Walker-Warburg Syndrome via the B3GNT1(B4GAT1) Gene

Walker-Warburg syndrome (WWS) 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 and Campbell 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. CNS 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. Mutations in a newly discovered gene, B3GNT1(B4GAT1), have been found to be causative for WWS in two families. Functional studies in human cells and a model system confirmed pathogenicity of two missense variants found in one of the families (Buysse et al. 2013). Unexpectedly, both missense variants were in the homozygous state in affected family members. Clinical features of affected individuals included hypotonia, hydrocephalus, Dandy–Walker malformation, and retinal dysplasia. Serum CpK levels were greatly elevated and brain imaging showed cobblestone lissencepahly. Affected individuals from the second family presented with severe WWS including occipital encephalocele, anencephaly, and agenesis of the optic nerve (Shaheen et al. 2013).

B4GAT1-related congenital muscular dystrophy is inherited as an autosomal recessive disorder. In the first family described, two missense variants of conserved amino acids were found to segregate with disease and parents were shown to be heterozygous for both (Buysse et al. 2013). The second reported family was found to segregate a homozygous truncating mutation (Shaheen et al. 2013). B4GAT1 encodes a transmembrane protein that has a glycosyltransferase domain, although enzymatic activity has not yet been demonstrated. Pathogenic variants in B4GAT1 reported to date include amino acid substitutions and a frame-shifting truncating mutation (http://www.LOVD.nl/B3GNT1).

Too few cases with confirmed mutations in the B4GAT1 gene have been reported to arrive at an estimate of clinical or analytical sensitivity.

This test provides full coverage of all coding exons of the B4GAT1 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).