Phosphoglucomutase 1 (PGM1) enzyme plays a central role in metabolism, by bridging glycolysis, glycogen metabolism and glycosylation. PGM1 deficiency is a rare congenital disorder of glycosylation (CDG) known for its unusually high incidence of lethal cardiac complications. While the role of PGM1 in glycosylation has been partially elucidated, little is known about the role of PGM1 in the heart. Similarly, while the current therapy such as D-galactose supplementation is able to treat the glycosylation aspect of PGM1-deficiency, there is no treatment for the cardiac complications in this disorder. Therefore, there is a critical need to understand the role of PGM1 in the heart and propose new cardiac-specific therapies. Here, by leveraging multiomics approach on human induced pluripotent stem cell-derived cardiomyocytes (iCMs) from individuals with PGM1 deficiency, we show that PGM1 deficiency results in profound changes in energy metabolism and extracellular matrix (ECM). Moreover, by in silico drug repurposing, we identify several drug candidates that might treat cardiac failure possibly by upregulating energy metabolism and downregulating ECM and improve the clinical outcome in affected individuals.