Longitudinal Study of TCF4 CTG Trinucleotide Repeat Length and Disease Severity in Fuchs’ Endothelial Corneal Dystrophy

<b>Objective:</b> This was a longitudinal study of <i>TCF4</i> CTG18.1 trinucleotide repeat lengths in 17 patients (27 eyes) diagnosed with Fuchs' endothelial corneal dystrophy (FECD), and it aimed to correlate the repeat expansion status with disease severity and progression. <b>Design:</b> This was a prospective cohort study looking at FECD clinical progression and <i>TCF4</i> CTG18.1 repeat length expansion status over time. <b>Methods:</b> A total of 27 eyes from 17 patients diagnosed with FECD were recruited. Only eyes with FECD disease severity of at least Grade 4 on the modified Krachmer clinical grading scale were included; eyes that had previously undergone any form of ocular surgery prior to the first genotyping or during the duration of follow-up were excluded. CTG trinucleotide repeat genotyping was performed on peripheral blood leukocytes at two time points over an average follow-up of 10 years. Over the follow-up period, the FECD progression of each subject was examined using pachymetry, Scheimpflug imaging (Pentacam), and endothelial cell density (ECD) readings, during the baseline visit, yearly thereafter, at the time of repeat CTG18.1 genotyping, and at their latest visit. <b>Main Outcome Measures:</b> The clinical progression of FECD patients was assessed using central corneal thickness (CCT), ECD, and any keratoplasty performed. CTG repeat length was assessed twice over the entire follow-up period. <b>Results:</b> The non-expanded alleles were shown to be stable over the period of follow-up and did not develop any expanded repeats. Repeat expansion did not influence the risk of attaining Threshold Disease, although more patients in the L ≥ 40 group (CTG18.1 repeat sequence of more than or equal to 40 repeats) underwent keratoplasty. <b>Conclusions:</b> Through this study, we found that the CTG18.1 allele lengths of <40 repeats in peripheral blood leukocytes showed minimal change over a 10-year period, and none became an expanded repeat. Hence, a single CTG expansion assessment, performed at any point in a patient's lifetime, is likely a good representation of genetic risk. Clinicians may use this information to better advise patients on the risk of clinical progression and the best therapeutic strategy.