Genetic Analysis of Two Patients with Compound Thalassemia Presenting with Elevated HbF and Normal HbA2 Levels.

β-Thalassemia is a common inherited disorder caused by reduced or absent expression of the β-globin gene (HBB). In routine screening, co-inherited modifying mutations can result in normal HbA2 levels even in the presence of elevated HbF, potentially masking a diagnosis of heterozygous β-thalassemia. Here, we report two women of reproductive age who presented with microcytosis, hypochromia, normal HbA2, and elevated HbF. Full-length sequencing of the α-, β-, δ-, Aγ-, and Gγ- globin genes was performed using third-generation sequencing combined with Sanger sequencing. Both patients were heterozygous for β-thalassemia and shared common γ-globin mutations (HBG1:c.-29G > A, HBG2:c.-211C > T). Patient 1 carried HBB:c.126_129del CTTT and a single δ-globin mutation (HBD:c.-127T > C). Patient 2 carried HBB:c.52A > T and two δ-globin mutations in cis (HBD:c.-127T > C; c.262C > T). The combined effects resulted in normalized HbA2 and elevated HbF, thereby complicating the phenotypic presentation. These patients highlight that compound mutations can act as phenotypic modifiers and represent an important cause of missed or delayed diagnosis of β-thalassemia on routine screening. For individuals presenting with elevated HbF and "normal" HbA2 levels, comprehensive genetic testing of the δ- and γ- genes is recommended to achieve genotype-phenotype correlation.