GYG1-Related Disorders via the GYG1 Gene

Glycogen Storage Disease Type XV (GSD XV) and Polyglucosan Body Myopathy Type 2 (PGBM2) are rare, allelic disorders caused by a deficiency of the glycogenin-1 protein, which is encoded by the GYG1 gene. To date, only one individual has been reported with GSD XV (Moslemi et al. 2010). This patient presented in the third decade of life with cardiomyopathy and muscle weakness associated with a profound depletion of glycogen in skeletal muscle. There was some suspicion that the onset of the myopathic features may have been in childhood.

More commonly, variants in the GYG1 gene have been reported to be associated with PGBM2. These patients present with muscle weakness without cardiomyopathy. The age of onset and severity are variable, although the myopathy has been reported to be progressive in nearly all patients. Serum creatine kinase (CK) levels have been reported to be slightly elevated in some patients. In all PGBM2 patients, partially amylase-resistant periodic acid-Schiff (PAS)-positive inclusions have been detected in a portion of muscle fibers, with normal glycogen detected in the remaining fibers. In many of the patients, the inclusions have been confirmed via electron microscopy to be polyglucosan bodies (Malfatti et al. 2014; Fanin et al. 2015; Akman et al. 2016). Polyglucosan bodies are accumulations or abnormally structured glycogen that are poorly branched and may be less spherical than normal glycogen granules.

Both GSD Type XV and PGBM2 are autosomal recessive disorders. Pathogenic variants in the GYG1 gene are the only known cause of both of these disorders. To date, nearly 10 different causative variants have been reported in a total of 16 patients. The most commonly reported variant is defined as c.143+3G>C, which has been shown to result in the skipping of exon 2 (Malfatti et al. 2014). This variant has been reported in the homozygous or compound heterozygous state in approximately two-thirds of patients. The remaining variants appear to be private, and include missense, nonsense, frameshift and other splice variants, and are spread throughout the gene (Human Gene Mutation Database).

The GYG1 gene encodes the protein glycogenin-1, which is necessary for the initiation of glycogen synthesis in muscle tissues. Autoglucosylation of glycogenin results in the formation of a short primer for glycogen synthesis, containing approximately 10 glucose residues. After the primer is generated, glycogen elongation and branching is catalyzed by glycogen synthase and glycogen branching enzyme (Moslemi et al. 2010; Chen et al. 2014).

Clinical sensitivity of this test is expected to be high as, to date, all identified patients have been found to have two pathogenic variants detectable via direct sequencing, suggesting a clinical sensitivity near 100% (Moslemi et al. 2010; Malfatti et al. 2014; Fanin et al. 2015; Akman et al. 2016).

This test provides full coverage of all coding exons of the GYG1 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).