Abstract
Background: Sickle Cell Disease (SCD) in India exhibits unique genetic and phenotypic diversity, shaped by the predominance of the Arab-Indian haplotype, frequent co-inheritance of β-thalassemia and α-thalassemia mutations, and modulation by HbF-promoting genetic variants. Despite the high disease burden, comprehensive insights into the mutation landscape and its phenotypic implications in the Indian population remain fragmented. We aimed to systematically review the spectrum of genetic variants associated with Indian SCD including β-globin gene mutations, α-thalassemia, and HbF-modifying loci and analyze their correlations with hemoglobin profiles and disease severity.
Methods: A systematic search of PubMed, Scopus, and Web of Science was conducted from January 1990 to June 2025. Eligible studies reported molecular and hematologic data from Indian patients with homozygous SCD or sickle/β-thalassemia. Inclusion criteria required genotyping for β-globin mutations, α-globin deletions/triplications, and HbF-associated loci (BCL11A, HBS1L-MYB, and Xmn1 polymorphism). Data on genotype frequency, HbF levels, and clinical outcomes were extracted and analyzed.
Results: Six studies encompassing over 1,400 Indian SCD patients were included. The Arab-Indian haplotype emerged as the predominant β-globin background, consistently associated with elevated fetal hemoglobin (HbF) and milder disease severity. α-thalassemia co-inheritance was reported in 27–30% of cases, reducing hemolysis and anemia. One study demonstrated the utility of HbS trimodal distribution as a cost-effective proxy for α-thalassemia screening. Genetic variants in BCL11A (rs1427407, rs11886868) and Xmn1 (rs7482144) showed significant positive correlation with HbF levels and reduced clinical complications, while HBS1L-MYB variants had inconsistent effects. An antenatal study further highlighted early co-inheritance of these modifiers. Patients harboring favorable genotypes exhibited better hydroxyurea response, with fewer transfusions and crises. A regional analysis identified a rare atypical haplotype in Andhra Pradesh, suggesting haplotypic diversity and possible gene conversion.
Conclusions: Indian SCD is genetically heterogeneous, with substantial influence of co-inherited hemoglobinopathies and fetal hemoglobin–modulating loci on disease expression. These findings support the integration of genetic screening into routine care and highlight the need for genotype-informed strategies for treatment optimization and future gene therapy eligibility.
