Molecular basis and haematological characterization of β‐thalassaemia major in Taiwan, with a mutation of IVS‐1 3’end TAG → GAG in a Chinese patient

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Abstract
Summary We studied 41 patients with β‐thalassaemia major and their parents by using a combination of polymerase chain reaction (PCR) amplification, slot‐blot hybridization of allele‐specific oligonucleotide (ASO), and direct genomic sequencing. Eight different point mutations were characterized. C to T substitution at nucleotide (nt) 654 of intervening sequences (IVS) 2, accounting for 46.3% of mutant β‐globin genes, is the most common mutation in Taiwan, followed by frameshift codons 41/42 with four nucleotides (TCTT) deletion for 31.7%, A to G substitution at position −28 of promotor area for 8.5%, A to T substitution at codon 17 for 6.1%, frameshift codons 27/28 (insertion of C) for 2.4%, G to T substitution at nucleotide 1 of IVS‐1 for 2.4%, frameshift codons 71/72 (insertion of A) and IVS‐1 3’end TAG→GAG for 1.2%. The former four mutations showed no obvious difference between two major ethnic groups in Taiwan. As to mutations in each individual of β‐thalassaemia major, the incidence of compound heterozygotes of two different mutations is much higher than homozygotes of single mutation, 78.0%v 22.0%. Compound heterozygotes of C to T substitution at nt 654 of IVS‐2 and frameshift codons 41/42 with four nucleotides deletion is the most common pattern of β‐thalassaemia mutations in each individual (41.5%). The results are somewhat different from other documented reports concerning the mutations of β‐thalassaemia in southern China. This is the first report of mutation of IVS‐1 3’end TAG→GAG which causes consensus change in Chinese people. Patients with heterozygotes of β° and –28 β+‐thalassaemia mutations would have a greater delay in initial transfusion in comparison to patients with homozygotes of both β°‐thalassaemia mutation, but their initial clinical manifestation might be aggravated when combined with a glucose‐6‐phosphate dehydrogenase (G‐6‐PD) deficiency and an insult such as exposure to infection and certain drugs.