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

• 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
• 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

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）：Fuchs角膜内皮营养不良（FECD）影响近4%的40岁以上美国人口，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。COL 8A 2、SLC 4A 11和TCF 8的遗传变异与FECD有关，但仅占一小部分病例。最近的GWAS研究发现跨越chr 18 q的1 Mb区域的SNP（包括TCF 4/FLJ 45743）与晚发型FECD之间存在关联，但潜在的因果变异仍然难以捉摸。在CTSA和部门资金的支持下，我们已经建立了一个大型的基因组DNA库，这些基因组DNA来自角膜疾病的良好表型患者，包括超过250例FECD病例。我们的研究团队最近开始应用遗传学和基因组学为基础的方法来研究FECD的分子基础。我们已经进行了全基因组连锁分析，并启动了下一代测序的三代，得克萨斯州家庭从我们的队列与双线性遗传的晚发型FECD分离作为常染色体显性性状。连锁分析揭示了chr 15 q（LOD得分为3.93）和chr 1 p（LOD得分为2.29）上有希望的区间。我们假设，两个疾病易感基因，一个为每一个血统，分离在这个独特的，通婚的家庭，当他们共同继承的原因早发性，严重的FECD。我们现在建议：确定常染色体显性形式FECD的致病变异。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，在一组无关的FECD受试者中筛选潜在的致病变异，并最终在人群样本中评估这些新的FECD突变。