MOLECULAR PATHOLOGY OF Β-THALASSEMIA: CLINICOGENETIC EVALUATION OF HBB GENE MUTATIONS IN AFFECTED POPULATIONS: A CROSS-SECTIONAL STUDY

Abstract

Background: One of the most common inherited hemoglobinopathies worldwide is β-thalassemia, in which the production of the β-globin chain is absent because of HBB gene mutations. The knowledge of population-specific mutation patterns is important in diagnosing, genetic counseling, and the development of successful prevention strategies. The purpose of this study was to assess the clinicogenetic range of HBB gene mutations within affected populations and to measure how these mutations relate to clinical phenotypes.

Methods: A cross-sectional study was conducted based on observations of 414 patients with confirmed β-thalassemia (major, n=289; intermediate, n=125). Records and structured interviews were used to gather demographic, clinical, and laboratory data. ARMS-PCR was used to detect mutations, with Sanger sequencing in unresolved cases. Genotype groups (homozygous IVS-I-5 [G>C], homozygous Codon 41/42 [ -TCTT], compound heterozygotes, and rare/other variants) were used to assess patients. Students’ t-test and Chi-square tests were used to conduct comparative analyses, and multivariate logistic regression evaluated the independent association of genotype and transfusion requirement, controlling effects of socioeconomic status and consanguinity.

Results: Patients with β-thalassemia major have a prior diagnosis (mean 1.9 ± 1.2 years vs. 6.8 ± 3.4 years, p<0.001), more splenectomy, 98 (33.9%) vs. 18 (14.4% ), p=0.001, iron overload, 172 (59.5%) vs. 42 (33.6%), p<0.001), and seropositive to HCV, 42 (14.5%) vs. 6 (4.8%), p=0.003. IVS-I-5 (G>C), 172 (41.5%), Codon 41/42 (–TCTT), 87 (21.0%), and IVS-I-1 (G>T), 61 (14.7%), were the most common mutations. Homozygous IVS-I-5 was higher in major as compared to intermediate, 138 (47.8%) vs. 34 (27.2%), p<0.001. Homozygous IVS-I-5 was significantly correlated to regular transfusion dependence (OR=3.8, 95% CI: 2.169, p<0.001), but not to codon 41/42 or compound heterozygotes.

Conclusion: This study established that HBB mutation type, specifically homozygous IVS-I-5, was a significant determinant of transfusion-dependent β-thalassemia. Clinicogenetic testing of demographic, clinical, and molecular data can help understand disease heterogeneity and offer implications for prognostication, family counseling, and targeted screening programs in high-prevalence populations.