α-Thalassemia in The Netherlands: a heterogeneous spectrum of both deletions and point mutations

Abstract

In this article we describe the molecular characterization of 104 independent α-thalassemia patients identified by hematological analysis and family studies. During the study, another six chromosomes were identified with rearrangements of the α-cluster or point mutations in the α₂-globin gene, not associated with α-thalassemia, in healthy relatives of the patients. The molecular defects were established by Southern blot analysis and, if no deletions could be identified, the α-globin genes were investigated by denaturing gradient gel electrophoresis and single strand conformation analysis for the presence of point mutations. Following this strategy, we were able to identify the molecular basis of 131 independent α-thalassemia chromosomes. In two individuals, the α-thalassemia determinant could not be demonstrated at the molecular level. We identified eight different deletion and five non-deletion α-thalassemias, three rearrangements in the α-cluster, two α-chain variants, and a silent mutation in the α₂-globin gene not associated with α-thalassemia. The large heterogeneity of α-thalassemia mutations seen in the Dutch population might be typical for nothern European countries where, besides 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 spectrum of both deletions and point mutations, identified 98% of the α-thalassemia determinants present in 133 chromosomes.