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.

Molecular heterogeneity of beta-thalassemia in Algeria: how to face up to a major health problem.

This study concerns the molecular characterization of beta-thalassemia (beta-thal) alleles in 210 chromosomes. In the studied population, mutations were detected in 98% of the beta-thalassemic chromosomes. Twenty-one molecular defects have been found, where the five dominant mutations, IVS-I-110 (G>A), nonsense mutation at codon 39 (C>T), the frameshift codon (FSC) 6 (-A), IVS-I-1 (G>A), and IVS-I-6 (T>C), account for 80% of the independent chromosomes. Among the remaining alleles, 16 different mutations were identified, half of them being described for the first time in Algeria. These include the -101 (C>T) and the -90 (C>T) mutations in the distal and proximal promoter elements, respectively, the FSC 8 (-AA), IVS-I-5 (G>T), IVS-I-128 (T>G), FSC 47 (+A), IVS-II-1 (G>A), and the substitution in the polyadenylation signal (poly A) site AATAAA>AATGAA. Haplotype analyses on rare variants were performed. The possible origin of these mutations either by founder effect or by migrations is discussed, and raises the question of an adequate strategy to be used adapted to socio-economical status.