Background The corneal dystrophies are a group of inherited disorders that are typically bilateral, symmetric, and slowly progressive, unaffected by environmental or systemic factors. Four types of corneal endothelial dystrophies, primarily affecting corneal endothelial cells, have been described. Here, we present a novel corneal endothelial dystrophy characterized by peripheral posterior corneal macular opacities and endothelial dysfunction without stromal opacity. Symptomatic individuals develop corneal edema, with successful restoration of vision achieved through endothelial keratoplasty (EK).

Methods Thirty-five individuals from seven families, including 13 affected individuals exhibiting peripheral posterior corneal macular opacities, endothelial guttae and corneal edema, and 22 unaffected family members were included in this retrospective case series. Whole-exome sequencing was performed in three families and Sanger sequencing of CHST6 was performed in all individuals. Histological examination of Descemet membrane (DM) excised at the time of EK was performed for three probands. Serum keratan sulfate (KS) levels were measured in members of six families. Functional analysis of identified mutations was performed using CHST6 promoter containing CHST6 expression vector in human keratocytes (HK) and corneal endothelial cells (HCEnC).

Results None of the affected individuals demonstrated a single corneal stromal deposit, either on slit lamp exam or on anterior segment OCT imaging, excluding the diagnosis of Macular Corneal Dystrophy. Five affected individuals from four families underwent EK, with resolution of the corneal edema. CHST6 sequencing revealed a non-coding promoter mutation (c.-690G>C) in all families, either in homozygous state in five affected individuals from three families or in a compound heterozygous state with a coding mutation (p.R211Q, p.Y268C or p.P280L) in seven affected individuals from the other four families. In silico analysis predicted c.-690G>C to be a regulatory variant, located at the RNA polymerase II binding site. Functional analysis demonstrated that c.-690G>C leads to increased KS sulfation in HCEnC with no change of KS sulfation in HK, while coding mutations p.P280L and p.Y268C resulted in decreased KS sulfation in HK and no change of KS sulfation in HCEnC. DM staining revealed elevated levels of sulfated and non-sulfated KS in DM and endothelium in affected probands. Minimum changes in serum sulfated KS levels were observed in affected individuals.

Conclusion A novel corneal endothelial dystrophy characterized by peripheral posterior corneal macular opacities and endothelial dysfunction without stromal opacities is associated with promoter mutation c.-690G>C in CHST6 gene. We suggest the name Peripheral Macular Endothelial Dystrophy (PMED) to describe this dystrophy that can be and should be managed with EK.