UW Center for Mendelian Genomics

威斯康星大学孟德尔基因组学中心

• 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
• 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

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.

项目概要/摘要（来自基金资助的奖学金） 到目前为止，已经发现了4,163种孟德尔条件（MC）的2,937个基因。但 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。在 2011年，NHGRI和NHLBI建立了孟德尔基因组学中心（CMG），以促进大规模的 发现负责MC的基因。在CMG计划的第一阶段，并与182 来自27个国家的117个机构的调查人员，华盛顿大学CMG（UW-CMG）评估了 迄今为止，该团队已经从2，404个家庭的6，598个样本中获得了4，116个外显子和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与基因的识别 获得237个MC，其中包括123个新发现。这些发现对诊断学的转化和影响 临床护理是即时和实质性的-当与遗传学的发现相结合时， 自2012年以来，被确定为潜在MC的基因变异代表了约25%的阳性 导致临床诊断努力。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以及方法学 创新包括MIP、smMIP和低输入外显子组和基因组测序方法。UW- CMG仍然致力于开放数据共享，滚动提交符合条件的外显子组和基因组 将数据传输到dbGaP（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），首次公开提供匿名链接， 个体水平的基因型，从超过3，000个外显子组，到个体临床表型，由人类定义 表型本体论术语。在这个更新应用程序中，我们从这些成功中建立最大化新基因 发现MC，利用从> 16，500个样本中立即获得> 22，000个序列就绪样本 家庭和163个MC，获得了几个大的出生缺陷队列，总计超过24，000个trios（> 94，000个 样本总数）和积极的样本征集计划，包括案例汇总和案例匹配， 接受过临床外显子组测序的未确诊患者。我们提出四个具体目标：（1） 征求，组织和策划表型信息和DNA样本的家庭与不明原因的（即，没有 已知的潜在基因）来自世界各地的样本保管人的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管道， 外显子组和基因组测序对应于无法解释的MC的样品，并改善这一过程 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， 通过使用有效的研究设计和有效的创新分析，尽可能地最大限度地提高新发现;（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的全部基因。

项目成果

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
• 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
• 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