Disease expression and familial transmission of fuchs endothelial corneal dystrophy with and without CTG18.1 expansion

PURPOSE. To characterize inheritance, penetrance, and trinucleotide repeat expansion stability in Fuchs endothelial corneal dystrophy (FECD). METHODS. One thousand unrelated and related subjects with and without FECD were prospectively recruited. CTG18.1 repeat length (CTG18.1_L) was determined via short tandem repeat assay and Southern blotting of leukocyte DNA. Multivariable logistic regression and generalized estimating equation models were employed. RESULTS. There were 546 unrelated FECD cases (67.6% female; 70 ± 10 years) and 235 controls (63.8% female; 73 ± 8 years; all ≥ 50 years). CTG18.1 expansion (CTG18.1exp+) was observed in 424 (77.7%) cases and 18 (7.7%) controls (P = 2.48 × 10^–44). CTG18.1 expansion was associated with FECD severity (P = 5.62 × 10^–7). The family arm of the study included 331 members from 112 FECD-affected families; 87 families were CTG18.1exp+. Autosomal dominant inheritance with variable expression of FECD was observed, regardless of expansion status. FECD penetrance of CTG18.1 expansion increased with age, ranging from 44.4% in the youngest (19–46 years) to 86.2% in the oldest (64–91 years) age quartiles. Among 62 parent–offspring transmissions of CTG18.1exp+, 48 (77.4%) had a change in CTG18.1_L ≤ 10 repeats, and eight (12.9%) were ≥50 repeats, including five large expansions (∼1000–2000 repeats) that contracted. Among 44 offspring who did not inherit the CTG18.1exp+ allele, eight (18.2%) exhibited FECD. CONCLUSIONS. CTG18.1 expansion was highly associated with FECD but demonstrated incomplete penetrance. CTG18.1_L instability occurred in a minority of parent–offspring transmissions, with large expansions exhibiting contraction. The observation of FECD without CTG18.1 expansion among family members in CTG18.1exp+ families highlights the complexity of the relationship between the FECD phenotype and CTG18.1 expansion.