Submission Details

HGSNAT was first reported in relation to autosomal recessive HGSNAT-related retinopathy in 2015 (Haer-Wigman et al., PMID: 25859010). This disease consists of only non-syndromic retinitis pigmentosa and does not include any other organ system. Loss of function mutations in HGSNAT have also been shown to cause mucopolysaccharidosis type IIIC. Based on detailed discussion between the Lysosomal Diseases and Retina GCEPs, expert opinion concluded that the two disorders noted in OMIM, i.e. mucopolysaccharidosis type IIIC (Sanfilippo C, MIM#: 252930) and retinitis pigmentosa 73 (MIM:# 616544), should remain split for the purposes of gene curation. While retinopathy can be one of the features observed in individuals with MPS IIIC, those individuals have involvement of multiple organ systems. At the time of precuration, the reported individuals with retinitis pigmentosa 73 (PMIDs: 25859010, 32347150, 32770643) have isolated retinopathy without extra-ocular features (except for one patient with mild hearing loss). When measured, N-acetyltransferase activity was usually reduced in patients with isolated retinopathy, but less so than in patients with MPS IIIC. There are no reports of identical genotypes causing isolated retinopathy and MPS IIIC. Therefore, the two disease entities will remain split for gene-disease clinical validity curation. However, it is recommended that patients with retinopathy and variants in HGSNAT be fully evaluated for other features of MPS IIIC.

This curation includes twelve variants (four missense, two frameshift, one large deletion, and five disrupting splicing) that have been reported in thirteen probands in five publications (PMIDs: 25859010, 32770643, 28981474, 27608171, 34795310). Each proband harbored biallelic variants in HGSNAT. These variants were either presumed loss of function variants (splice site, frameshift) or had functional evidence supporting complete or partial loss of function. Two previous studies that evaluated the effect of missense variants on HGSNAT activity were used to provide functional evidence for some of the variants included in this curation (PMID: 19823584, PMID: 20583299). More cases are available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The majority of cases had at least one copy of the p.Ala615Thr variant. This variant has been shown to reduce function in both of the functional studies mentioned above. Individuals homozygous for p.Ala615Thr may have later onset retinal degeneration or reduced penetrance of the disease. The mechanism of pathogenicity appears to be partial loss of function. It is important to note that full loss of function in both alleles leads to mucopolysaccharidosis type 3C while partial loss of function in both alleles or full loss of function in one allele combined with partial loss of function in the other allele results in HGSNAT-related retinopathy.

This gene-disease relationship is also supported by expression studies and a mouse model (PMIDs: 25859010, 36858249). The expression study showed that HGSNAT is expressed in both human and mouse retinas. A knockout mouse model exhibited significant rod specific photoreceptor degeneration compared to the wild-type control, which is consistent with the retinal degeneration seen in patients.

In summary, there is definitive evidence supporting the relationship between HGSNAT and autosomal recessive HGSNAT-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina GCEP on April 2, 2024 (SOP version 10).