Walker-Warburg Syndrome via the POMGNT1 Gene

Variants in the POMGNT1 gene cause muscular dystrophies in the dystroglycanopathy spectrum. Walker-Warburg syndrome (WWS; OMIM 236670), a severe congenital muscular dystrophy with defective neuronal migration and associated structural brain and eye abnormalities, is the most severe manifestation. Other patients with POMGNT1 variants present with muscle-eye-brain disease (MEB; OMIM 253280), while still others present with a severe form of Fukuyama congenital muscular dystrophy (FCMD; OMIM 253800, Godfrey et al. Brain 130:2725-2735, 2007).

The dystroglycanopathies are inherited in an autosomal recessive manner. Protein O-mannose beta-1,2-N-acetylglucosaminyltransferase activity is necessary for proper post-translational processing of the protein, alpha dystroglycan (ADG). In the absence of this enzyme, ADG remains hypoglycosylated and diverse pathologies follow (Barresi and Campbell. J Cell Sci 119:199-207, 2006). Molecular diagnosis (and classification) of the dystroglycanopthy subtypes is complex, because extensive locus heterogeneity exists for each disorder (Godfrey et al. Brain 130:2725-2735, 2007), and because the phenotypes caused by the six demonstrated and putative glycosyltransferase genes continue to expand (see for example van Reeuwijk et al. Hum Mut 27:453-459, 2006). Evaluation of a patient’s muscle biopsy by immunofluorescence can detect abnormal glycosylation of ADG and can, therefore, help direct a diagnostic evaluation. It should be noted that five other genes (POMT1, POMT2, FCMD, FKRP, and LARGE) also encode proteins required for processing of ADG.

POMGNT1 variants were found in approximately 7% of a patient cohort with ADG hypoglycosylation in muscle (Godfrey et al. Brain 130:2725-2735, 2007). Clinical phenotypes included WWS, MEB-FCMD, and LGMD without mental retardation. Missense, small deletions and duplications, and nonsense variants are distributed throughout the gene (POMGNT1 @ www.dmd.nl). Because dystroglycanopathies exhibit extensive locus and allelic heterogeneity, a negative POMGNT1 sequence result does not rule out a diagnosis of one of these disorders when classic clinical findings are present. If a muscle biopsy is available, immunostaining may also be an appropriate diagnostic approach.

This test provides full coverage of all coding exons of the POMGNT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.