CHST6

Inheritance Pattern: AR

Disease ID:MONDO:0009020

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009020

Submitter: ClinGen

*CHST6* was first reported in relation to autosomal recessive macular corneal dystrophy (MCD) in 2000 (Hasegawa et al., PMID: 11053262). MCD is an ocular disease characterized by bilateral, progressive corneal opacification, and reduced corneal sensitivity. The age of onset occurs in the first decade of life. Characteristics of MCD can include painful attacks with photophobia, foreign body sensations, and recurrent erosions. MCD is divided into the clinically indistinguishable types I, IA, and II based on analysis of the normally sulfated, or antigenic, keratan sulfate levels in serum and immunohistochemical evaluation of the cornea. Patients with types I and IA macular corneal dystrophy have undetectable serum levels of antigenic keratan sulfate, whereas those with type II macular corneal dystrophy have normal or low levels, depending on the population examined. Seventeen variants (missense, nonsense, frameshift) that have been reported in fifteen probands and one non-human model organism in four publications (PMIDs: 26585178, 20539220, 19365571, 27829782) are included in this curation. MCD is due to deposition of an unsulfated keratan sulfate both within the intracellular space (within the keratocytes and endothelial cells) and in the extracellular corneal stroma. *CHST6* coding variants only occur within the third exon of three, meaning that there is no predicted nonsense mediated decay. However, several variants scored showed a reduction between 20% and 50% of the predicted protein sequence. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models (PMIDs: 39642091, 11053262). *CHST6* results in the protein GlcNAc6ST being made. Paper chromatography and High-Performance Liquid Chromatography (HPLC) show a relationship between the activity of GlcNAc6ST and MCD, in where GlcNAc6ST may be decreased or disappear in cornea with MCD (PMID:11053262). The decrease in GlcNAc6ST activity in the cornea with MCD might result in the occurrence of low- or nonsulfated keratan sulfate and thereby cause corneal opacity. Zebrafish models show that disrupted *CHST6* results in opaque accumulations formed in the eye, loss of cKS in the corneal stroma, and a decrease in corneal thickness which are consistent with human MCD. Pont Labrador Retrievers models show that the inheritance of a homozygous variant (c.814C>A, p.R272S) results in MCD the same way it presents in humans, with corneal clouding being a prominent feature. In summary, there is definitive evidence supporting the relationship between *CHST6* and autosomal recessive macular corneal dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen CDG GCEP on the meeting date February 2, 2026 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0009020

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009020

Submitter: G2P