The relationship between the SGSH gene and mucopolysaccharidosis type IIIA (MPS IIIA), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 30, 2022. SGSH encodes N-sulfoglucosamine sulfohydrolase, a lysosomal enzyme that involved in the degradation of heparan sulfate, through catalyzing the release of the sulfate groups linked to the amino group of glucosamine (PMID: 7493035). SGSH deficiency, which is present among individuals with MPS type IIIA, leads to accumulation of incompletely degraded oligosaccharides in lysosomes in the brain and other tissues, resulting in neurodegeneration with variable extra-neurologic manifestations (PMID: 18392742)
The disease mechanism of MPS IIIA is loss of function. MPS IIIA was first reported in 1971 (PMID: 4252428) and the first report of biallelic variants in SGSH among patients with MPS IIIA was published in 1995 (PMID: 7493035). Since then, at least 68 unique variants have been identified (PMID: 11668611). Both case-level (genetic) and experimental evidence support the relationship between MPS IIIA and SGSH. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants. In total, 10 variants from five probands in five publications were curated (PMID: 9158154, PMID: 21671382, PMID: 15146460, PMID: 27590925, PMID: 11343308); 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 SGHS and MPS IIIA includes the biochemical function of the gene product (the MPS IIIA enzyme) being consistent with the clinical and biochemical findings identified individuals with MPS IIIA (PMID: 7493035, PMID: 18392742), the biochemical and clinical features of a mouse animal model homozygous for the p.D31N variant (PMID: 11181566, PMID: 15698885, PMID: 17913701), and the impact of hematopoietic stem cell transplant therapy in a MPS IIIA mouse model (PMID: 22547151). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, SGSH is definitively associated with MPS type IIIA. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time.
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.