Co-inherited β-thalassemia and hereditary elliptocytosis associated with EPB41 mutations in a Chinese family: a case report

β-Thalassemia is a common inherited disorder of hemoglobin synthesis in southern China, primarily caused by point mutations and small deletions or insertions in the β-globin gene (HBB). Hereditary elliptocytosis (HE) is a red blood cell membrane disorder characterized by elliptical erythrocytes. The coexistence of β-thalassemia and hereditary elliptocytosis is exceedingly rare and may present a diagnostic challenge due to overlapping hematological characteristics. We conducted a molecular investigation in a proband with chronic hemolytic anemia from a Chinese family to clarify the underlying etiology and associated clinical manifestations. Hematological and biochemical evaluations, hemoglobin fraction analysis, and α- and β-globin gene analysis using third-generation sequencing were performed in the proband and family members. Whole-exome sequencing (WES) was performed to identify candidate variants, followed by confirmation via Sanger sequencing; pathogenicity was assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Two heterozygous EPB41 variants NM_001376013.1(EPB41):c.906-1G > A and NM_001376013.1(EPB41):c.731 A > G were identified and confirmed by Sanger sequencing, demonstrating co-segregation with the elliptocytic phenotype in affected family members. Both variants are documented in gnomAD and dbSNP; NM_001376013.1(EPB41):c.731 A > G is also listed in ClinVar (Variation ID: 2194273). In addition, a frameshift mutation in the HBB gene NM_000518.5:c.126_129delCTTT, consistent with β-thalassemia, was identified. Integration of peripheral blood morphology, family segregation, and molecular genetic findings supported a diagnosis of co-inherited hereditary elliptocytosis and β-thalassemia. This report expands the genotype–phenotype spectrum of EPB41-associated hereditary elliptocytosis and highlights the diagnostic utility of integrating morphology and genetics in complex anemias.