Abstract
BACKGROUND: Mutations of HBB give rise to two prevalent haemoglobin disorders-sickle cell disease (SCD) and β-thalassaemia. While SCD is caused by a single base substitution, nearly 300 mutations that downregulate expression of HBB have been described. The vast majority of β-thalassaemia alleles are point mutations or small insertion/deletions within the HBB gene; deletions causing β-thalassaemia are very rare. We have identified three individuals with haemoglobin Sβ(0)-thalassaemia in which the β(0)-thalassaemia mutation is caused by a large deletion. OBJECTIVE: To use whole genome sequence data to determine whether these deletions arose from a single origin. METHODS: We used two approaches to confirm unrelatedness: pairwise comparison of SNPs and identity by descent analysis. Eagle, V.2.4, was used to generate phased haplotypes for the 683 individuals. The Neighbor-Net method implemented in SplitsTree V.4.13.1 was used to construct the network of haplotypes. RESULTS: All three deletions involved 1393 bp, encompassing the β-promoter, exons 1 and 2, and part of intron 2, with identical breakpoints. The cases were confirmed to be unrelated. Haplotypes based on 29 SNPs in the HBB cluster showed that the three individuals harboured different β(S) haplotypes. In contrast, the haplotype harbouring the 1393 bp deletion was the same in all three individuals. CONCLUSION: We suggest that all the reported cases of the 1393 bp HBB deletion, including the three cases here, are likely to be of the same ancestral origin.