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

BACKGROUND AND OBJECTIVES: We report on two families in which the beta(0)-thalassemia mutation IVS2+1G-->A occurs either in the homozygous or compound heterozygous condition with other beta-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 beta-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 deltabeta(0)-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 beta-thalassemia 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 beta-gene cluster. These are potentially implicated in chromatin environment modifications, and could, therefore, be responsible for sustained HbF synthesis during development.