Fuchs Endothelial Corneal Dystrophy: Genetic, Demographic And Phenotypic Correlations
Published 2024 - 42nd Congress of the ESCRS
Reference: FP22.01 | Type: Free paper | DOI: 10.82333/b7jz-ty95
Authors: Siyin Liu* 1 , Amanda Sadan 2 , Anita Szabo 2 , Nihar Bhattacharyya 2 , Christina Zarouchlioti 2 , Marcos Costa 2 , Lubica Dudakova 3 , Marc Ciosi 4 , Pavlina Skalicka 3 , Mark Wilkins 5 , Bruce Allan 5 , Alison Hardcastle 2 , Nikolas Pontikos 2 , Catey Bunce 6 , Darren Monckton 4 , Kirithika Muthusamy 5 , Petra Likova 7 , Stephen Tuft 1 , Alice Davidson 2
1UCL Institute of Ophthalmology,London,United Kingdom;Moorfields Eye Hospital,London,United Kingdom, 2UCL Institute of Ophthalmology,London,United Kingdom, 3Charles University and General University Hospital in Prague,Prague,Czech Republic, 4University of Glasgow,Glasgow,United Kingdom, 5Moorfields Eye Hospital,London,United Kingdom, 6National Institute for Health and Care Research (NIHR) BRC at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research,London,United Kingdom, 7Department of Ophthalmology,Charles University and General University Hospital in Prague,Prague,Czech Republic
Purpose
Fuchs endothelial corneal dystrophy (FECD) is a degenerative corneal disease commonly associated with an intronic CTG repeat expansion (termed CTG18.1) in TCF4. In a minority of FECD cases, rare disease-associated variants in other genes have also been reported. Here we present findings from a large multi-centre extensively genotyped and sequenced FECD cohort to explore correlations between genotype, ethnicity, sex, and age of first corneal transplantation surgery (a surrogate metric for disease severity).
Setting
Moorfields Eye Hospital, London, United Kingdom; General University Hospital, Prague, Czech Republic
Methods
This study received approvals from Moorfields Eye Hospital (MEH) and the General University Hospital (GUH) in the Czech Republic. Genomic DNA was collected from participants recruited at MEH (n=569) and GUH (n=353). FECD diagnosis was ascertained by cornea fellowship-trained ophthalmologists. We determined the ethnicity from genome-wide SNP array data using FRAPOSA. CTG18.1 repeat length was determined by capillary electrophoresis of CTG18.1 PCR. Cases with one or more expanded alleles (≥50 CTG repeats) were classified as expanded (Exp+). Biallelic unexpanded (Exp−) cases underwent exome/genome sequencing to explore the alternative FECD-associated genes COL8A2, SLC4A11, ZEB1, AGBL1, LOXHD1.
Results
A CTG18.1 expansion was detected in 672/836 (80.4%) of European cases, conferring >77-fold increased odds for FECD (OR=77.3, P<0.0001). In the Exp+ group, the CTG18.1 length was inversely correlated with age-at-first keratoplasty (r=-0.0859, P=0.011), but independent of sex and ethnicity. Females were enriched in the total cohort (58.25%), with a more marked difference in the Exp-group (76.1%). Biallelic Exp+ cases in European patients were enriched compared to ethnicity-matched controls (Chi-square=218.62, P<0.00001). Furthermore, biallelic Exp+ cases had surgery at a younger mean age (66 vs 69 years, P=0.02). Candidate pathogenic variants (MAF<0.01; CADD >10) in FECD-associated genes were identified in 6.4% of Exp- cases.
Conclusions
We demonstrated that CTG18.1 repeat length is a modifier of FECD severity. The female preponderance in FECD is mainly driven by CTG18.1 independent factors. The notable enrichment of homozygous vs heterozygous Exp+ allele status in the FECD cohort, coupled with the younger age of needing corneal transplantation surgery in the biallelic Exp+ cases, indicates that CTG18.1 allelic dosage elevates both disease penetrance and severity. Interrogation of FECD-associated genes in the Exp− group suggests additional important genetic causes and modifiers remain to be discovered.