Genetic and Demographic Determinants of Fuchs Endothelial Corneal Dystrophy Risk and Severity

Abstract

Importance: Understanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) is essential for developing gene-targeted therapies. Objective: To investigate associations between demographic data and age at first keratoplasty in a large 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). Ancestry was inferred from genome-wide SNP array data. CTG18.1 status was determined by short tandem repeat and/or triplet-primed PCR. One or more expanded alleles (>49 repeats) were classified as expansion-positive (Exp+). Expansion-negative (Exp-) cases were whole exome sequenced. Main Outcome(s) and Measure(s): Association between variants in FECD-associated genes, demographic data and age at first keratoplasty. Results: Within the total cohort (n=894), 77.3% were Exp+. The majority of European (668/829, 80.6%) and South Asian (14/22, 63.6%) patients were Exp+, whereas the majority of those with African (30/37, 81.1%), East Asian (2/3,66.7%), and American Admixture (2/3, 66.7%) ancestry were Exp-. The percentage of females was significantly higher (151, 74.4%) in the Exp- cohort compared to the Exp+ (395, 57.2%; P<.001). The median (IQR) age at first keratoplasty of the Exp+ patients (68.2 [63.2 to 73.6] years) was older than the Exp- patients (61.3 [52.6 to 70.4] years; P<.001). The CTG18.1 repeat length of the largest expanded allele within the Exp+ group was inversely correlated with the age at first keratoplasty (r = -0.087 [95% CI: -0.162 to -0.012], P=.02). The ratio of biallelic to monoallelic expanded alleles was higher in the FECD cohort compared to an unaffected control group (P<.001), indicating that two Exp+ alleles increase disease penetrance compared to one expansion. We only identified potentially pathogenic variants (MAF <0.01; CADD >15) in FECD-associated genes in 13 (10.1%) Exp- individuals. Conclusions and Relevance: CTG18.1 expansions are present in most European and South Asian patients with FECD. Repeat length and zygosity status of CTG18.1 modify disease severity and penetrance. Known disease-associated genes account for only a minority of Exp- cases, with unknown risk factors determining disease in the rest of this subgroup. These data have important implications for the development of future FECD gene-targeted therapies.