Decoding genetic complexity in glycogen storage diseases: three novel variants in SLC37A4, GAA, and PHKG2 identified...

Glycogen storage diseases (GSDs) are a group of inherited disorders caused by enzyme or transport protein defects that affect glycogen metabolism, leading to glycogen accumulation in tissues and overlapping clinical symptoms. This study aimed to identify pathogenic genetic variants in Iranian patients suspected of having GSDs and to characterize novel variants. Whole-exome sequencing was performed on 20 patients from consanguineous families, revealing 12 known and three novel pathogenic variants. Novel variants included a homozygous frameshift variant in SLC37A4 in a GSD-Ib patient, a homozygous frameshift variant in GAA in a GSD-II patient, and a homozygous nonsense variant in PHKG2 in a GSD-IXc patient. In silico analyses and structural modelling suggested these variants disrupt protein function, with two variants triggering nonsense-mediated decay and one causing protein truncation. These findings expand the genetic spectrum of GSDs in the Iranian population and highlight the importance of early molecular diagnosis and genetic counselling, especially in consanguineous communities, to improve patient management and prognosis.