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：
8461549
负责人：
Venkateswara Vinod Mootha
金额：
$ 30.21万
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/8461549
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 sequencing novel novel therapeutics operation population based repository

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.

描述（由申请人提供）：福克斯内皮性角膜营养不良 (FECD) 影响近 4% 的 40 岁以上美国人口，并可能导致角膜水肿、视力下降和疼痛。 FECD是该国角膜移植的主要适应症。 COL8A2、SLC4A11 和 TCF8 的基因变异已与 FECD 相关，但仅占病例的一小部分。最近的一项 GWAS 研究发现，跨越 Chr 18q 1 Mb 区域（包括 TCF4/FLJ45743）的 SNP 与晚发 FECD 之间存在关联，但潜在的因果变异仍然难以捉摸。借助 CTSA 和部门资金，我们建立了一个大型的基因组 DNA 存储库，该数据库来自表型良好的角膜疾病患者，其中包括 250 多例 FECD 病例。我们的研究团队最近开始应用基于遗传学和基因组学的方法来研究 FECD 的分子基础。我们已经进行了全基因组连锁分析，并开始对我们队列中的一个三代德克萨斯家族进行下一代测序，该家族具有晚发 FECD 双系遗传，作为常染色体显性性状分离。连锁分析揭示了 chr 15q（LOD 得分为 3.93）和 chr 1p（LOD 得分为 2.29）上有希望的区间。我们假设两个疾病诱发基因（每个谱系各一个）在这个独特的通婚家庭中分离，当它们共同遗传时，会导致早发性严重 FECD。我们现在建议：确定 FECD 常染色体显性遗传形式背后的因果变异。我们将对与 FECD 相关的基因组间隔应用下一代测序，确定哪些潜在的致病变异与我们大谱系中的 FECD 表型共分离，在一组不相关的 FECD 受试者中筛选潜在的致病变异，并最终评估这些新的变异。群体样本中的 FECD 突变。