The relationship between the ARSB gene and mucopolysaccharidosis type 6 (MPS6), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 9, 2022. ARSB encodes aryl sulfatase B (ASB), an enzyme that catalyzes the removal of the C4 sulfate ester group from the N-acetylgalactosamine sugar residue at the nonreducing terminus of the glycosaminoglycans (GAGs) dermatan sulfate (DS) and chondroitin sulfate (CS) during lysosomal degradation (as reviewed in PMID: 17458871; PMID: 30118150). Among individuals with MPS6, ASB deficiency results in accumulation of DS and CS, which leads to symptoms including short stature, coarse facies, dysostosis multiplex, hepatosplenomegaly, corneal clouding, and cardiac disease.
The disease mechanism of MPS6 is loss of function. MPS6 was first reported in 1963 (PMID: 14091597) and the first report of biallelic variants in ARSB among patients with MPS6 was published in 1991 (PMID: 1718978). Since then, at least 201 unique variants in 478 cases have been identified (PMID: 30118150). Both case-level (genetic) and experimental evidence support the relationship between MPS6 and ARSB. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants, as well as larger deletions and duplications. In total, fourteen variants from nine probands in six publications were curated. Of note, three missense variants, c.454C>T (p.Arg152Trp), c.962T>C (p.Leu321Pro), and c.629A>G (p.Tyr210Cys), are estimated to account for 18.5% of reported cases. 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 ARSB and MPS6 includes the biochemical function of the gene product (the ASB enzyme) being consistent with the clinical and biochemical findings identified individuals with MPS6 (PMID: 20385007; PMID: 4271367), the biochemical and clinical features of a feline animal model homozygous for the p.Leu476Pro variant (PMID: 8910299), and the impact of enzyme replacement therapy among human MPS6 patients (PMID: 16647419). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, ARSB is definitively associated with MPS6. 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).
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