The great heterogeneity of thalassemia molecular defects in Sicily

This paper reports the results of 1428 beta-thalassemia chromosomes studied in Sicily during a hemoglobinopathy control program starting in 1983. Molecular screening was performed by direct restriction enzyme analysis, allele specific oligonucleotide (ASO) hybridization, reverse dot blot analysis (RDB) and, for the rare or new mutations, by direct sequencing of polymerase chain reaction (PCR) products. Using these approaches 1410 (98.7%) out of 1428 beta-globin gene defects were characterized, involving 22 different beta-thalassemia mutations. Three of these were present at high frequency (beta(0)39, IVS1, 110 and IVS1,6); the other beta-globin gene defects were found at lower frequency. In the latter, we found a smaller group of mutations at a frequency lower than 10% (IVS1, 1, IVS2, 745, beta S) and a larger one at a frequency lower than 2% [-87, IVS1,2, IVS2,1, fr 6, fr 8 (-AA), fr 44, fr 76, -101, IVS1, 116, IVS1, 3'end G-C, IVS1,5 G-A, IVS1,5 G-C, cod 30, Lepore, delta beta, beta C]. The possible origin of this very large number of mutations is discussed, taking into account the historical point of view. Moreover, this approach has made a first trimester prenatal diagnosis program possible in our region in practically all cases, with a great improvement in general thalassemia management.