Fetal Hemoglobin Modulation in Sickle Cell Disease: βs Haplotypes, Key Polymorphisms Identified by GWAS, and Advances in γ-Globin Editing: An Updated Overview

Fetal hemoglobin (HbF) plays a central role in mitigating the pathophysiological effects of sickle cell disease (SCD). Understanding the genetic determinants influencing HbF expression is essential for identifying the factors contributing to its modulation. This review provides an updated synthesis of evidence on HbF modulation, focusing on βs haplotypes and their molecular characterization through Sanger sequencing, polymorphisms consistently associated with HbF levels in genome-wide association studies (GWAS), and recent advances in gene editing targeting HbF expression. An integrative review (2016–2025) was conducted using PubMed/MEDLINE, Scopus, and Web of Science, encompassing original research, experimental studies, systematic reviews, and genomic analyses. Key regulatory loci such as BCL11A, HBS1L-MYB (HMIP), and the HBB cluster explain a significant proportion of HbF variability across populations. Furthermore, additional variants in KLF1, NFIX, BACH2, and ZBTB7A have emerged as potential modulators in specific cohorts. Regarding advances in γ-globin editing, “prime editing”, although still in the experimental phase, has recently emerged as an innovative approach capable of introducing multiple HPFH-like mutations within γ-globin promoters, expanding future therapeutic possibilities in SCD. This review also provides a comparative overview of prime editing and other gene-editing strategies for HbF modulation, such as CRISPR-Cas9 and Base editing. Collectively, this work outlines the current landscape of HbF modulation and provides an informative basis for future research aimed at advancing precision-oriented therapeutic strategies in sickle cell disease.