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

Area of Science:

• Ophthalmology
• Genetics
• Corneal Diseases

Background:

• Fuchs endothelial corneal dystrophy (FECD) pathogenesis is not fully understood, hindering targeted therapies.
• Identifying genetic and demographic associations can refine understanding of FECD.
• Previous studies suggest genetic factors play a role in FECD development and progression.

Purpose of the Study:

• To investigate associations between demographic data and age at first keratoplasty in a genetically refined FECD cohort.
• To determine the prevalence of CTG18.1 expansions in different ethnic groups within the FECD cohort.
• To explore the relationship between CTG18.1 repeat length, zygosity, and disease severity.

Main Methods:

• Retrospective cohort study of 894 individuals with FECD from London and Prague.
• Genome-wide SNP array data for ancestry inference.
• Short tandem repeat and triplet-primed PCR for CTG18.1 repeat analysis; exome sequencing for expansion-negative cases.

Main Results:

• 77.3% of patients were expansion-positive (Exp+); most European and South Asian patients were Exp+.
• Expansion-negative (Exp-) patients were younger and had a higher percentage of females compared to Exp+ patients.
• CTG18.1 repeat length was inversely correlated with age at first keratoplasty; biallelic expansions were associated with increased disease penetrance.

Conclusions:

• CTG18.1 expansions are prevalent in FECD, with repeat length and zygosity modifying disease severity and penetrance.
• Known disease genes explain only a small fraction of expansion-negative FECD cases, indicating other risk factors.
• These findings have implications for developing gene-targeted therapies for FECD.