Corneal Dystrophy, Fuchs Endothelial, 6

A number sign (#) is used with this entry because of evidence that Fuchs endothelial corneal dystrophy-6 (FECD6) is caused by heterozygous mutation in the ZEB1 gene (189909) on chromosome 10p11.

Fuchs endothelial corneal dystrophy (FECD) is the most common genetic disorder of the corneal endothelium. Late-onset FECD is marked by thickening of Descemets membrane and excrescences, called guttae, that typically appear in the fourth or fifth decade. Disease progression results in decreased visual acuity as a result of increasing corneal edema, and end-stage disease is marked by painful epithelial bullae (summary by Riazuddin et al., 2013).

For a discussion of genetic heterogeneity of Fuchs endothelial corneal dystrophy, see FECD1 (136800).

Riazuddin et al. (2010) analyzed the ZEB1 gene in 192 unrelated patients with adult-onset Fuchs endothelial corneal dystrophy (FECD) and identified 4 different heterozygous missense mutations in 4 patients, respectively, that were not found in 560 unrelated, ethnically matched controls. Sequencing the ZEB1 gene in an independent cohort of 192 FECD probands, Riazuddin et al. (2010) identified 3 missense mutations in 3 patients, respectively, 2 of which had been identified in the earlier cohort, N78T (189909.0003) and Q840P (189909.0004). One of the probands with the Q840P mutation came from a large pedigree in which none of 7 unaffected members carried 840P, but the mutation was present in only 7 of 12 affected individuals. A genomewide scan in the pedigree identified an additional locus for late-onset FECD on chromosome 9p24.1-p22.1 (see FECD7, 613271) in 10 of the 12 affected individuals. The 3 oldest of 5 individuals carrying both the Q840P mutation and the disease-transmitting haplotype on 9p had a severe FECD phenotype and all 3 had undergone corneal transplantation; Riazuddin et al. (2010) suggested that mutations in either ZEB1 or at the 9p locus are sufficient for disease, and that genetic interaction between the 2 loci can lead to a more severe form of the disease.

By direct sequencing of the ZEB1 gene in 82 patients from northern India with late-onset Fuchs endothelial corneal dystrophy, Gupta et al. (2015) identified a novel splice site mutation (IVS2+276C-T) in 11 patients (14%) as well as 2 novel missense mutations and 1 novel nonsense mutation in 1 patient each. One patient was found to have a previously identified missense mutation (189909.0004).