Whole genome sequence-based haplotypes reveal a single origin of the 1393 bp <i>HBB</i> deletion.

Abstract

Mutations of <i>HBB</i> 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 <i>HBB</i> have been described. The vast majority of β-thalassaemia alleles are point mutations or small insertion/deletions within the <i>HBB</i> gene; deletions causing β-thalassaemia are very rare. We have identified three individuals with haemoglobin Sβ⁰-thalassaemia in which the β⁰-thalassaemia mutation is caused by a large deletion. To use whole genome sequence data to determine whether these deletions arose from a single origin. 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. 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 <i>HBB</i> 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. We suggest that all the reported cases of the 1393 bp <i>HBB</i> deletion, including the three cases here, are likely to be of the same ancestral origin.