Variant burden predicts glycogen storage disease type IV phenotype: A systematic review

BACKGROUNDGlycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by biallelic GBE1 variants.The resulting polyglucosan accumulation produces a broad phenotypic spectrum.Genotype-phenotype correlations remain unclear, limiting prognostication and genetic counseling. AIMTo determine whether truncating-variant burden predicts clinical phenotype in GBE1related GSD IV. METHODSWe report 2 unrelated individuals with congenital neuromuscular GSD IV confirmed by muscle biopsy.We also conducted a systematic review of PubMed and EMBASE (1968-2025) following PRISMA guidelines.Phenotypes were grouped as neuromuscular (congenital, childhood, or adult), hepatic, and cardiac.Variants were classified as truncating or nontruncating (missense).Multinomial logistic regression evaluated associations between truncating-variant burden (0-2 alleles) and phenotype. RESULTSWe identified 178 individuals from 159 families across 94 studies: Neuromuscular (n = 130), hepatic (n = 45), and cardiac (n = 3).Seventeen families showed 100% intrafamilial concordance.In the neuromuscular-congenital group, 53.8% carried 2 truncating alleles, whereas no hepatic or neuromuscular-adult case did.Each additional truncating allele markedly increased the odds of congenital disease vs adult [odds ratio (OR), 10.1; 95% confidence interval (CI): 4.4-23.2]and vs hepatic (OR, 5.3; 95%CI: 2.6-10.5).5 / 30 CONCLUSION Biallelic truncating GBE1 variants occur exclusively in congenital neuromuscular disease, but catalytic-region missense variants also cause this form.Incorporating variant type and position into counseling guides prenatal and perinatal management.