Submission Details

The GYG1 gene was first reported in relation to glycogen storage disease in 2010, with the publication of an affected proband harboring two variants in compound heterozygosity (PMID: 20357282). The young adult proband was identified following an episode of dizziness and palpitations after exercise, with ventricular fibrillation and tachycardia. History of shortness of breath dated back to childhood, with reduced muscle mass and strength, particularly in the chest and upper arms. Muscle biopsy revealed reduced muscle fiber size, mitochondrial proliferation, and dramatically reduced glycogen staining in the cytoplasm yet vacuolar staining with periodic acid-Schiff-positive material (PMID: 20357282). Subsequent studies with additional cases identified difficulty exercising or loss of grip strength as common presenting symptoms, with sites of muscle weakness varying from patient to patient and potentially including the pelvic girdle, shoulder girdle, proximal limbs, lower legs, long finger extensor, and/or foot dorsiflexor. Electromyography generally shows myopathic abnormalities, and some cases exhibit muscle atrophy and/or elevated circulating creatine kinase. Muscle biopsy reveals the presence of polyglycosan bodies showing accumulation of abnormal glycogen that is periodic acid-Schiff-positive, as well as positive-staining for both ubiquitin and sequestosome 1, identifying the structures as targeted for degradation by autophagy (PMID: 25272951). Despite the presentation of the initial patient, cardiac disease has not been reported in the majority of subsequent cases (PMID: 25272951, PMID: 29264399, PMID: 32419263). Cases harboring biallelic variants GYG1 are most often diagnosed with polyglucosan body myopathy 2. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (biallelic GYG1 loss-of-function) was found to be consistent across all known cases, while the histologic and phenotypic differences between the diverse cases appeared to represent a single spectrum of disease. Therefore, cases caused by inherited GYG1 variants have been lumped into a single disease entity referred to as GYG1-related disorder of glycogen metabolism, with an autosomal recessive mode of inheritance.

Nine suspected pathogenic variants have been scored as part of this curation (two missense, four nonsense, 1 frameshift, and two triggering splicing defects), which have been collectively reported in seven probands in three publications (PMID: 20357282, PMID: 25272951, PMID: 32419263). The mechanism of pathogenicity appears to be biallelic loss of GYG1 function conferred by null and/or hypomorphic variants. The initial proband was characterized as having a glycogen storage disease (PMID: 20357282), while subsequent probands were found to exhibit polyglucosan body myopathy (PMID: 25272951, PMID: 32419263). Segregation evidence was not available in any of these publications and did not contribute to the scoring of the gene-disease relationship. Additional case-level evidence is available in the literature but was not included in this curation as the maximum score for this category of evidence had already been reached (PMID: 29264399).

This gene-disease association is also supported by multiple lines of experimental evidence demonstrating that GYG1 encodes an enzyme that autoglucosylates to initiate glycogen synthesis (PMID: 1281472, PMID: 22198226). This function is consistent with the severe depletion of normal glycogen and accumulation of abnormal glycogen characteristic of affected patients. The GYG1 gene product physically interacts the skeletal muscle isoform of glycogen synthase, which is similarly encoded by a gene (GYS1) in which loss of function variants are associated with glycogen storage disease (PMID: 25416956). GYG1 is highly expressed in skeletal muscle, according to transcriptomic profiling of human tissues by the GTEx project (PMID: 23715323). Mice with targeted disruption of Gyg1 recapitulate a number of phenotypes from the human patients, including exercise intolerance, difficulty performing physical tasks as measured by reduced consumption of oxygen and energy, and enhanced accumulation of glycogen material in abnormally large granules or inclusion bodies in the muscle (PMID: 28683291).

In summary, GYG1 is definitively associated with GYG1-related disorder of glycogen metabolism. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on March 24th, 2023 (SOP Version 9).