Genetic and Demographic Determinants of Fuchs Endothelial Corneal Dystrophy Risk and Severity
Authors: Liu Siyin , Sadan Amanda N. , Bhattacharyya Nihar , Zarouchlioti Christina , Szabo Anita , Costa Marcos Abreu , Hafford-Tear Nathaniel J. , Kladny Anne-Marie S. , Dudakova Lubica , Ciosi Marc , Moghul Ismail , Wilkins Mark R. , Allan Bruce , Skalicka Pavlina , Hardcastle Alison J. , Pontikos Nikolas , Bunce Catey , Monckton Darren G. , Muthusamy Kirithika , Liskova Petra , Tuft Stephen J. , Davidson Alice E. 
Published: October 2024

AbstractImportanceUnderstanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) is essential for developing gene-targeted therapies.ObjectiveTo investigate associations between demographic data and age at first keratoplasty in a large genetically refined FECD cohort.Design, Setting, and ParticipantsThis 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 (≥50 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.ResultsWithin 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 [63.2–73.6] years) was older than the Exp-patients (61.3 [52.6–70.4] 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 RelevanceCTG18.1 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.Key PointsQuestionHow do demographics and genetic risk factors determine FECD disease risk and severity?FindingsThis multi-center FECD cohort (n=894) study revealsTCF4repeat expansions (CTG18.1) underlie disease in 77.3% of total cases, with longer repeats and biallelic expansion correlating with earlier keratoplasty and increased penetrance, respectively.Female overrepresentation is driven by cases without CTG18.1 expansions, where missing heritability remains high.MeaningDemographic factors and molecular diagnosis, including CTG18.1 repeat length and expanded allele dosage, are clinically relevant metrics that should inform future therapeutic strategies and clinical trial design.