Genetic risk factors in Finnish patients with Fuchs endothelial corneal dystrophy

To study the genetic risk factors of Fuchs endothelial corneal dystrophy (FECD) in the Finnish population using hospital-based and large biobank cohorts.

We genotyped a cohort of 107 Finnish patients with FECD for the primary associated genetic risk factor, the TCF4 (CTG)_>50 expansion, and studied their clinical phenotype. For 18 TCF4 (CTG)_≤50 patients, we performed exome-based candidate gene analysis. We also utilised FinnGen biobank-based samples to perform a genome-wide association study (GWAS).

In the cohort, 83% (89/107) carried one allele with the TCF4 (CTG)_>50 expansion. Those without the expansion were younger at enrolment and at the time of first keratoplasty (p = 0.011, p = 0.044, respectively). A genome-wide association study of 892 patients and 497 827 controls identified a lead variant rs11659764 (AF = 2.3%, OR = 8.2, p = 2.9 × 10^-195). Genotyping showed that 89% of TCF4 (CTG)_>50 carriers had the associated TA genotype rather than the TT genotype, whereas none of the TCF4 (CTG)_≤50 carriers did. Exome-based analyses of the 18 TCF4 (CTG)_≤50 carriers identified a candidate gene variant, AGBL1 c.901 + 2 T>G in one patient.

In Finland, the TCF4 (CTG)_>50 expansion is a significant risk factor for FECD. A nearby single-nucleotide polymorphism (SNP) was found to perform well as a surrogate for genotyping. However, not all patients carried the expanded repeat, and a variant in a previously associated gene was observed in a single patient. Further research is needed to investigate the origins of FECD in individuals without the repeat expansion.