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

## TL;DR

This study finds that β-thalassaemia trait is rare in Nigeria, even among those with sickle cell disease, and highlights the importance of genetic testing over screening methods for accurate diagnosis.

## Contribution

The first molecular confirmation of β-thalassaemia trait prevalence in the Yoruba population and identification of two rare genetic variants.

## Key findings

- Molecular analysis revealed a β-thalassaemia trait prevalence of less than 1% in both groups.
- Two rare variants (rs537944366T>C and rs33915217C>A) were identified for the first time in the Yoruba population.
- The β-thalassaemia mutation was found on a minor ancestral haplotype atypical of Africa.

## Abstract

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.

To ascertain the prevalence and genetic basis of β-thalassaemia trait in Nigerians with and without SCD.

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.

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.

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.

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.