Genetics and Genomics of Fuchs Endothelial Corneal Dystrophy

福克斯内皮性角膜营养不良的遗传学和基因组学

基本信息

批准号：
8305374
负责人：
Venkateswara Vinod Mootha
金额：
$ 31.77万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305374
关键词：
15q 18q Accounting Affect Age Age-Years Applied Genetics Blindness Cohort Studies Collaborations Cornea Corneal Diseases Corneal Endothelium Corneal dystrophy Corneal edema Country DNA Disease Doctor of Philosophy Exons Eye diseases Family Foundations Funding Future General Population Generations Genes Genetic Genetic Variation Genome Genomics Genotype Grant Heart Human Genetics Individual Inherited Keratoplasty Lead Link Liquid substance Medical Medical center Molecular Mutation Nucleotides Pain Pathogenicity Patients Penetrance Phenotype Plant Roots Play Population Prevalence Research Role Sampling Scientist Susceptibility Gene TCF7L2 gene Texas United States Universities Variant Vision Washington autosomal dominant trait base cohort early onset gene discovery genetic linkage analysis genetic pedigree genetic variant genome wide association study genome-wide linkage improved next generation novel novel therapeutics operation population based repository

15q 18q Accounting Affect Age Age-Years Applied Genetics Blindness Cohort Studies Collaborations Cornea Corneal Diseases Corneal Endothelium Corneal dystrophy Corneal edema Country DNA Disease Doctor of Philosophy Exons Eye diseases Family Foundations Funding Future General Population Generations Genes Genetic Genetic Variation Genome Genomics Genotype Grant Heart Human Genetics Individual Inherited Keratoplasty Lead Link Liquid substance Medical Medical center Molecular Mutation Nucleotides Pain Pathogenicity Patients Penetrance Phenotype Plant Roots Play Population Prevalence Research Role Sampling Scientist Susceptibility Gene TCF7L2 gene Texas United States Universities Variant Vision Washington autosomal dominant trait base cohort early onset gene discovery genetic linkage analysis genetic pedigree genetic variant genome wide association study genome-wide linkage improved next generation novel novel therapeutics operation population based repository

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项目摘要

DESCRIPTION (provided by applicant): Fuchs' endothelial corneal dystrophy (FECD) affects nearly 4% of the U.S. population over 40 years of age and may cause corneal edema with decreased vision and pain. FECD is the leading indication for corneal transplantation in the country. Genetic variants in COL8A2, SLC4A11, and TCF8 have been linked to FECD but account for only a small fraction of cases. A recent GWAS study found an association between SNPs spanning a 1 Mb region of chr 18q including TCF4/FLJ45743 and late-onset FECD, but the underlying causal variant remains elusive. With CTSA and departmental funds, we have built a large repository of genomic DNA from well-phenotyped patients with corneal disorders including over 250 FECD cases. Our research team has recently begun to apply genetics and genomics-based approaches to investigate the molecular basis of FECD. We have performed genome-wide linkage analysis and have initiated next-generation sequencing on a three generation, Texas family from our cohort with bilineal inheritance of late-onset FECD that segregates as an autosomal dominant trait. Linkage analysis revealed promising intervals on chr 15q (LOD score of 3.93) and chr 1p (LOD score of 2.29). We hypothesize that two disease predisposing genes, one for each lineage, segregate in this unique, inter-married family and when they are co-inherited cause an early-onset, severe FECD. We now propose to: Identify the causal variant(s) underlying an autosomal dominant form of FECD. We will apply next-generation sequencing to the genomic intervals linked to FECD, determine which potential disease causing variants co-segregate with the FECD phenotype in our large pedigree, screen potential pathogenic variants in a cohort of unrelated FECD subjects, and finally assess these novel FECD mutations in a population sample. PUBLIC HEALTH RELEVANCE: Fuchs' endothelial corneal dystrophy (FECD) occurs in nearly 4% of the United States population over the age of 40. With no proven medical treatment, FECD is the leading indication for corneal transplantation accounting for 4,400 operations performed annually in this country. The proposed project aims to define the genes operative in FECD which could be targeted in future medical treatments.

描述（由申请人提供）：Fuchs的内皮角膜营养不良（FECD）影响了40岁以上美国人群的近4％，并且可能导致视力和疼痛减少的角膜水肿。 FECD是该国角膜移植的主要指标。 COL8A2，SLC4A11和TCF8中的遗传变异与FECD有关，但仅占一小部分病例。 GWAS最近的一项研究发现，SNP跨越了1 MB区域的CHR 18Q，包括TCF4/FLJ45743和晚期发作的FECD，但基本的因果变体仍然难以捉摸。有了CTSA和部门资金，我们已经建立了大量的基因组DNA存储库，这些基因组DNA来自良好的角膜疾病患者，包括250多例FECD病例。我们的研究团队最近已开始采用基于遗传学和基因组学方法来研究FECD的分子基础。我们已经进行了全基因组链接分析，并在我们的队列中启动了三代德克萨斯家族的下一代测序，该家族具有双收入的遗传，该遗传是后期发作的FECD，该遗传是将常染色体显性特征分开的。链接分析表明，CHR 15Q（LOD得分为3.93）和CHR 1P（LOD得分为2.29）的有希望的间隔。我们假设两个疾病诱发的基因，一个针对每个谱系，在这个独特的，结婚的家族中分离出来，当它们共同诞生时，会导致早期发病，严重的FECD。我们现在建议：确定fecd常染色体显性形式的基本因果变体。我们将将下一代测序应用于与FECD相关的基因组间隔，确定导致变异的潜在疾病与我们的大家谱中的FECD表型在我们的大型谱系，筛查筛查潜在的致病变异中共同隔离，并在一系列无关的FECD受试者中，并最终评估了这些新型FECD在人群样本中的新型FECD突变。公共卫生相关性：Fuchs的内皮角膜营养不良症（FECD）发生在40岁以上的美国人口中的近4％。如果没有经过证实的医疗，FECD是该国每年进行4,400次手术的领先迹象。拟议的项目旨在定义FECD中的基因，该基因可能针对以后的医疗治疗。