The relationship between the GNS gene and mucopolysaccharidosis type IIID (MPS3D), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 2, 2022. GNS encodes N-acetylglucosamine-6-sulfatase (PMID: 3391615), an enzyme that is involved in the glycosaminoglycan degradation via catalyzing the hydrolysis of the 6-sulfate groups of the N-acetyl-D-glucosamine 6-sulfate moieties of heparan sulfate and keratan sulfate (PMID: 3689315). Individuals with MPS3D show impaired N-acetylglucosamine-6-sulfate sulfatase activity, resulting in lysosomal accumulation of glycosaminoglycans in multiple tissues, which leads to characteristic disease manifestations including CNS degeneration and skeletal dysostosis (PMID: 18392742).
The disease mechanism of MPS3D is loss of function. MPS3D was first reported in 1980 by Kresse et al. (PMID: 6450420) and the first reports of biallelic variants in GNS among MPS3D cases in 2003 by Mok et al. (PMID: 12573255) and Beasley et al. (PMID: 12624138). Both case-level (genetic) and experimental evidence support the relationship between GNS and MPS3D. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 12573255, PMID: 12624138, PMID: 17998446, PMID: 17998446, PMID: 19650410, PMID: 16990043, PMID: 16990043, PMID: 20232353). In total, eight variants from eight probands in eight 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 GNS and MPS3D includes: the biochemical function of the gene product (N-acetylglucosamine-6-sulfatase) being consistent with the clinical and biochemical findings identified individuals with MPS3D (PMID: 18392742); the biochemical and clinical features of GNS knockout mice (PMID: 28334745); and rescue of enzyme function via gene therapy in GNS knockout mice (PMID: 28334745). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, GNS is definitively associated with MPS3D. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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