Genetics and Genomics of Fuchs Endothelial Corneal Dystrophy

描述（由申请人提供）：Fuchs的内皮性角膜营养不良（FECD）影响了近4%的40岁以上的美国人口，并可能导致角膜水肿，视力下降和疼痛。FECD是国内角膜移植的主要指征。COL8A2、SLC4A11和TCF8的遗传变异与FECD有关，但只占病例的一小部分。最近的一项GWAS研究发现，包括TCF4/FLJ45743在内的跨越1mb chr 18q区域的snp与晚发性FECD之间存在关联，但潜在的因果变异仍然难以捉摸。在CTSA和部门的资助下，我们已经建立了一个大型的基因组DNA库，这些基因组DNA来自表型良好的角膜疾病患者，包括250多例FECD病例。我们的研究小组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。我们进行了全基因组连锁分析，并对来自我们队列的德克萨斯三代家族进行了下一代测序，该家族具有双系遗传的迟发性FECD，分离为常染色体显性特征。连锁分析显示，chr 15q （LOD评分为3.93）和chr 1p （LOD评分为2.29）具有较好的区间。我们假设两个疾病易感基因，每个谱系一个，在这个独特的，通婚的家庭中分离，当它们共同遗传时导致早发性，严重的FECD。我们现在建议：确定常染色体显性形式的FECD的因果变异。我们将对与FECD相关的基因组间隔进行下一代测序，确定在我们的大谱系中，哪些潜在的致病变异与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，并最终在群体样本中评估这些新的FECD突变。

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.