CALRins5-mediated clonal hematopoiesis causes severe hemolytic anemia in a female PGK1Ser320Asn carrier

Morales, M. L., Cano, H., de la Morena-Barrio, B., Vives-Corrons, J. L., Cuenca-Zamora, E. J., Garrido-Rodríguez, P., Bento, B., Pereira, J., Martínez Nieto, J., Cheng-Liang, TH., Fuster, JL., Caracena, S., Lozano, ML., Teruel-Montoya, R., Corral, J. & Ferrer-Marín, F. (2025). CALR ins5-mediated clonal hematopoiesis causes severe hemolytic anemia in a female PGK1 Ser320Asn carrier. Blood Cancer Journal, 15(1), 8.

DOI: 10.1038/s41408-025-01216-w

Hereditary hemolytic anemias (HHA) are rare inherited red blood cell (RBC) disorders caused by genetic abnormalities (hemoglobino/membrano/enzymopathies), characterized by anemia due to premature RBC destruction and intrinsic RBC defects. One of the rarer enzymopathies involves a deficiency in phosphoglycerate kinase 1 (PGK1), an X-linked gene critical for ATP production via glycolysis. PGK1 mutations causing deficiency (OMIM#300653) follow an X-linked recessive inheritance pattern, affecting hemizygous males, while female carriers are generally asymptomatic or may have mild symptoms -consistent with mosaicism for PGK1 activity-.

Despite PGK1 is ubiquitously expressed, its deficiency mainly affects the blood, central nervous system (CNS), and skeletal muscle, resulting in chronic hemolysis -with or without anemia-, neurological disorders, or myopathies. Likely explained by the causative PGK1 mutation, hemolytic anemias (HA) tends to co-occur with CNS defects, whereas myopathies are almost exclusively observed.

To date, approximately 40 patients harboring 30 different mutations have been reported. This report presents the first case of severe HA in a female PGK1 mutation heterozygous carrier, which became apparent coinciding with the diagnosis of essential thrombocythemia (ET); and elucidates the mechanism by which a clonal disorder transforms a germline recessive disease into a tissue-specific dominant condition.