Significance of variant annotation for molecular diagnosis of thalassaemia.

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. We read with great interest the article by Zhuang …