Common origin of a rare beta-globin initiation codon mutation (ATG-->AGG) in Asians

In this report, we describe two Thai siblings presenting with mild hypochromic microcytic anaemia and splenomegaly since 2(1/2) years of age. However, both patients were otherwise well with normal weight and height development and did not require transfusion during the 6-year follow-up period. Haematological and haemoglobin analyses were consistent with the clinical diagnosis of Hb E/beta-thalassaemia disease. To provide proper genetic counselling for this family, a definitive diagnosis of beta-thalassaemia was achieved using molecular analysis. We identified a rare initiation codon mutation (ATG-->AGG) of the beta-globin gene in combination with the Hb E mutation (codon 26: GAG-->AAG). The initiation codon mutation has previously been reported in several East Asian populations but has never been found in Southeast Asia and in combination with Hb E before. The haplotype analysis revealed a common origin of this mutation in the Asian population (5': - + - + + - +: 3', type IV with framework 3 according to Orkin S, et al.). Although this rare mutation abolished the beta-globin expression and was considered as beta(0)-thalassaemia, the relatively mild phenotype in our patients may be attributed to a strong association between this mutation and the -158 (G)gamma (C-->T) polymorphism, an XmnI cleavage site (+), resulting in a high propensity of postnatal gamma-globin expression and ameliorating the clinical phenotypes.