Walker-Warburg Syndrome via the Glycosyltransferase-Like Domain-Containing Protein 2 (POMGNT2) Gene

Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy in which seven causative genes have been previously identified. These genes are POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, and ISPD, each of which is believed to be involved in post translational modification of the sarcolemma-spanning protein alpha dystroglycan (ADG). Loss of function of any of the seven 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. 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. The seven genes referenced above account for only approximately half of all cases of WWS. A newly discovered gene, POMGNT2 (OMIM 614828), has been shown to lead to WWS in a small number of consanguineous families, and to recapitulate many of the clinical features of WWS in an animal model (Manzini et al. 2012).

Mutations in the POMGNT2 gene are the eighth documented cause of Walker-Warburg syndrome (Manzini et al. 2012). POMGNT2 encodes a protein with a putative glycosyltransferase domain, consistent with the function of most other alpha dystroglycanopathy genes. POMGNT2-related WWS is inherited in an autosomal recessive manner. POMGNT2 mutations reported thus far include nonsense and missense mutations.

Clinical sensitivity cannot be estimated at this time because of the small number of reported cases with POMGNT2 mutations. Analytical sensitivity may be high because the mutations reported to date are all detectable by this method.

This test provides full coverage of all coding exons of the POMGNT2 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).