Next Generation Mendelian Genetics

下一代孟德尔遗传学

• 批准号: 7943999
• 负责人: MICHAEL Joseph BAMSHAD
• 金额: $ 195.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943999
• 关键词: Address; Adult; Affect; Biology; Candidate Disease Gene; Childhood; Chromosome Mapping; Code; Collection; Coupled; Coupling; DNA Resequencing; DNA Sequence; Data; Development; Diagnosis; Disease; Disease Management; Exhibits; Family; Gene Mutation; Genes; Genetic; Genetic Research; Genotype; Goals; Hereditary Disease; Human; Human Genetics; Human Genome; Individual; Inheritance Patterns; Medical; Medical Genetics; Medicine; Methods; Molecular; Mutation; National Human Genome Research Institute; Online Mendelian Inheritance In Man; Open Reading Frames; Proteins; Public Health; Rare Diseases; Sampling; Structure; Variant; abstracting; base; cohort; comparative; database of Genotypes and Phenotypes; exome; follow-up; genetic linkage analysis; genetic pedigree; genome-wide; human disease; improved; next generation; novel strategies; novel therapeutics; tool

DESCRIPTION (provided by applicant): This application addresses NHGRI RFA-OD-09-004 for Medical Sequencing Discovery Projects. The ultimate goal of this proposal is to scale a new approach to identify the candidate genes and mutations that underlie rare Mendelian diseases in humans by exome resequencing. For decades, linkage analysis has been the mainstay of human genetics. However, for rare Mendelian diseases where family collection is difficult or pedigrees are small, this approach is less useful. Although the molecular bases of more than 2,600 Mendelian diseases have been determined by linkage mapping or a candidate gene approach, a nearly equal number remain to be solved (OMIM). We have assembled a collection of rare pediatric and adult Mendelian diseases that are representative of this unsolved set. In every instance, the identification of the causal gene remains intractable to either linkage mapping or exhaustive candidate gene analysis. Exome resequencing offers a new way forward for dissecting the underlying causes of rare Mendelian diseases. In our preliminary studies, we show that selective capture of protein coding sequences across the human genome coupled with massively parallel resequencing to define coding variation can accurately identify the gene underlying a monogenic disorder. In this example, comparative analysis of exome variation data from as few as two unrelated individuals affected with the disease reduced the list of candidate genes to less than ten. The candidate list was further reduced to a single gene with exome data from as few as four unrelated cases. Once identified, each candidate gene will be screened for disease-causing variants by conventional methods in a larger set of cases. Discovery of the genetic basis of a large collection of rare disorders that have, to date, been unyielding to traditional analysis will substantially expand our understanding of the biology of the human genome, facilitate accurate diagnosis and improved management of these diseases, and provide the information needed for the development of novel therapeutics. If successful, this approach is likely to replace linkage analysis as the dominant paradigm for studying diseases exhibiting Mendelian inheritance patterns and will provide a new path forward for medical genetics. PUBLIC HEALTH RELEVANCE: As we enter an era of personalized medicine, DNA sequencing will be increasingly important to public health, contributing to our understanding of the genetic basis of human disease. The targeted capture and massively parallel sequencing of all protein coding regions in the human genome (the exome) has the potential to markedly accelerate human genetics research as an efficient method for identifying highly penetrant variants at a genome-wide scale. This project will apply and evaluate exome resequencing as a new tool to rapidly identify the causes of dozens of rare genetic diseases in humans.

描述（由申请人提供）：本申请针对医疗测序发现项目，提出 NHGRI RFA-OD-09-004。该提案的最终目标是扩展一种新方法，通过外显子组重测序来识别人类罕见孟德尔疾病的候选基因和突变。几十年来，连锁分析一直是人类遗传学的支柱。然而，对于家族收集困难或家系较小的罕见孟德尔疾病，这种方法的用处不大。尽管已经通过连锁图谱或候选基因方法确定了 2,600 多种孟德尔疾病的分子基础，但仍有几乎相同数量的疾病有待解决 (OMIM)。我们收集了一系列罕见的儿科和成人孟德尔疾病，这些疾病是这一未解决的疾病的代表。在每种情况下，因果基因的识别仍然难以通过连锁图谱或详尽的候选基因分析来解决。外显子组重测序为剖析罕见孟德尔疾病的根本原因提供了一种新的方法。在我们的初步研究中，我们表明，选择性捕获人类基因组中的蛋白质编码序列，再加上大规模并行重测序来定义编码变异，可以准确识别单基因疾病背后的基因。在这个例子中，对来自最少两个患有该疾病的无关个体的外显子组变异数据进行比较分析，将候选基因列表减少到不到十个。候选列表进一步缩减为单个基因，其外显子组数据仅来自四个不相关的病例。一旦确定，每个候选基因将通过常规方法在更多病例中筛选致病变异。迄今为止，传统分析无法解决大量罕见疾病的遗传基础，发现这些疾病将大大扩展我们对人类基因组生物学的理解，促进准确诊断和改进这些疾病的管理，并提供信息开发新疗法所需的。如果成功，这种方法可能会取代连锁分析，成为研究孟德尔遗传模式疾病的主导范式，并将为医学遗传学提供一条新的前进道路。 公共健康相关性：随着我们进入个性化医疗时代，DNA 测序对公共健康将变得越来越重要，有助于我们了解人类疾病的遗传基础。对人类基因组（外显子组）中所有蛋白质编码区的靶向捕获和大规模并行测序有可能显着加速人类遗传学研究，作为在全基因组范围内识别高渗透变异的有效方法。该项目将应用和评估外显子组重测序作为一种新工具，以快速识别人类数十种罕见遗传病的病因。

项目成果

KIAA0586 is Mutated in Joubert Syndrome.

• DOI: 10.1002/humu.22821
• 发表时间: 2015-09
• 期刊: Human mutation
• 影响因子: 3.9
• 作者: Bachmann-Gagescu R;Phelps IG;Dempsey JC;Sharma VA;Ishak GE;Boyle EA;Wilson M;Marques Lourenço C;Arslan M;University of Washington Center for Mendelian Genomics;Shendure J;Doherty D
• 通讯作者: Doherty D

"Mandibulofacial dysostosis with microcephaly" caused by EFTUD2 mutations: expanding the phenotype.

• DOI: 10.1002/ajmg.a.35696
• 发表时间: 2013-01
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Luquetti, Daniela V.;Hing, Anne V.;Rieder, Mark J.;Nickerson, Deborah A.;Turner, Emily H.;Smith, Joshua;Park, Sarah;Cunningham, Michael L.
• 通讯作者: Cunningham, Michael L.