Identification of a Novel Missense Mutation Offers Initial Evidence of a Phenotype-Genotype Correlation for Macular Corneal Dystrophy

Abstract

Purpose:: To report a novel mutation in the CHST6 gene associated with an unusual clinical expression of macular corneal dystrophy (MCD), providing initial evidence of a genotype-phenotype correlation for MCD.

Methods:: Slit lamp examination and photo-documentation of an affected individual and his unaffected parents was performed. DNA was collected from each individual for PCR amplification and automated sequencing of the CHST6 coding region, as well as TFGBI exons 4 and 12. Serum antigenic keratan sulfate (AgKS) levels were measured for each individual. Quantitative real-time PCR (qPCR) was performed to differentiate between homozygous and hemizygous sequence variants.

Results:: Examination of the proband revealed bilateral, discrete, axially-distributed, gray-white deposits at the level of Bowman layer, associated with a diffuse fine corneal stromal haze. Screening of TGFBI exons 4 and 12 in the proband did not reveal any allelic variants. However, screening of CHST6 in the proband demonstrated a novel homozygous missense mutation involving a highly conserved amino acid (c.1210T>C; Leu173Pro). The pathogenicity of the Leu173Pro mutation was confirmed by an undetectable serum AgKS level in the proband, diagnostic of MCD. This mutation was present in the heterozygous state in the patient’s mother, but not in the patient’s father. qPCR confirmed that both copies of CHST6 were present in the patient , excluding the possibility that the mutation was present in the hemizygous state, and thus the most likely explanation for the origin of the second mutated allele is maternal isodisomy

Conclusions:: The novel Leu173Pro mutation in the CHST6 gene is associated with an atypical phenotype of MCD, providing initial evidence of a phenotype-genotype correlation in MCD.

Keywords: cornea: stroma and keratocytes • degenerations/dystrophies • gene/expression