The triplicated α‐globin gene locus in β‐thalassaemia heterozygotes: clinical, haematological, biosynthetic and molecular studies

Excess α‐globin chains play a major role in the pathophysiology of homozygous β‐thalassaemia. In β‐thalassaemia carriers a minor effect of α‐globin chain excess is reflected in a minimal or mild anaemia without clinical symptoms. Factors that increase α‐chain excess in heterozygotes are expected to accentuate the severity of the clinical and haematological phenotype. We report the clinical, haematological, biosynthetic and molecular data in three β‐thalassaemia heterozygotes with the rare interaction of homozygosity for α‐globin gene triplication, and in 17 heterozygotes with a single additional α‐globin gene. The three patients homozygous for the α‐globin gene locus (anti 3.7 kb arrangement) had β °‐thalassaemia mutations and a diagnosis of thalassaemia intermedia, preserving haemoglobin levels around 7–8 g/dl. Of the 17 β‐thalassaemia heterozygotes (six children and 11 adults), 16 had severe β‐thalassaemia mutations interacting with an additional α‐globin gene (13 with ααα anti‐37 and four with ααα anti‐42 ). Compared to simple β‐thalassaemia heterozygotes, they had lower haemoglobin levels and red cell indices, but higher α/β biosynthesis, HbF levels and reticulocytes. Our results suggest that homozygous α‐gene triplication interacts with a severe β‐thalassaemia mutation to cause an α‐chain excess equivalent to that observed in homozygous β‐thalassaemia intermedia. In heterozygotes for severe β‐thalassaemia mutations with one additional α‐globin gene, the α‐chain excess causes a more pronounced degree of anaemia than is usually seen in simple β‐thalassaemia heterozygotes.