Asymptomatic and mild β-thalassemia in homozygotes and compound heterozygotes for the IVS2+1G>A mutation: role of the β-globin gene haplotype

Background and Objectives. We report on two families in which the β0-thalassemia mutation IVS2+1G→A occurs either in the homozygous or compound heterozygous condition with other β-thalassemia determinants. In the first family the proband, homozygous for the IVS2+1 determinant, is asymptomatic and was detected by chance during a screening program for β-thalassemia. In the second family, the proband is a 43-year old female with a very mild thalassemia intermedia due to compound heterozygosity for the IVS2+1G>A and IVS1+110G>A mutations. Her father was diagnosed as having a thalassemic disorder only during the family studies carried out because of the proband's condition. He is a compound heterozygote for the Sicilian type δβ0-thalassemia and the IVS2+1 mutation and has a normal level of hemoglobin. Design and Methods. In both families, the heterozygous carriers of the IVS2+1G>A have unusually elevated levels of fetal hemoglobin (HbF), and the homozygotes showed 98% HbF, reflecting an increased production of well hemoglobinized F-cells not associated with a significant erythroid expansion. Results. The high HbF levels co-segregate with the β0thalassemia mutation; the size and structure of both pedigrees do not allow the contribution of unlinked genes to the elevated production of HbF to be assessed. Interpretation and Conclusions. We propose that the unusual phenotypes resulting from homozygosity and compound heterozygosity for IVS2+1 are, against the background of a polygenic quantitative control of HbF expression, principally due to elements, such as repetitive sequences or single nucleotide polymorphisms, within or closely linked to the β-gene cluster. These are potentially implicated in chromatin environment modifications, and could, therefore, be responsible for sustained HbF synthesis during development.