The β-goblin gene architecture in individuals with and without sickle cell disease in Nigeria: Implications for β-thalassaemia trait diagnosis.

Background: β-thalassaemia is considered rare in Africa; however, recent screening-based studies suggest a β-thalassaemia trait prevalence of 6% - 10% among individuals with sickle cell disease (SCD) and up to 25% in those without SCD. Co-inheritance with SCD may modify disease severity, highlighting the need for molecular confirmation. Objective: To ascertain the prevalence and genetic basis of β-thalassaemia trait in Nigerians with and without SCD. Methods: We recruited 260 participants (130 per group; aged 3 years - 69 years, median [interquartile range] = 16 [9-29]). Haemoglobin fractions were analysed using high-performance liquid chromatography, and full blood counts were obtained. A 1.6 kb region of the β-globin gene was amplified and sequenced by Sanger sequencing. Variants were annotated and haplotypes constructed. An additional 26 samples from a separate SCD cohort were also genotyped. Results: Molecular analysis revealed a β-thalassaemia trait prevalence of < 1% in both groups, contrasting with recent screening-based reports. In addition to sickle cell, haemoglobin C, and β-thalassaemia mutations, eight other variants were identified, three of which were unique to SCD patients and in linkage disequilibrium. Sickle cell and haemoglobin C mutations occurred on the major ancestral haplotype, whereas the only β-thalassaemia mutation detected (rs33915217C>A) was associated with a minor ancestral haplotype atypical of Africa. Two rare variants (rs537944366T>C and rs33915217C>A) are reported for the first time in the Yoruba population. Conclusion: These findings indicate a low prevalence of β-thalassaemia trait in Nigeria and underscore the need to re-evaluate diagnostic approaches in African populations for optimal clinical management of SCD and other anaemias. What this study adds: This study provides the first molecular confirmation of the low prevalence of β-thalassaemia trait in the Yoruba population. It identifies two rare variants, including a β-thalassaemia mutation on a minor, atypical haplotype, and highlights the limitations of high-performance liquid chromatography, underscoring the importance of genetic testing for accurate diagnosis.