Novel mutation in the CHST6 gene causes macular corneal dystrophy in a black South African family

Abstract

Background: Macular corneal dystrophy (MCD) is a rare autosomal recessive disorder that is characterized by progressive corneal opacity that starts in early childhood and ultimately progresses to blindness in early adulthood. The aim of this study was to identify the cause of MCD in a black South African family with two affected sisters.

Methods: A multigenerational South African Sotho-speaking family with type I MCD was studied using whole exome sequencing. Variant filtering to identify the MCD-causal mutation included the disease inheritance pattern, variant minor allele frequency and potential functional impact.

Results: Ophthalmologic evaluation of the cases revealed a typical MCD phenotype and none of the other family members were affected. An average of 127 713 variants per individual was identified following exome sequencing and approximately 1.2 % were not present in any of the investigated public databases. Variant filtering identified a homozygous E71Q mutation in CHST6, a known MCD-causing gene encoding corneal N-acetyl glucosamine-6-O-sulfotransferase. This E71Q mutation results in a non-conservative amino acid change in a highly conserved functional domain of the human CHST6 that is essential for enzyme activity.

Conclusion: We identified a novel E71Q mutation in CHST6 as the MCD-causal mutation in a black South African family with type I MCD. This is the first description of MCD in a black Sub-Saharan African family and therefore contributes valuable insights into the genetic aetiology of this disease, while improving genetic counselling for this and potentially other MCD families.

Keywords: African; CHST6; Macular corneal dystrophy; Whole exome sequencing.

Fig. 1

Schematic representation of the MCD pedigree. The 9 sequenced individuals are indicated with a + and their genotype for the E71Q mutation is indicated below the Individual ID. Individuals IV.3 and IV.4 (shaded black) show clinical manifestations of macular corneal dystrophy (MCD), while their consanguineous parents, siblings IV.1 and IV.6 and children did not

Fig. 2

Bioinformatic analysis pipeline

Fig. 3

Clinical phenotypes. a. Pre-operative photograph of the right eye of IV.3 demonstrating ill-defined corneal stromal opacities. b. Cornea of IV.3. Hale’s colloidal iron 20x. The presence of the granular deposits (arrows) are highlighted by a Hale’s colloidal iron stain. c. Cornea of IV.3. Hale’s colloidal iron 100x. Higher magnification demonstrates the presence of the granular deposits (arrows) among the lamellae of the substantia propria and within the corneal endothelium. d. Control cornea: Hale’s colloidal iron 40x. Control cornea stained with Hale’s colloidal iron fails to identify the presence of basophilic deposits within the substantia propria

Fig. 4

Results form CHST6 Sanger Sequencing. Electropherograms from Sanger sequencing indicating homozygous E71Q genotype in the two affected sisters (IV.3 and IV.4), heterozygous genotype in the carrier mother (III.8) and homozygous reference genotype in the unaffected brother (IV.1). The red arrow indicates the position of the E71Q mutation and the sequences are given for the reverse strand