Dystroglycan-Related Congenital Muscular Dystrophy Panel

The congenital muscular dystrophies are a clinically and genetically heterogeneous group of disorders characterized by elevated serum CpK levels, muscle weakness, a dystrophic process observed in biopsied muscle, and variable associated findings such as central nervous system abnormalities, cardiac muscle involvement, skeletal effects, and developmental delay. Onset of symptoms generally occurs at birth, although some symptoms do not manifest themselves until later in life. See Sparks et al. (2012) for diagnostic strategies and a comprehensive review of the congenital muscular dystrophies.

Pathogenic variants in a growing number of proven or putative O-linked and N-linked glycosyltransferase genes and one putative lipid biosynthesis gene (CRPPA/ISPD, Willer et al. 2012; Roscioli et al. 2012) cause muscular dystrophies in the dystroglycanopathy spectrum. Walker-Warburg syndrome (WWS), a severe congenital muscular dystrophy with defective neuronal migration and associated structural brain and eye abnormalities, is the most severe manifestation. Other presentations include muscle-eye-brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), and congenital or limb girdle muscular dystrophy with associated cognitive impairment, but without structural brain abnormalities (eg., LGMD2K) (Godfrey et al. 2007). Dystroglycanopathy may manifest primarily as a cardiomyopathy with minimal skeletal muscle involvement (Margeta et al. 2009).

The dystroglycanopathies are inherited in an autosomal recessive manner. Glycosyltransferase activity is necessary for proper post translational processing of alpha dystroglycan (ADG), a protein encoded by DAG1. In the absence of these proteins, ADG remains hypoglycosylated and diverse pathologies follow (Barresi and Campbell 2006). Molecular diagnosis (and classification) of the dystroglycanopathy subtypes is complex because extensive genetic heterogeneity exists for each disorder (Godfrey et al. 2007), and because the reported phenotypes caused by the glycosyltransferase genes continue to expand (van Reeuwijk et al. 2006). Evaluation of a patient’s muscle biopsy by immunofluorescence can detect abnormal glycosylation of ADG and can, therefore, aid in a diagnostic evaluation.

See individual gene test descriptions for information on molecular biology of gene products.

Because of extensive phenotypic and locus heterogeneity for these disorders, clinical sensitivity is difficult to estimate. In one cohort of ninety fetuses with severe cobblestone lissencephaly and associated findings consistent with Walker-Warburg syndrome, Vuillaumier-Barrot et al. (2012), obtained a genetic diagnosis in 58 cases, or 64%. These diagnosed cases had relative frequencies as follows: POMT1 (42%), POMT2 (17%), POMGNT1 (17%), CRPPA/ISPD (9%), RXYLT1/TMEM5 (9%), LARGE1 (3%) and FKRP (3%).

Clinical sensitivity of deletion/duplication testing for the dystroglycanopathy genes is low. Gross copy number mutations are found at a significant frequency only in the CRPPA/ISPD and LARGE1 genes, and not the other dystroglycanopathy genes.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).

This test includes coverage of the FKTN deep intronic Korean founder variant c.648-1243 G>T as well as c.1045-22A>G. This test will not detect the FKTN Japanese founder variant which is a 3kb retrotransposan insertion in the 3' UTR.

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).