Genotype and Phenotype Description in Individuals With GYG1 Variants—A Case Report and Systematic Review

ABSTRACT

Glycogen Storage Disease Type XV (GSD XV) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in GYG1 , encoding glycogenin‐1. Although primarily a myopathic disease, cardiac involvement is increasingly recognized and overlapping features with other neuromuscular disorders contribute to underdiagnosis. We performed a systematic search of databases without restrictions on publication dates. Twenty‐one articles describing individuals with GSD XV were included, providing clinical, histological, and genetic data. In addition to the systematic review, we present an illustrative case of GSD XV diagnosed at our institution. We identified 49 individuals, of whom 98% were symptomatic with onset ranging from childhood to late adulthood; manifestations were isolated neuromuscular (81.6%), cardiac (8.2%), or mixed (8.2%). One case (2.0%) was asymptomatic. Among neuromuscular cases, 12% required a walking aid, while four cardiac patients required implantable cardioverter‐defibrillators and two underwent heart transplantation. Muscle biopsy frequently revealed PAS‐positive, diastase‐resistant polyglucosan bodies, although polyglucosan bodies were not consistently identified by electron microscopy. Molecular diagnosis was confirmed in all cases, with c.143+3G>C in GYG1 being the most prevalent variant, homozygous in 36.7% of patients and associated with both juvenile and adult‐onset phenotypes. GSD XV should be considered in cases with unexplained myopathy or cardiomyopathy, regardless of age at onset. Genetic testing remains the gold standard for diagnosis, although muscle biopsy can guide investigations, particularly in atypical cases or when genetic analysis is inconclusive. Further studies are needed to clarify the full clinical spectrum, refine genotype–phenotype correlations, and guide long‐term management strategies.