HGSNAT

Inheritance Pattern: AR

Disease ID:MONDO:0018937

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0009657

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009657

Submitter: ClinGen

The relationship between the HGSNAT gene and mucopolysaccharidosis type IIIC (MPS3C), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 8, 2022. HGSNAT encodes acetyl–CoA:α-glucosaminide N-acetyltransferase, a lysosomal membrane enzyme that is involved in the degradation of the glycosaminoglycan heparan sulfate via acetylating the nonreducing, terminal alpha-glucosamine residue of intralysosomal heparin and heparan sulfate, converting it into a substrate for alpha-N-acetylglucosaminidase (PMID: 16960811). Among patients with MPS3C, deficient acetyl–CoA:α-glucosaminide N-acetyltransferase activity (PMID: 33384) results in lysosomal accumulation of heparan sulfate, leading to progressive neurological disease whose features include developmental delay, behavioral problems and mental deterioration, and motor dysfunction, with variable extra-neurological manifestations (as reviewed in PMID: 18392742). Lumping and splitting: 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 mutiple organ systems. At the time of precuration, the reported individuals with Retinitis pigmentosa 73 have isolated retinopathy without extra-ocular features (except for one patient with mild hearing loss) (e.g. PMID: 25859010, 32347150, 32770643). 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. Biallelic null genotypes are seen in some MPS IIIC families but never in those with late-onset retinal disease (PMID: 32770643). In summary, isolated retinopathy was not felt to represent an attenuated form of MPS IIIC. As such, the two disease entities will remain split. However, it is recommended that patients with retinopathy and variants in HGSNAT be evaluated for other features of MPS IIIC. The disease mechanism of MPS3C is loss of function. MPS3C was first reported by Kresse et al. in 1976 (Kresse H, Von Figura K, Bartsocas C. 1976. Clinical and biochemical findings in a family with Sanfilippo disease, type C. (Abstract) Clin Genet 10:364.) and the first report of biallelic variants in HGNSAT among MPS type IIIC patients was by Fan et al. in 2006 (PMID: 16960811). Both case-level (genetic) and experimental evidence support the relationship between HGSNAT and MPS3C. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 19479962, PMID: 16960811, PMID: 17033958, PMID: 18518886, PMID: 20825431). In total, nine variants from five probands in four publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between HGSNAT and MPS3C includes: the biochemical function of the gene product (acetyl–CoA:α-glucosaminide N-acetyltransferase) being consistent with the clinical and biochemical findings identified individuals with MPS3C (PMID: 16960811, PMID: 18392742); the biochemical and clinical features of HGSNAT knockout mice (PMID: 25567323); and rescue of neurologic impairment and HGSNAT enzymatic activity via recombinant adeno-associated virus (AAV)-mediated gene therapy in HGSNAT knockout mice (PMID: 29788236). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, HGSNAT is definitively associated with MPS3C. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, December 4, 2023 (SOP v9).

Inheritance Pattern: AR

Disease ID:MONDO:0009657

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0014687

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009657

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009657

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009657

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0014687

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009657

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014687

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: ClinGen

*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).

Inheritance Pattern: AR

Disease ID:MONDO:0009657

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014687

Submitter: Labcorp Genetics (formerly Invitae)