Dystroglycanopathies via the POMK Gene

Pathogenic variants in the POMK gene cause muscular dystrophies in the dystroglycanopathy spectrum. Walker-Warburg syndrome (WWS), a severe congenital muscular dystrophy with defective neuronal migration and associated with structural brain and eye abnormalities, is the most severe manifestation (van Reeuwijk et al. 2005) seen in the dystroglycanopathy spectrum. Several patients with pathogenic POMK variants have presented with typical WWS, including macrocephaly, hypotonia at birth, tonic seizures, ocular abnormalities, elevated CK levels and cobblestone lissencephaly (Jae et al. 2013; Di Costanzo et al. 2014). However, clinical heterogeneity exists and other milder forms of congenital muscular dystrophy (CMD) (von Renesse et al. 2014) or limb girdle muscular dystrophy with cognitive impairment (Di Costanzo et al. 2014) have been observed. In a milder case, the patient presented in infancy with weakness and delayed motor development and at age 22 has proximal weakness, calf pseudohypertrophy, mild facial weakness, mild intellectual disability and elevated CK, but was still ambulatory (Di Costanzo et al. 2014). In a Lebanese family, two affected siblings presented with congenital muscular dystrophy including hypotonia at birth, motor developmental delay, white matter changes, hearing impairment, and myopathic changes and deficient laminin alpha-2 staining on the muscle biopsy. Both siblings have had progressive muscle weakness and are wheelchair dependent in their teens (von Renesse et al. 2014).

Dystroglycanopathies due to POMK pathogenic variants are inherited in an autosomal recessive manner. Protein O-mannose kinase (POMK) activity is necessary for proper post translational processing of the protein, alpha dystroglycan (ADG). The ADG protein is extensively glycosylated, which is essential for binding to extracellular matrix ligands (in particular laminin-alpha 2). In addition, these branched sugars can be further modified through phosphorylation. POMK is an atypical kinase that phosphorylates the 6-position of O-mannose, specifically after the mannose has been modified by the POMGNT2 and B3GALNT2 enzymes (Yoshida-Moriguchi et al. 2013). Molecular diagnosis (and classification) of the dystroglycanopathy subtypes is complex because extensive locus heterogeneity exists for each disorder (Endo 2015), and because the phenotypes caused by the genes involved with post translational processing of ADG are varied. Pathogenic variants in POMK reported to date include missense, nonsense, and a small deletion (Human Gene Mutation Database).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be almost 100% because all reported pathogenic variants are detectable by sequencing.

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