Background: Fuchs endothelial corneal dystrophy (FECD) is one of the most common indications for corneal transplants. FECD is associated with various genes, e.g., COL8A2 or SLC4A11. Among other things a TGC trinucleotide repeat expansion in intron 2 of the TCF4 gene has been characterised in FECD patients and the allele G of the polymorphism rs613872 in intron 3 of the same gene has been associated with this disease. Our intention was to investigate sources in molecular genetics in the German population and to calculate the odds ratio as indicator for the chance to suffer from FECD.
Patients and method: 42 unrelated FECD patients, 93 unrelated controls and 17 members of a family with four FECD affected patients have been examined for the described changes in the TCF4 gene. After amplification of the TGC repeats with specific PCR the obtained products were electrophoretically divided according to their length and investigated with a triplet-primed PCR. Polymorphism rs613872 was analysed by Sanger sequencing. All coding exons of the adjacent genes TCF4 and LOXHD1 were sequenced in six patients in order to exclude potential disease associated mutations.
Results: 33 out of 42 unrelated analysed patients (79 %) had a TGC repeat expansion (> 50 TGC repeats) in intron 2 of the TCF4 gene. Out of 93 controls only 10 (10.8 %) showed an expanded allele. In the family the four diseased and four healthy subjects of the 17 examined family members had an expanded allele. Analysis of the polymorphism rs613872 in intron 3 of the TCF4 gene exhibited 33 of 42 unrelated patients (78.6 %) heterozygous TG and four homozygous GG (9.5 %). 65 of 93 controls were homozygous TT (69.9 %) and only 21 heterozygous TG (22.6 %). Of the 17 family members nine had the genotype TG, including the four FECD patients. Sequencing of the coding exons of TCF4 and LOXHD1 in six patients showed no variant described with FECD. The odds ratio as indicator for being affected by FECD in our data for the expanded TGC allele is 30. The chance of being affected is thus 30 times higher when someone exhibits the expanded allele. For a carrier of the risk allele G the chance is 16.5 times higher.
Discussion: An expanded TGC allele with more than 50 TGC repeats in intron 2 and the described risk allele G of the polymorphism rs613872 in intron 3 of the TCF4 gene appear as an association to FECD. The chance to be affected by FECD is up to 30 times higher. With molecular genetics also donors with clinically unknown FECD may be detected.
Georg Thieme Verlag KG Stuttgart · New York.