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Significance of variant annotation for molecular diagnosis of thalassaemia
  1. Kok-Siong Poon1,2,
  2. Evelyn Siew-Chuan Koay2,
  3. Karen Mei-Ling Tan1
  1. 1 Department of Laboratory Medicine, National University Hospital, Singapore
  2. 2 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  1. Correspondence to Kok-Siong Poon, Department of Laboratory Medicine, National University Hospital, Singapore 119074, Singapore; kok_siong_poon{at}

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Beta thalassaemia is one of the most common heritable haematological disorders worldwide. Although beta thalassaemia has an autosomal recessive mode of inheritance, the clinical presentations can be classified according to different categories of severity aligning to zygosity of the affected Beta Globin (HBB) gene and the effects of the pathogenic variants to beta globin chain production. Most of the beta globin variants have been named after the alphabets, geographical regions and HBB gene codons. Such ‘legacy’ tradition has also been commonly practised in naming alpha globin variants. Being the most studied gene in the human genome by the mid-1980s,1 the HBB gene is one of the earliest annotated genes. Located at 11p15.5,2 the HBB has three exons encoding 147 amino acids. The promoter and 5′ untranslated region (UTR) have multiple binding sites for transcriptional factors. The 3′ UTR contains a site of polyadenylation signal which is important for mRNA cleavage and RNA stability. Mutational spectrum of the HBB gene is highly heterogeneous, including mostly single-base substitutions, small insertions or deletions of one or a few bases in the gene sequences with functional importance. Many pathogenic variants reported in the intronic regions are known to and could potentially activate cryptic splice-sites affecting the transcribed mRNAs. The current standard genomic and mRNA reference sequences are NG_059281.1 and NM_000518.5, respectively.

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  • Handling editor Mary Frances McMullin.

  • Contributors KSP conceived the study, analysed the data, and wrote the manuscript. ESCK and KMLT critically appraised the data and wrote the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.