ALPHA-THALASSEMIA IN THE NETHERLANDS - A HETEROGENEOUS SPECTRUM OF BOTH DELETIONS AND POINT MUTATIONS

In this article we describe the molecular characterization of 104 inde pendent alpha-thalassemia patients identified by hematological analysi s and family studies. During the study, another six chromosomes were i dentified with rearrangements of the alpha-cluster or point mutations in the alpha(2)-globin gene, not associated with alpha-thalassemia, in healthy relatives of the patients. The molecular defects were establi shed by Southern blot analysis and, if no deletions could be identifie d, the alpha-globin genes were: investigated by denaturing gradient ge l electrophoresis and single strand conformation analysis for the pres ence of point mutations. Following this strategy, we were able to iden tify the molecular basis of 131 independent alpha-thalassemia chromoso mes. In two individuals, the alpha-thalassemia determinant could not b e demonstrated at the molecular level. We identified eight different d eletion and five non-deletion alpha-thalassemias, three rearrangements in the alpha-cluster, two alpha-chain variants, and a silent mutation in the alpha(2)-globin gene not associated with alpha-thalassemia. Th e large heterogeneity of alpha-thalassemia mutations seen in the Dutch population might be typical for nothern European countries where, bes ides the more common mutations; introduced by migration, a variety of sporadic mutations was also found in the autochthonous population. The screening strategy as described here, capable of identifying a wide s pectrum of both deletions and point mutations, identified 98% of the a lpha-thalassemia determinants present in 133 chromosomes.