Annotated definition of BCL11A and HMIP-2 haplotypes through the analysis of sicilian ß-thalassemia patients with high levels of fetal hemoglobin.

Fetal hemoglobin (Hb F) is the principal ameliorating factor of ß-thalassemia (ß-thal) and sickle cell disease. Persistent production in adult life is a quantitative trait regulated by loci inside or outside the ß-globin gene cluster. From genome-wide association studies, principal quantitative trait loci (QTL) (accounting for 50.0% of Hb F variability in different populations) have been identified in the BCL11A gene, HBS1L-MYB intergenic polymorphism and the ß-globin gene cluster itself. In this study, we analyzed quantitative trait haplotypes in two Sicilian families with extremely mild ß-thal and unusually high Hb F expression, in order to examine possible genetic background variations in a similar ß-thalassemic phenotype. This study redefines the linkage disequilibrium blocks at these loci, but also shows slight differences between probands in haplotype combinations which could reflect different mechanisms of high Hb F production in patients with ß-thal. We proposed a haplotype-based approach as a useful tool for the understanding of ß-thal phenotype variation in patients with similar ß-thalassemic backgrounds in an attempt to answer the recurring question of why patients with the same ß-thalassemic genotype show different phenotypes.