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Importance: Understanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) could contribute to developing gene-targeted therapies. Objective: To investigate associations between demographic data and age at first keratoplasty in a genetically refined FECD cohort. Design, Setting, and Participants: This retrospective cohort study recruited 894 individuals with FECD at Moorfields Eye Hospital (London) and General University Hospital (Prague) from September 2009 to July 2023. Ancestry was inferred from genome-wide single nucleotide polymorphism array data. CTG18.1 status was determined by short tandem repeat and/or triplet-primed polymerase chain reaction. One or more expanded alleles (≥50 repeats) were classified as expansion-positive (Exp+). Expansion-negative (Exp-) cases were exome sequenced. Main Outcomes and Measures: Association between variants in FECD-associated genes, demographic data, and age at first keratoplasty. Results: Within the total cohort (n = 894), 77.3% of patients were Exp+. Most European (668 of 829 80.6%) and South Asian (14 of 22 63.6%) patients were Exp+. The percentage of female patients was higher (151 74.4%) in the Exp- cohort compared to the Exp+ cohort (395 57.2%; difference, 17.2%; 95% CI, 10.1%-24.3%; P 15) were only identified in FECD-associated genes in 13 Exp- individuals (10.1%). Conclusions and Relevance: In this multicenter cohort study among individuals with FECD, CTG18.1 expansions were present in most European and South Asian patients, while CTG18.1 repeat length and zygosity status were associated with modifications in disease severity and penetrance. Known disease-associated genes accounted for only a minority of Exp- cases, with unknown risk factors associated with disease in the rest of this subgroup. These data may have implications for future FECD gene-targeted therapy development.
Liu et al. (Thu,) studied this question.