Hematological and genetic basis of clinical heterogeneity of HemoglobinE/β-thalassemia in Bangladesh

Abstract Patients with HbE/β-thalassemia inheriting the same β-globin mutations display varied clinical manifestations, the mechanism of which is only partially known. The study aimed to decipher the heterogenous basis of HbE/β-thalassemia patients in more details by focusing on both hematological and genetic modifiers influencing the disease severity, which included-(i) HbF and HbE levels using Hb electrophoresis, (ii) β-thalassemia mutations, (iii) αααanti3.7triplication using Gap-PCR, (iv) individual and cumulative effects of HbF-inducing SNPs in 4 major modifier genes, namely HBG2, BCL11A, HBSB1L_MYB intergenic-region, and HBBP1 which were genotyped using DNA sequencing and Real-time PCR-HRM methods. Accordingly, 130 diagnosed Bangladeshi patients with HbE/β-thalassemia were enrolled and categorized as mild, moderate, and severe as per Mahidol scoring system. c.79G>A+IVS1_5G>C was the most predominant (73.8% of total) mutation pair across all the 3 severity groups, indicating secondary modifiers might influence the severity. Our study found both HbF and HbE protective to HbE/β-thalassemia, as both were inversely related to the severity score (HbF: p