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（摘自资助的父母奖）迄今为止，已经发现了4,163个孟德尔条件（MC）的基因2,937个基因。但是，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。在 2011年，NHGRI和NHLBI建立了Mendelian基因组学中心（CMG），以促进大规模的大规模发现负责MC的基因。在CMG计划的第1阶段，并与182合作华盛顿大学CMG大学（UW-CMG）的117个机构的调查人员评估了来自2,404个家族的6,598个样品，迄今为止已经产生了4,116个外显子组和97个整个基因组序列。这项广泛的协作努力导致了与基因识别的无与伦比的发现空间对于237个MC，包括123个新颖的发现。这些发现对诊断的翻译和影响临床护理是直接和实质性的 - 与遗传学一起发现的发现社区一般，自2012年以来被识别为基础MC的基因的变体代表左右的25％导致临床诊断工作。此外，UW-CMG开发了多种新的分析工具包括CADD，Primus，Simrare，Star，RV-TDT，CHP，VAT和Spliceosaurus以及方法论低输入外显子组和基因组测序的创新，包括MIP，SMMIP和方法。 UW- CMG仍然致力于通过符合资格的外显子组和基因组的滚动来打开数据共享 DBGAP的数据（614个沉积和1,748个待处理）和开发新数据浏览器（http://geno2mp.gs.washington.edu）首次公开提供匿名链接从3,000多个外部到个人临床表型，由人类定义的个体基因型到个体的临床表型表型本体论术语。在此续签应用中，我们从这些成功构建到最大化新型基因 MC的发现，利用> 16,500的即时访问> 22,000个序列的样本家庭和163个MC，访问总数超过24,000个三人的几个大量出生缺陷（> 94,000 总共样本）和积极的样本征集计划，包括案例聚集和案例匹配接受过临床外显子组测序的未诊断患者。我们提出了四个具体目标：（1）从具有无法解释的家族的征求，组织和策划表型信息和DNA样品（即无来自世界各地样本保管人的基本基因MC），通过提交我们的中心测序或序列数据的样本，用于进一步分析；（2）将我们既定的生产管线应用于外显子组和基因组测序与对应于意外MC的样品并改善此过程通过正在进行的技术创新；（3）确定尽可能多的意外MC的遗传基础通过使用有效的研究设计和有效，创新的分析，可以最大化新颖的发现；（4）扮演领导角色来传播并公开共享方法和数据，以促进全球努力发现MC的基因的完整完成。

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