Abstract
Fuchs endothelial corneal dystrophy (FECD) is a common, familial disease of the corneal endothelium and is the leading indication for corneal transplantation. Variation in the transcription factor 4 (TCF4) gene has been identified as a major contributor to the disease. We tested for an association between an intronic TGC trinucleotide repeat in TCF4 and FECD by determining repeat length in 66 affected participants with severe FECD and 63 participants with normal corneas in a 3-stage discovery/replication/validation study. PCR primers flanking the TGC repeat were used to amplify leukocyte-derived genomic DNA. Repeat length was determined by direct sequencing, short tandem repeat (STR) assay and Southern blotting. Genomic Southern blots were used to evaluate samples for which only a single allele was identified by STR analysis. Compiling data for 3 arms of the study, a TGC repeat length >50 was present in 79% of FECD cases and in 3% of normal controls cases (p<0.001). Among cases, 52 of 66 (79%) subjects had >50 TGC repeats, 13 (20%) had <40 repeats and 1 (2%) had an intermediate repeat length. In comparison, only 2 of 63 (3%) unaffected control subjects had >50 repeats, 60 (95%) had <40 repeats and 1 (2%) had an intermediate repeat length. The repeat length was greater than 1000 in 4 FECD cases. The sensitivity and specificity of >50 TGC repeats identifying FECD in this patient cohort was 79% and 96%, respectively Expanded TGC repeat was more specific for FECD cases than the previously identified, highly associated, single nucleotide polymorphism, rs613872 (specificity = 79%). The TGC trinucleotide repeat expansion in TCF4 is strongly associated with FECD, and a repeat length >50 is highly specific for the disease This association suggests that trinucleotide expansion may play a pathogenic role in the majority of FECD cases and is a predictor of disease risk.
Highlights
Fuchs corneal dystrophy (FECD) is a common, progressive, late onset disease affecting the endothelial cell monolayer on the internal surface of the cornea
Direct DNA sequencing of the PCR products confirmed that the increased size of the products produced from the DNA of patients with Fuchs endothelial corneal dystrophy (FECD) was due to expansions of the TGC trinucleotide repeat
Our data demonstrate a strong association between expansion of a non-coding trinucleotide repeat in the transcription factor 4 (TCF4) gene and FECD
Summary
Fuchs corneal dystrophy (FECD) is a common, progressive, late onset disease affecting the endothelial cell monolayer on the internal surface of the cornea. Mutations in several genes, including LOXHD1 [8] and SLC4A11 [9,10] and TCF8 [11] have been associated with a small proportion of FECD cases, and variation in the COL8A2 gene is responsible for a rare early-onset Fuchs-like disease. Breschel et al [14] (1997) previously described an unstable trinucleotide repeat within the third intron of TCF4 They noted expanded, unstable alleles in approximately 3% of the population that they studied. Our work suggests the likelihood that FECD is a trinucleotide repeat expansion disorder in the majority of cases
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