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

Abstract

In this report, we describe two Thai siblings presenting with mild hypochromic microcytic anaemia and splenomegaly since 21/2 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/β-thalassaemia disease. To provide proper genetic counselling for this family, a definitive diagnosis of β-thalassaemia was achieved using molecular analysis. We identified a rare initiation codon mutation (ATG → AGG) of the β-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 β-globin expression and was considered as β0-thalassaemia, the relatively mild phenotype in our patients may be attributed to a strong association between this mutation and the -158Gγ (C → T) polymorphism, an XmnI cleavage site (+), resulting in a high propensity of postnatal γ-globin expression and ameliorating the clinical phenotypes. © 2005 Blackwell Publishing Ltd.