Date Published: February 15, 2019
Publisher: Impact Journals
Author(s): Jing Zhang, Dan Wu, Yue Li, Yidan Fan, Yiqin Dai, Jianjiang Xu.
Macular corneal dystrophy (MCD) is an autosomal recessive disease featured by bilateral progressive stromal clouding and loss of vision, consequently necessitating corneal transplantation. Variants in CHST6 gene have been recognized as the most critical genetic components in MCD. Although many CHST6 variants have been described until now, the detailed mechanisms underlying MCD are still far from understood. In this study, we integrated all the reported CHST6 variants described in 408 MCD cases, and performed a comprehensive evaluation to better illustrate the causality of these variants. The results showed that majority of these variants (165 out of 181) could be classified as pathogenic or likely pathogenic. Interestingly, we also identified several disease causal variants with ethnic specificity. In addition, the results underscored the strong correlation between mutant frequency and residue conservation in the general population (Spearman’s correlation coefficient = -0.311, P = 1.20E-05), thus providing potential candidate targets for further genetic manipulation. The current study highlighted the demand of further functional investigations to evaluate the causality of CHST6 variants, so as to promote earlier accurate diagnosis of MCD and future development of potential targets for genetic therapy.
Macular corneal dystrophy (MCD; OMIM 217800) is an autosomal recessive disease featured by bilateral progressive stromal clouding and loss of vision, finally necessitating corneal transplantation [1, 2]. Cases of MCD have been recognized worldwide, while it is found to have high prevalence in India, Saudi Arabia, and Iceland . The clinical symptoms usually manifest in the first decade of life, presented by a diffuse central stromal haze that progressively extends to the periphery of the cornea, which yields loss of corneal transparency and decreased vision. It is reported that MCD constitutes 10% to 75% of the corneal dystrophies that demand corneal grafting . Generally, MCD could be divided into three immunophenotypes (MCD types IA, I and II) depending on the levels of keratan sulfate (KS) that detected in the serum and in the cornea. Patients with MCD type I lack KS in the serum and cornea, whilst patients with MCD type II contain detectable KS both in the serum and cornea . The third type, IA, in which sulfated KS can be detected in the keratocytes instead of the serum and the cornea, has also been described .
To date, many efforts have been made on the molecular diagnosis of MCD, and the implementation of next-generation sequencing (NGS) in clinical diagnosis greatly helps expand the genetic spectrums of MCD worldwide. In the current study, we performed a comprehensive evaluation on all the reported CHST6 variants found in MCD patients, including the distribution of these variants across populations, the conservation scores among residues, the correlation between mutant frequency and residue conservation, and the potential genotype phenotype correlation. Accordingly, we further classified all the reported CHST6 variants based on the ACMG guideline. To our knowledge, this is the first study comprehensively analyzing the genetic findings on MCD pathogenesis, and the current study may help shed light on earlier accurate diagnosis of MCD and future development of potential targets for genetic therapy.