The relationship between the NAGLU gene and mucopolysaccharidosis type IIIB (MPS IIIB), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of June 29, 2022. NAGLU encodes alpha-N-acetylglucosaminidase, a lysosomal enzyme that catalyzes the hydrolysis of terminal non-reducing N-acetyl-D-glucosamine residues in the degradation of heparan sulfate, a glycosaminoglycan (GAG) (PMID: 8650226). Among individuals with MPS IIIB, alpha-N-acetylglucosaminidase deficiency results in accumulation of incompletely degraded oligosaccharides in lysosomes in the brain and other tissues, resulting in neurodegeneration with variable extra-neurologic manifestations (as reviewed in PMID: 18392742, PMID: 11668611).
The disease mechanism of MPS IIIB is loss of function. MPS IIIB was first reported in 1973 (Neufeld, Personal Communication. Bethesda, Md. 1973) and the first report of biallelic variants in NAGLU among patients with MPS IIIB was published in 1996 (PMID: 8650226). Both case-level (genetic) and experimental evidence support the relationship between MPS IIIB and NAGLU. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants, as well as larger intragenic deletions (PMID: 11668611). In total, 10 variants from six probands in five 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 NAGLU and MPS IIIB includes the biochemical function of the gene product (the alpha-N-acetylglucosaminidase enzyme) being consistent with the clinical and biochemical findings identified individuals with MPS IIIB (PMID: 8650226, PMID:18392742, PMID:11668611), the biochemical and clinical features of a NAGLU knockout mouse animal (PMID: 10588735), and the impact of gene therapy among human MPS IIIB patients (PMID: 28713035). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, NAGLU is definitively associated with MPS IIIB. 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 August 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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