Mosaic pathogenic PRKAG2 variant and pathologic diagnosis of glycogen storage disease in an infant with negative whole-genome sequencing.

PRKAG2 syndrome is a rare, autosomal dominant, glycogen storage disease of the heart characterized by a triad of ventricular hypertrophy, progressive conduction abnormalities, and pre-excitation. In severe cases, patients may present with neonatal onset of significant ventricular dysfunction with outflow obstruction resulting in sudden cardiac death or the need for transplantation. We present a unique case of an infant with non-diagnostic whole genome sequencing who developed progressive biventricular hypertrophy, ultimately requiring mechanical circulatory support and heart transplantation. Pathological evaluation of the explanted heart revealed excessive free glycogen accumulation within cardiomyocytes. Genetic testing identified a mosaic PRKAG2 pathogenic variant, confirming the diagnosis of PRKAG2 syndrome. This case suggests mosaicism should be considered in the diagnostic workup of early-onset cardiomyopathy.