IDENTIFICATION IN SOUTHERN ITALY OF -alpha3.7 THALASSEMIA ASSOCIATED WITH THE DELETION OF AC AT POSITION -2 AND -3 PRECEDING THE AUG CODON

alpha-thalassaemia may be caused by large deletions of the alpha-globin gene(s), or rarely, non-deletional mutations. Both types of mutations may co-exist, and if located on the same allele can cause an alpha0-thalassemia phenotype, producing a reproductive risk of hydrops fetalis. In a study on the molecular epidemiology of alpha-thalassemia in Southern Italy we found that the most frequent mutant is the -alpha3.7 deletion with a relative frequencies of 58%. Some asymptomatic patients with -alpha3.7 thalassaemia trait and normal iron status were noted to have significant microcytosis that was insufficiently explained by a single -alpha3.7 deletion. Molecular characterization revealed the deletions of AC at the dinucleotides preceding the AUG codon, associated to the -alpha3.7 allele1. An ARMS protocol was set up for the direct identification of the -alpha3.7-AC and used for the wide analysis of about 700 -alpha3.7 alleles2. The analysis of the data indicated the presence of the -AC microdeletion in 5% of the -alpha3.7 carriers, in families coming from different Italian regions. T-Test analysis revealed that the MCV and MCH value of 35 -alpha3.7-AC carriers was intermediate and with difference statistically significant respect either to alpha+thal and alpha0thal carriers. We observed also complex genotype: in 2 unrelated families, with high level of Hb A2 (5.8-6.1), the patients were double heterozygotes for -alpha3.7-AC and alpha-thalassemia; 2 members of 1 family were compound heterozygotes for the -alpha3.7-AC/alphaPolyA SAalpha; 1 patient was homozygotes for the -alpha3.7-AC. The last two class of patients are very interesting to highlights the weak contribution of the -alpha3.7-AC allele to the synthesis of alpha-globin gene as indicated by the severe phenotype with Hb value respectively of 10.4 and 7.2 (compound heterozygotes) and 8.4 (homozygotes). The homozygote -alpha3.7-AC patients showed a typical HbH disease phenotype with the presence of 7.7% of HbH. These data indicated that the -alpha3.7-AC show a severe phenotype and is present in Italy: its identification through accurate genotyping of alpha-globin determinant is absolutely required considering that could give rise to a reproductive risk for Hb Bart's hydrops fetalis if in association with a alpha0 thal. 1. Morle F et al. EMBO J 1985;4:1245-1250 2. Lacerra G et al, Hematologica 2007,92(2):254-5