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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Mckie, George Ann
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Saade, Joanna S; Xing, Chao; Gong, Xin et al. (2018) Instability of TCF4 Triplet Repeat Expansion With Parent-Child Transmission in Fuchs' Endothelial Corneal Dystrophy. Invest Ophthalmol Vis Sci 59:4065-4070
Hu, Jiaxin; Rong, Ziye; Gong, Xin et al. (2018) Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy. Hum Mol Genet 27:1015-1026
Mootha, V Vinod; Hansen, Brock; Rong, Ziye et al. (2017) Fuchs' Endothelial Corneal Dystrophy and RNA Foci in Patients With Myotonic Dystrophy. Invest Ophthalmol Vis Sci 58:4579-4585
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Mootha, V Vinod; Hussain, Imran; Cunnusamy, Khrishen et al. (2015) TCF4 Triplet Repeat Expansion and Nuclear RNA Foci in Fuchs' Endothelial Corneal Dystrophy. Invest Ophthalmol Vis Sci 56:2003-11
Soliman, Ahmed Z; Xing, Chao; Radwan, Salma H et al. (2015) Correlation of Severity of Fuchs Endothelial Corneal Dystrophy With Triplet Repeat Expansion in TCF4. JAMA Ophthalmol 133:1386-91
Mootha, V Vinod; Gong, Xin; Ku, Hung-Chih et al. (2014) Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs' endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 55:33-42
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