Expansion of CTG18.1 trinucleotide repeat in TCF4 is a potent driver of fuchs’ corneal dystrophy

PURPOSE. To analyze the expansion of CTG18.1 allele associated with Fuchs’ corneal dystrophy (FCD) in our large cohort of late-onset FCD cases. METHODS. CTG repeats within the CTG18.1 allele were estimated by short tandem repeat (STR) and triplet primed PCR (TP-PCR) assays in our large cohort of 574 late-onset FCD cases and 354 controls and large multigeneration familial cases. The age versus severity relationships were analyzed in FCD genotypes, namely, nonexpanded (N/N), monoallelic expansion (N/X), and biallelic expansion (X/X) with N ≤ 40 CTG monomers. The threshold for causality conferred by an expansion of CTG18.1 was identified by excluding the population of FCD cases who harbored an allele length equivalent to the maximum CTG monomers observed in the controls. RESULTS. The expanded CTG18.1 for (CTG)_n>40showed a strong association (P= 1.56 X 10^-82) with FCD. Importantly, we delineated the threshold of expansion to 103 CTG repeats above which the allele confers causality in 17.8% of FCD cases. Regression analyses demonstrated a significant correlation between disease severity and age in individuals who harbor either a monoallelic expansion or a biallelic expansion at (CTG)_n>40. These analyses helped predict FCD in two previously unaffected individuals based on their CTG18.1 expansion genotype. CONCLUSIONS. A monoallelic expansion of CTG18.1 contributes to increased disease severity and is causal at (CTG)_n>103, whereas a biallelic expansion is sufficient to be causal for FCD at (CTG)_n>40. This study highlights the largest contributory causal allele for FCD.