Fetal hemoglobin elevation in Hb lepore heterozygotes and its correlation with β globin cluster linked determinants

We have analysed, at the hematological and molecular level, 51 Hb lepore heterozygotes and three compound heterozygotes for Hb Lepore and HbS (HbLep/HbS) in 26 unselected Portuguese families. The Lepore Boston variant was present in one family, in association with classical haplotype V. All of the other Lepore alleles present haplotype III in association with Xmnl (+)5′ of ^Gγ gene, in tight linkage disequilibrium to the major mutation found in the Portuguese population, the Lepore Baltimore variant (δ^68Leu-β^84Thr). The three compound heterozygotes are the first HbLep/HbS individuals reported in the literature, with the Lepore Baltimore mutation linked to haplotype III. In agreement with other studies, these Lepore Baltimore heterozygotes have higher HbF (1.4-14.1% of total hemoglobin) than published cases of Lepore Boston (0.8-5.4%), which is associated with Xmnl(-). Among the Lepore Baltimore heterozygotes, the (AT)_xT_y repeat region at -540 bp of the β globin gene in trans to the Lepore chromosome, can account for much of the variability in HbF level. The allele (AT)₇T₇ is associated with lower HbF, and (AT)₉T₅ is associated with higher HbF. As we previously reported for β thalassemic carriers, we observe in Lepore Baltimore carriers an effector in trans, linked to the (AT)_xT_y sequence, acting as an HPFH (Hereditary Persistence of Fetal Hemoglobin) determinant.