Integrated Monogenic And Polygenic Risk Predicts Disease Progression In Fuchs Endothelial Corneal Dystrophy
Published 2026 - 44th Congress of the ESCRS
Reference: FP14.14 | Type: Free paper | DOI: 10.82333/c2mq-2w25
Authors: Siyin Liu* 1 , Ms Anita Szabo 1 , Christina Zarouchlioti 1 , Nihar Bhattacharyya 1 , Quang Nguyen 1 , Marcos Abreu Costa 1 , Robert Luben 1 , Lubica Dudakova 2 , Pavlina Skalicka 2 , Martin Horak 3 , Anthony Khawaja 1 , Nikolas Pontikos 1 , Kirithika Muthusamy 4 , Stephen Tuft 1 , Petra Liskova 2 , Alice Davidson 1
1UCL Institute of Ophthalmology,London,United Kingdom, 2Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague,Prague,Czech Republic, 3Department of Ophthalmology, University Hospital Kralovske Vinohrady and 3rd Faculty of Medicine, Charles University,Prague,Czech Republic, 4Moorfields Eye Hospital,London,United Kingdom
Purpose
Fuchs endothelial corneal dystrophy (FECD) is a leading indication for endothelial keratoplasty (EK), yet its clinical course is highly variable. While EK remains the definitive treatment, several disease-modifying and preventive therapies are currently under development, increasing the need for tools capable of predicting which individuals are most likely to progress to surgery. Genetic factors play a central role in FECD. Although a CTG18.1 repeat expansion is the primary risk factor, it does not fully explain the heterogeneity observed in disease progression. This study aims to evaluate whether CTG18.1 expansion status, in combination with a FECD-specific polygenic risk score (PRS), enables genomic prediction of progression to EK.
Setting
Multicentre study conducted at two tertiary referral corneal centres (Moorfields Eye Hospital, London, UK, and General University Hospital, Prague, Czech Republic).
Methods
We retrospectively included 589 individuals with clinically confirmed FECD from the above centres. We recruited a validation cohort of 185 individuals using identical protocols. Only participants of genetically confirmed European ancestry were included. CTG18.1 status was determined by polymerase chain reaction-based fragment analysis, with ≥50 CTG repeats on either allele defined as expansion-positive (Exp+). An FECD PRS was derived from the largest publicly available FECD genome-wide association study. Outcome measures were the association of Exp+ status and PRS with EK risk, adjusting for sex and ancestry principal components (PCs).
Results
In the primary cohort, 456 (77%) were Exp+, and 347 (59%) had a keratoplasty. Being Exp+ was associated with earlier progression to EK (HR, 2.30; 95%CI, 1.62–3.26; P < .001). The PRS improved model discrimination (C-index, wth PRS 0.614 vs without PRS 0.602; likelihood-ratio χ²=6.04; P = .014), yielded higher AUC(t) values (P = .03). A higher PRS was associated with earlier progression to EK (HR per 1-SD, 1.16; 95%CI, 1.03–1.30; P = .015). Individuals in the highest PRS quartile had a greater cumulative EK incidence at 60, 70, and 80 years of age compared with those in the lowest quartile (9.6%, 16.4%, 10.2% respectively; all P < .05). Findings were replicated in the validation cohort (HR per 1-SD, 1.42; 95%CI, 1.15–1.75; P = .001).
Conclusions
Exp+ status is a predictor of clinical progression of FECD to EK, and polygenic burden provides additional prognostic information. As genotyping becomes increasingly accessible and disease-modifying therapies emerge, integrating monogenic and polygenic risk enables genomic prediction of FECD progression. This approach supports clinical genomic risk stratification to inform individualised monitoring and to stratify trial enrolment for individuals at the highest risk of progression.