Alpha-Mannosidosis via the MAN2B1 Gene

Alpha-mannosidosis (OMIM# 248500) is an inheritable lysosomal storage disorder characterized by facial and skeletal abnormalities, hearing impairment, immune deficiency, and intellectual disability (Malm et al. Orphanet J Rare Dis 3:21, 2008; Malm et al. GeneReviews, 2001). Neurological abnormalities include gradual impairment of mental functions and speech, motor function disturbances and periods of psychiatric symptoms. Minor features include ocular changes and hepatosplenomegaly. After a normal birth, clinical symptoms develop progressively and the severity is markedly variable from early death to an asymptomatic form in adulthood. Diagnosis of the disease is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells.

Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene (Berg et al. Am J Hum Genet 64:77-88, 1999). Lysosomal alpha-mannosidase is required for the catabolism of N-linked carbohydrates released during glycoprotein turnover in the lysosomes. Genetic aberrations throughout the MAN2B1 gene include missense, nonsense, splicing mutations and small deletion/insertions. Large deletions within the MAN2B1 gene have also been reported but are relatively uncommon (Human Gene Mutation Database). Most mutations are private. The missense mutation c.2248C>T (p.Arg750Trp) in exon 18, accounting for more than 30% of pathogenic alleles, is most frequent among Alpha-mannosidosis patients in European populations (Berg et al. Am J Hum Genet 64:77-88, 1999; Malm et al., 2008).

DNA sequencing can detect 98% of disease-causing MAN2B1 mutations in patients who have been subjected to biochemical pre-screening (Nilssen et al. Eur J Hum Genet 19(7), 2011).

This test provides full coverage of all coding exons of the MAN2B1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.