A CASE OF NON-BETA-GLOBIN GENE LINKED BETA-THALASSEMIA IN A DUTCH FAMILY WITH 2 ADDITIONAL ALPHA-GENE DEFECTS - THE COMMON -ALPHA(3-CENTER-DOT-7) DELETION AND THE RARE IVS1-116 (A-]G) ACCEPTOR SPLICE-SITE MUTATION

We describe a family with beta thalassaemia, apparently not linked to the beta-globin gene cluster, in combination with or 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 HbA(2) concentration, which is usually increased in beta thalassaemia, was normal. The in vitro biosy nthetic rate of the globin chains was strongly unbalanced even in the presence of a coexisting alpha-thalassaemia defect. Routine analysis o f the beta genes, including the promoter region, was performed repeate dly by polymerase chain reaction (PCR), denaturing gradient gel electr ophoresis (DGGE) and direct sequencing. No molecular abnormalities wer e detected. Large beta deletions were excluded by haplotype determinat ion, using seven polymorphic markers distributed over an area of 50 kb , from 1 kb 5' of the epsilon gene to 4kb 3' of the beta gene. The hap lotype analysis of the beta-gene cluster revealed that the unaffected daughter had received the same beta haplotype as her beta-thalassaemic brother from their beta-thalassaemic father. These data suggest that the beta-gene cluster shared by father and son was not directly associ ated with a reduced beta-globin chain expression. In order to exclude the remote possibility of a beta-locus-control region (LCR) rearrangem ent in the paternal haplotype of the daughter, the sequence of the HS2 element was examined in the nuclear family. We compared the haematolo gical and clinical data of this family with the data reported in the l imited number of similar cases. We discuss the possibility that the mu tation of a trans-acting erythroid factor(s), not linked to the beta-g enes cluster, may impair the beta-gene expression of both alleles.