The relationship between the MANBA gene and beta-mannosidosis (MANSB), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 25, 2022. MANBA encodes beta-mannosidase, a lysosomal enzyme involved in the degradation of N-linked oligosaccharide moieties of glycoproteins via catalyzing the cleavage of the beta-mannoside linkage of Man-(β 1→4)GlcNAc (PMID: 9384606). Among patients with beta-mannosidosis (MANSB), beta-mannosidase deficiency results in the characteristic disease manifestation of accumulation of undegraded Man-(β 1→4)GlcNAc in multiple tissues (PMID: 2317928, PMID: 3128685).
The disease mechanism of MANSB is loss of function. MANSB was first reported in 1986 by Wenger (PMID: 2945113) and Cooper (PMID: 3762648) and the first report of biallelic variants in MANBA among MANSB patients in 1998 by Alkhayat (PMID: 9384606). Both case-level (genetic) and experimental evidence support the relationship between ABHD5 and CDS. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 9384606, PMID: 16401745, PMID: 12468273, PMID: 18565776, PMID: 12890191, PMID: 17420068, PMID: 16904924). In total, twelve variants from eight probands in seven 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 MANBA and MANSB includes: the biochemical function of the gene product (beta-mannosidase) being consistent with the clinical and biochemical findings identified individuals with MANSB (PMID: 9384606, PMID: 2317928, PMID: 3128685); the biochemical and clinical features of MANBA knockout animal models (PMID: 8921369); and rescue of beta-mannosidase enzyme function via allogeneic hematopoietic cell transplantation in a patient with MANSB (PMID: 31115173). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, MANBA is definitively associated with MANSB. 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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