Submission Details

The relationship between the GUSB gene and mucopolysaccharidosis type 7 (MPS7), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of June 27, 2022. GUSB encodes beta-glucuronidase, a lysosomal enzyme that catalyzes the hydrolysis of beta-D-glucuronic acid residues in the degradation of glycosaminoglycans (GAGs), including the degradation of heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate (PMID: 3468507). Among individuals with MPS7, beta-glucuronidase deficiency results in accumulation of these GAGs in the lysosomes of multiple tissues, resulting in the characteristic disease manifestations of MPS7, which include neurologic impairment, hepatosplenomegaly, and skeletal dysplasia (as reviewed in PMID: 26908836). In addition to skeletal dysplasia, cases can present with fetal hydrops and reduced β-glucuronidase activity prenatally (PMID 8644704, 8111413, 811412).

The disease mechanism of MPS7 is loss of function. MPS7 was first reported in 1973 (PMID: 4265197) and the first report of biallelic variants in GUSB among patients with MPS7 was published in 1900 (PMID: 2115490). Both case-level (genetic) and experimental evidence support the relationship between MPS7 and GUSB. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants, as well as larger intragenic deletions (PMID: 19224584). In total, 11 variants from seven probands in six publications were curated, including the prevalent missense variants c.526C>T (p.L176F), c.1856C>T (p.A619V), and c.1144C>T (p.R382C), which are estimated to respectively account for 20.4%, 4.9%, and 3.9% 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 GUSB and MPS7 includes the biochemical function of the gene product (the beta-glucuronidase enzyme) being consistent with the clinical and biochemical findings identified individuals with MPS7 (PMID: 4265197, PMID: 26908836), the biochemical and clinical features of a GUSB knockout mouse animal (PMID: 2495302, PMID: 8101990), and the impact of enzyme replacement therapy among human MPS7 patients (PMID: 32063397). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, GUSB is definitively associated with MPS7. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP on July 5, 2022 (SOP v9). Additional information, regarding the prenatal presentation of MPS7, was added by the Prenatal GCEP on Jan 3, 2025.