Submission Details

The relationship between the MAN2B1 gene and alpha-mannosidosis (MANSA), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 5, 2022. MAN2B1 encodes alpha mannosidase (PMID: 8166692), a lysosomal enzyme that is involved in the degradation of N-linked oligosaccharides via cleaving the α-mannosidic linkages (α(1 → 2), α(1 → 3) and α(1 → 6) mannosidic linkages) in high mannose and hybrid type glycans (PMID: 2338081). Individuals with alpha-mannosidosis (MANSA) show deficient alpha-mannosidase activity, leading to accumulation of undegraded N-linked oligosaccharides in lysosomes (histopathologically seen as lysosomal vacuolization) and in the urine and characteristic disease manifestations including neurologic dysfunction (mental retardation, motor deficits), coarse facial features, skeletal anomalies, and hearing deficiency (as reviewed in PMID: 18651971).

The disease mechanism of MANSA is loss of function. MANSA was first reported in 1967 by Ockerman (A GENERALISED STORAGE DISORDER RESEMBLING HURLER'S SYNDROME, The Lancet, Volume 290, Issue 7509, 1967); first reports of biallelic variants in MAN2B1 among MANSA cases in 1997 by Nilssen et al. (PMID: 9158146). Both case-level (genetic) and experimental evidence support the relationship between MAN2B1 and MANSA. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 18651971, PMID: 9158146, PMID: 9758606, PMID: 9915946, PMID: 22161967). In total, ten variants from seven probands in four 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 MAN2B1 and MANSA includes: the biochemical function of the gene product (alpha-mannosidase) being consistent with the clinical and biochemical findings identified individuals with MANSA (PMID: 2338081, PMID: 18651971); the biochemical and clinical features of MAN2B1 knockout mice (PMID: 10400983); and rescue of systemic accumulation of mannose N-linked oligosaccharides via enzyme replacement therapy in MAN2B1 knockout mice (PMID: 18713755). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, MAN2B1 is definitively associated with MANSA. 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 September 2, 2022 (SOP v9).