Correlation of Severity of Fuchs Endothelial Corneal Dystrophy With Triplet Repeat Expansion in TCF4.

Importance: The CTG18.1 triplet repeat expansion in TCF4 has recently been found to be a common functional variant contributing significant risk to the development of Fuchs endothelial corneal dystrophy (FECD) in Eurasian populations.

Objectives: To determine the effect of the expanded CTG18.1 allele of TCF4 on FECD severity and to correlate CTG triplet repeat allele length to the severity of FECD.

Design, Setting, And Participants: In a cross-sectional analysis, we studied 139 index cases (probands and unrelated individuals) with FECD recruited from a cornea referral practice at the University of Texas Southwestern Medical Center, Dallas, from April 2010 through February 2015. The triplet repeat polymorphism CTG18.1 was genotyped using a combination of short tandem repeat analysis, triplet repeat-primed polymerase chain reaction assay, and Southern blot analysis. Severity of FECD was graded using a modified Krachmer grading system (severity scale of 0-6 based on extent of confluent guttae).

Main Outcomes And Measures: The CTG triplet repeat length of the largest allele was compared with the Krachmer grade of FECD severity, keratoplasty proportion, and central corneal thickness in the white subset.

Results: Eighty-five of 122 white index cases with FECD (69.7%) harbored the triplet repeat expansion. The mean (SD) Krachmer grade was 5.61 (0.76) in the group with the repeat expansion compared with 5.11 (1.05) in the group without the expanded repeats (P = .01). Forty-seven participants with the repeat expansion (55.3%) had undergone keratoplasty at the time of recruitment, compared with 13 (35.1%) of those without the expansion (P = .0497). There was a positive correlation of Krachmer grade to triplet repeat number (P = .002) and a nominal association of the keratoplasty proportion with triplet repeat number (P = .04). The mean (SD) central corneal thickness was 605.9 (50.5) μm in the group with the expanded repeats compared with 581.3 (50.5) μm in the group without the expansion (P = .04).

Conclusions And Relevance: The Krachmer grade of disease severity was greater in FECD cases with the CTG18.1 triplet repeat expansion in TCF4 than in those without the expansion. The CTG triplet repeat allele length was positively correlated with the Krachmer grade of severity. The TCF4 triplet repeat expansion resulted in a more severe form of FECD, with clinical and surgical therapeutic implications.