Review Articles
Vol. 18 No. 1 (2026): Mediterranean Journal of Hematology and Infectious Diseases
COMPREHENSIVE REVIEW OF GENETIC AND EPIGENETICS REGULATION OF FETAL HEMOGLOBIN IN β-HEMOGLOBINOPATHIES: FROM MOLECULAR MECHANISMS TO CLINICAL APPLICATIONS
HbF Genetics in Anemia
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: April 30, 2026
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Fetal hemoglobin (HbF) is the predominant form of hemoglobin during fetal life, facilitating efficient oxygen transfer from maternal to fetal circulation. At birth, HbF accounts for approximately 10–30% of total hemoglobin; however, its levels decline rapidly within the first year of life, with only minimal amounts remaining in healthy adults. Interestingly, certain genetic and acquired hematological disorders, including β-thalassemia, sickle cell anemia (SCA), and hereditary persistence of fetal hemoglobin (HPFH), are associated with persistently elevated HbF levels. These conditions frequently present with anemia, defined as hemoglobin concentrations below 12.0 g/dL in women and 13.0 g/dL in men, resulting in fatigue, pallor, and other clinical complications. Consequently, strategies that can modulate HbF levels hold significant therapeutic potential for the management of anemia in β-hemoglobinopathies. Recent advances in molecular genetics have identified key genetic modifiers that regulate HbF expression. Among these, single nucleotide polymorphisms (SNPs) play a central role. Notably, the XmnI polymorphism located on chromosome 11p15, near the γ-globin gene promoter, has been associated with increased HbF production. Similarly, variants in the BCL11A gene on chromosome 2p16 and the HBS1L-MYB intergenic region on chromosome 6q23 have emerged as critical regulators of γ-globin gene silencing. Understanding how these genetic variants interact to influence HbF levels provides valuable insight into the pathophysiology of hemoglobinopathies. This review highlights the genetic mechanisms governing HbF expression, emphasizing their implications for therapeutic intervention. By elucidating the molecular pathways involved in HbF regulation, novel therapeutic approaches—such as pharmacological induction of HbF or gene-editing strategies—can be developed to ameliorate anemia severity, improve patient outcomes, and reduce the need for blood transfusions in individuals with β-thalassemia and sickle cell anemia.
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How to Cite
“COMPREHENSIVE REVIEW OF GENETIC AND EPIGENETICS REGULATION OF FETAL HEMOGLOBIN IN β-HEMOGLOBINOPATHIES: FROM MOLECULAR MECHANISMS TO CLINICAL APPLICATIONS: HbF Genetics in Anemia” (2026) Mediterranean Journal of Hematology and Infectious Diseases, 18(1), p. e2026046. doi:10.4084/MJHID.2026.046.
Copyright (c) 2026 Yousef Saeed Mohammad Abu Za’ror, Joseph Bagi Suleiman, Fatima Azzahra Delmani, Jehad Farouq Alhmoud, Amer Mohammad Ayasreh, Sarah Ihsan Al-wendawi, Maryam Azlan
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
