A case of non-β-globin gene linked β thalassaemia in a Dutch family with two additional α-gene defects: The common -α^3.7 deletion and the rare IVS1-116 (A → G) acceptor splice site mutation

We describe a family with β thalassaemia, apparently not linked to the β-globin gene cluster, in combination with α thalassaemia. The propositus, an adult Dutch Caucasian male, and his son presented with microcytic hypochromic parameters. Their lysates displayed the normal adult pattern on electrophoresis. The HbA₂ concentration, which is usually increased in β thalassaemia, was normal. The in vitro biosynthetic rate of the globin chains was strongly unbalanced even in the presence of a coexisting α-thalassaemia defect. Routine analysis of the β genes, including the promoter region, was performed repeatedly by polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGGE) and direct sequencing. No molecular abnormalities were detected. Large β deletions were excluded by haplotype determination, using seven polymorphic markers distributed over an area of 50 kb, from 1 kb 5' of the β gene to 4 kb 3' of the β-gene. The haplotype analysis of the β-gene cluster revealed that the unaffected daughter had received the same β haplotype as her β-thalassaemic brother from their β-thalassaemic father. These data suggest that the β-gene cluster shared by father and son was not directly associated with a reduced β-globin chain expression. In order to exclude the remote possibility of a β-locus-control region (LCR) rearrangement in the paternal haplotype of the daughter, the sequence of the HS2 element was examined in the nuclear family. We compared the haematological and clinical data of this family with the data reported in the limited number of similar cases. We discuss the possibility that the mutation of a trans-acting erythroid factor(s), not linked to the β-genes cluster, may impair the β-gene expression of both alleles.