Dystroglycanopathy via the B3GALNT2 Gene

Walker-Warburg syndrome (WWS, OMIM 236670) is a genetically heterogeneous congenital muscular dystrophy in which many causative genes have been previously identified. Each of these genes is believed to be involved in post translational modification of the sarcolemma-spanning protein alpha dystroglycan (ADG). Loss of function of any of these genes results in hypoglycosylation of ADG and reduced binding of ADG to the basal lamina through laminin (Barresi, R. and Campbell, K. P. J Cell Sci 119(PT 2):199-207, 2006). WWS is the most severe form of ADG-related congenital muscular dystrophy, presenting with profound hypotonia, defective neuronal migration and associated structural brain and eye abnormalities. Central nervous system findings include cobblestone lissencephaly, cerebellar malformations, microophthalmia and cataracts. Patients have profound mental retardation and typically die in the first year of life. Muscle biopsies demonstrate a dystrophic process and markedly reduced or absent staining with antibodies to the glycolepitope of ADG. A newly discovered gene, B3GALNT2, has been shown to be causative for a range of dystroglycanopathies (Stevens, E. et al. Amer J Hum Genet 92(3):354-365, 2013). Patients with severe manifestations consistent with WWS were found to have at least one truncating mutation while less severely affected patients had two missense mutations. All patients had structural brain malformations.

B3GALNT2-related dystroglycanopathy is an autosomal recessive disorder. Small deletions and duplications resulting in prematurely truncated proteins, as well as nonsense and missense mutations have been reported to date (http://www.LOVD.nl/B3GALNT2).

The beta-1,3-N-acetylgalactosaminyltransferase 2 protein is encoded by exons 1 through 12 of the B3GALNT2 gene located on chromosome 1q42.

In two separate cohorts of dystroglycanopathy patients totaling 102 individuals, six unrelated patients were identified with causative B3GALNT2 mutations (Stevens, E. et al. Am J Hum Genet 92(3):354-365, 2013).

This test provides full coverage of all coding exons of the B3GALNT2 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).