β-Mannosidase Deficiency via the MANBA Gene

β-Mannosidosis is a rare lysosomal storage disorder caused by defects in the enzyme β-Mannosidase. Defects in this enzyme lead to the accumulation of the disaccharide Man(β1→4)GlnNAc in lysosomes as well as its excretion in the urine of affected patients (Alkhayat et al. 1998; Bedilu et al. 2002). Very few patients have been reported in the literature and thus it is somewhat difficult to determine a cohesive clinical picture, but the most common features of β-Mannosidosis seem to be hearing loss, intellectual disability and developmental delay, behavior disturbances and susceptibility to respiratory infections. Less commonly reported features are facial dysmorphism, skeletal deformities, seizures, hypotonia, and skin involvement (such as angiokeratomas) (Alkhayat et al. 1998; Bedilu et al. 2002; Sedel et al. 2006; Molho-Pessach et al. 2007). A few patients have been reported with additional clinical features, such as Gilles de la Tourette Syndrome (Sedel et al. 2006), spinocerebellar ataxia (Labauge et al. 2009) and nystagmus (Yu et al. 2015), although it is not clear that these features are attributable to β-Mannosidase deficiency. Onset of symptoms has been reported to range from the neonatal period to adolescence (Bedilu e tal. 2002), and there seems to be a wide variability in severity of symptoms, even within families (Alkhayat et al. 1998). Many of the reported patients have survived to maturity (Bedilu e tal. 2002).

β-Mannosidosis is an autosomal recessive disorder caused by defects in the enzyme β-Mannosidase, which is encoded by the MANBA gene located on chromosome 4 (at 4q24). To date, fewer than 20 pathogenic variants have been reported in the MANBA gene. The majority of reported variants have been nonsense, frameshift and splice variants that lead to premature protein termination, although about a third of reported variants are missense substitutions (Riise Stensland et al. 2008; Human Gene Mutation Database).

The β-Mannosidase enzyme is responsible for one of the last steps in the degradation of N-linked oligosaccharides of glycoproteins (Alkhayat et al. 1998). Deficiencies in this enzyme lead to defective cleavage of a β-Mannoside linkage, resulting in the accumulation of the disaccharide Man(β1→4)GlnNAc.

Clinical sensitivity is difficult to estimate because only a small number of patients have been reported. Analytical sensitivity should be high because all variants reported are detectable by direct sequencing.

No large deletions or duplications have been reported in the MANBA gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the MANBA gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).