Association of α globin gene quadruplication and heterozygous β thalassemia in patients with thalassemia intermedia.

Ten patients with thalassemia intermedia with variable severity and apparent simple heterozygosis for beta0 39 C>T nonsense mutation were submitted to clinical, hematologic and molecular studies. The presence of an unknown molecular defect (silent beta-thalassemia) unlinked to the beta cluster interacting with the heterozygous beta thalassemia, was previously postulated in these families. Analysis of the alpha globin gene cluster with PCR-based methods (MLPA, GAP-PCR, digestion with restriction enzymes) detected complex rearrangements in the alpha cluster. A duplication of the alpha globin gene locus, including the upstream regulatory region, was present in all the patients, associated in some of them with deletion or non-deletion alpha thalassemia. The variability of the clinical phenotype correlates with the degree of the globin chain imbalance. The presence of alpha globin cluster duplication should be considered in patients heterozygote for beta-thalassemia with thalassemia intermedia phenotype and in the carriers of suspected silent beta thalassemia.