Beta-thalassaemia mutations and the underlying beta gene cluster haplotypes in the Greek population

The polymorphic sites across the beta gene cluster (restriction haplotypes) in association with specific thalassaemic mutations were analyzed in representative samples of normal and thalassaemic Greeks in comparison to similar data of other populations around the mediterranean basin. We studied 316 normal chromosomes, 218 chromosomes from patients with thalassaemia major and 72 chromosomes from patients with thalassaemia intermedia. In the former group, haplotype frequencies followed the order I, IX, II, V etc.. In the group of patients with transfusion-dependent thalassaemia the order was I, II, V and VI, while in those with thalassaemia intermedia the most frequent haplotypes were I and VI. The frequency of haplotypes I and VI was higher among the thalassaemic chromosomes in comparison to those of the normal population; haplotype IX showed the inverse relation. These findings imply that the thalassaemic mutations occurred at a very early stage on haplotypes I and VI and much later on haplotype IX. Micromapping did not reveal any significant variations. Haplotypes I, II, V and VI were associated with the molecular defects IVS-1 nt 110, beta zero-39, IVS-1 nt 1 and IVS-1 nt 6 respectively. A number of other mutations were also identified. The molecular defect was identified also on a random sample of beta-thalassaemia carriers (424 chromosomes). On the basis of the overall data, the feasibility of prenatal diagnosis of thalassaemia by allele specific hybridization is ca. 80%, with the four most common oligomers and 95% when the set of probes expands to eight.