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 Sβ0-thalassaemia in which the β0-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 βS 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.
- haematology (incl blood transfusion)
- clinical genetics
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Contributors XW, JZX, DS, MP and SLT wrote the manuscript. AC and LM retrieved data. All authors have reviewed and edited the manuscript.
Funding This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (SLT and MP) and the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH, DS). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology and the Office of the Director at the National Institutes of Health (1ZIAHG200362).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study has been approved by the National Heart, Lung, and Blood Institute’s Investigational Review Board (NCT#00011648).
Provenance and peer review Not commissioned; externally peer reviewed.