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

Abstract

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 < .001). The median (IQR) age at first keratoplasty of the Exp + patients (68.2 years [63.2-73.6]) was older than the Exp- patients (61.3 years [52.6-70.4]; difference, 6.5 years; 95% CI, 3.4-9.7; 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 (β, -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 (1:14) compared to an unaffected control group (1:94; P < .001), indicating that 2 Exp+ alleles were associated with increased disease penetrance compared with 1 expansion. Potentially pathogenic variants (minor allele frequency, <0.01; combined annotation dependent depletion, >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.

eFigure 1. Overview of the study workflow.

FECD, Fuchs endothelial corneal dystrophy; STR, short tandem repeat; TP, triplet repeat-primed; PCR, polymerase chain reaction; Exp+, CTG18.1 expansion positive allele defined as ≥50 CTG repeats; Exp-, CTG18.1 expansion positive allele defined as <50 CTG repeats. ^aRecruitment may have occurred prior, concurrently or after keratoplasty; Not all participants had undergone keratoplasty. ^bTo control for non-genetic factors that could distort the genotype-phenotype relationship, only cases of endothelial keratoplasty were included, as thresholds for surgical intervention varied greatly in the previous era of penetrating keratoplasty compared to contemporary practices. Cases with prior intraocular surgeries (e.g., cataract extraction), that could potentially accelerate corneal endothelial cell loss, were also excluded.

eFigure 2. CTG18.1 repeat length distributions vary with ancestry within a large FECD patient cohort.

Frequency histograms comparing the allelic distributions of CTG18.1 repeat length within (A) European (EUR; 829), (B) South Asian (SAS; 22) and (C) African (AFR; 37) ancestry groups. The percentage of European patients with a CTG18.1 expansion (80.7%) was greater than that of non-Europeans (35.4%). A larger proportion of South Asian patients also harbored at least one expanded CTG18.1 allele (63%), compared to patients of African ancestry (18%). Abbreviation: CTG18.1 expansion positive allele defined as ≥50 CTG repeats; Exp-, CTG18.1 expansion negative allele defined as <50 CTG repeats.

Figure 1. CTG18.1 repeat length is associated with FECD and its distribution varied with sex within a large FECD patient cohort.

(A) Frequency histograms comparing the relative distribution of CTG18.1 repeat length within the total cohort (894). (B) Bar chart of the sex ratio across the total cohort (1.57 female:male, black bar) and subgroups stratified by CTG18.1 status: Exp- group (2.90 female:male, purple bar), Exp+ group (1.33 female:male, green bar). Abbreviation: CTG18.1 expansion positive allele defined as ≥50 CTG repeats; Exp-, CTG18.1 expansion negative allele defined as <50 CTG repeats.

Figure 2. Age at first keratoplasty varies depending on CTG18.1 expansion status, repeat length and zygosity.

(A) Age at first keratoplasty (median [IQR]) was more heterogeneous in the expansion-negative (Exp-) group (61.3y [52.6–70.4]) compared to the expansion-positive (Exp+) group (68.2y [63.2–73.6]), including both mono- and bi-allelic Exp+ cases (P<.001). (B)The median age at first keratoplasty in FECD patients with biallelic Exp+ (67.7y [62.4–72.4]) was not different (P<.69) than in monoallelic Exp+ patients (68.2y [63.3–73.7]).(C) The scatter plot demonstrates a negative correlation between the CTG18.1 repeat length and age at first keratoplasty in Exp+ patients (β = -0.087 [95% CI: -0.162 to -0.012], P = .02). Green dots, monoallelic Exp+ cases; green open circles, biallelic Exp+ cases.