A C----G mutation at nt position 6 3' to the terminating codon may be the cause of a silent beta-thalassemia

We describe the hematological and clinical data for a young Greek patient with beta-thalassemia intermedia and for several members of her family. The patient had inherited the common IVS-I-1 (G----A) mutation from her mother, while the second beta-globin gene had a C----G mutation at position 6 3' to the terminating codon (term. + 6). Her father and three additional relatives with a heterozygosity for this newly discovered mutation had no hematological abnormalities, normal Hb A2 values, and a nearly normal in vitro chain synthesis ratio. Analyses of nearly 500 additional beta-thalassemia and normal chromosomes failed to detect this mutation which eliminates it as a common polymorphism. Although our findings may indicate a rare polymorphism, the probability that it represents the cause of diminished beta chain synthesis is very high indeed. We suggest that the C----G mutation in this untranslated region of the beta-globin gene causes a slight decrease in the stability of the mRNA which becomes clinically important only in situations when beta chain synthesis in trans is eliminated.