ullah A;Umair M;Muhammad D;Bilal M;Lee K;Leal SM;Ahmad W
通讯作者：
Ahmad W

A disease-causing novel missense mutation in the ST14 gene underlies autosomal recessive ichthyosis with hypotrichosis syndrome in a consanguineous family.

DOI：
10.1684/ejd.2017.3210
发表时间：
2018-04-01
期刊：
European journal of dermatology : EJD
影响因子：
0
作者：
Ahmad F;Ahmed I;Nasir A;Umair M;Shahzad S;Muhammad D;Santos-Cortez RLP;Leal SM;Ahmad W
通讯作者：
Ahmad W