Update on the genetics of corneal endothelial dystrophies

Abstract

Corneal endothelial dystrophies are a heterogeneous group of diseases with different modes of inheritance and genetic basis for each dystrophy. The genes associated with these diseases encode transcription factors, structural components of the stroma and Descemet membrane, cell transport proteins, and others. Congenital hereditary endothelial dystrophy (CHED) is associated with mutations in two genes, OVOL2 and SLC4A11, for dominant and recessive forms of CHED, respectively. Mutations in three genes are known to cause posterior polymorphous corneal dystrophy (PPCD). They are OVOL2 (PPCD1), ZEB1 (PPCD3), and GRHL1 (PPCD4). The PPCD2 locus involving the collagen gene COL8A2 on chromosome 1 is disputed due to insufficient evidence. Mutations in the COL8A2 gene are associated with early-onset Fuchs' endothelial corneal dystrophy (FECD). Several genes have been associated with the more common, late-onset FECD. Alterations in each of these genes occur in a fraction of patients, and the most prevalent genetic alteration in FECD patients across the world is a triplet repeat expansion in the TCF4 gene. Knowledge of the genetics of corneal endothelial dystrophies has considerably advanced within the last decade and has contributed to better diagnosis of these dystrophies as well as opened up the possibility of novel therapeutic approaches based on the molecular mechanisms involved. The functions of genes identified to date provide insights into the pathogenic mechanisms involved in each disorder.

Keywords: CHED; FECD; PPCD; corneal endothelium; endothelial dystrophy; genetics; genotype; phenotype.

Figure 1

Corneal phenotypes of patients with corneal endothelial dystrophy (CED) Representative slit-lamp photographs (slit view) of the right (a) and the left (b) eyes of two different patients with CHED, showing diffuse corneal haze and thick cornea limbus to limbus throughout. Image B shows secondary spheroidal degeneration due to longstanding corneal edema; (c) slit-lamp photograph of a patient with FECD showing focal corneal edema; (d) specular microscopy of the right and left eyes of a patient with FECD showing reduced endothelial cell density and characteristic dropout areas suggestive of guttae; (e) slit-lamp photograph of a patient who has PPCD showing edema and secondary epithelial changes; (f) the optical coherence tomography of the same patient (as in e), showing deposits at the level of Descemet-endothelial complex with epithelial bullae and scarring