Phenotype variability of the dominant beta-thalassemia induced in four Dutch families by the rare cd121 (G -> T) mutation

Eight patients who were carriers of beta-thalassemia induced by the cd121 ( G-->T) mutation are described in four nonrelated Dutch families. This mutan t, which is considered rare and inherited in a dominant manner, is expresse d in a different way among each of the four families and even among carrier s of the same family. The symptoms vary from an hemolytic anemia of interme diate gravity with hepatosplenomegaly, inclusion bodies and erythroblastosi s, to a mild anemia with minor hematological abnormalities. We report the a nalytical procedures used for the detection of the mutant, the hematologica l and clinical data of the four families and discuss the variable physiopat hology of this molecular defect. We also compare the variation in fetal hem oglobin expression in relation to the haplotypes of the beta-gene cluster a nd to the different hematological conditions. The presence of this rare mut ant in four nonrelated Dutch families could derive from a single mutation o r from multiple events. The existence of the four mutations in three differ ent haplotypes suggests the occurrence of at least two independent events. The presence of five abnormal hemoglobins and the beta-thalassemia defect o n different haplotypes at cd121 also suggests a relatively increased rate o f mutations at this particular site.