A frequent A?-persistence of fetal hemoglobin in northern Sardinia: its molecular basis and hematologic phenotype in heterozygotes and compound heterozygotes with ?-thalassemia

A survey of hemoglobinopathies in northern Sardinia revealed a high frequency (0.3%) of carriers of a hematologic condition characterized by increased expression of fetal hemoglobin during adult life (hereditary persistence of fetal hemoglobin or HPFH). In spite of a normal hematologic phenotype, the heterozygous carriers for this condition display about 12% HbF, almost exclusively of the Aγ type; compound heterozygotes with β-thalassemia have 20%–26% HbF and run a very mild clinical course. The sequence analysis of the cloned Aγ gene linked to the HPFH determinant revealed the presence of a G→A substitution at position-117 of the Aγ- gene promoter; the same mutation occurs also in Greek HPFH, although associated with different restriction polymorphisms. Another hereditary condition characterized by increased HbF (α2 Aγ2) level and a mild thalassemic phenotype in Sardinia is associated with the-196 C→T substitution in the Aγ-globin gene promoter (Sardinian δβ-thalassemia). Population studies using oligonucleotides complementary both to the-117 G→A and-196 C→T mutations and the corresponding normal sequences confirm the presence of these mutations only in HPFH and δβ-thalassemia chromosomes and exclude these changes being common DNA polymorphisms.