Severe Transfusion-Dependent Infantile Hemolytic Anemia Associated With a Novel Homozygous PKLR Variant of Uncertain Significance (c.1376C>G, p.Ala459Gly) and Coexisting G6PD Deficiency: A Case Report.

Pyruvate kinase deficiency (PKD) results from pathogenic variants in the PKLR gene and demonstrates marked clinical heterogeneity ranging from compensated hemolysis to severe transfusion-dependent anemia; however, novel variants continue to expand the genotypic spectrum of the disease. We report a case of a 10-month-old girl with transfusion-dependent chronic hemolytic anemia found to harbor a novel homozygous PKLR missense variant c.1376C>G (p.Ala459Gly). This variant has not previously been reported in the literature and was classified as a variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. This report expands the mutational spectrum of PKD and highlights the importance of molecular testing in infants with unexplained chronic hemolytic anemia, especially in populations with high consanguinity rates. Although functional validation of the identified PKLR variant was not available, the patient's clinical and hematologic phenotype was highly consistent with severe PKD, supporting the variant as a candidate disease-associated alteration.