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

Authors

Ying Zhao, Jiwu Lou, Youqing Fu, Yunshi Dai, Wanling Ye, Fuxiao Liang, Tizhen Yan

Published in

Hemoglobin. Pages 1-7. Jul 27, 2026. Epub Jul 27, 2026.

Abstract

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.

PMID:
42509210
Bibliographic data and abstract were imported from PubMed on 28 Jul 2026.

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