Genetic heterogeneity of β‐thalassemia in southeast sicily

Abstract

In this study we have defined the spectrum of the beta-thalassemia mutations, the beta-thalassemia haplotypes, and the genotype-to-phenotype correlations in a large number of patients with different beta-thalassemia conditions. Seventeen different beta-thalassemia mutations were detected which included one chromosome each with Hb Dhonburi and Hb Lepore. Five alleles, namely, codon 39 (C-->T), IVS-I-110 (G-->A), IVS-I-6 (T-->C), IVS-II-745 (C-->G), and IVS-I-1 (G-->A), account for 90% of all beta-thalassemia mutations in 846 thalassemic chromosomes studied. Haplotyping for a large number of subjects showed that the five common mutations are linked to a few haplotypes. The presence of milder mutations, mainly IVS-I-6 (T C), in about 19% of our patients explains some of the clinical variables. Among the 37 patients with thalassemia of intermediate severity, only 6 were homozygous or compound heterozygous for two severe alleles. The type of beta-thalassemia is the main factor responsible for differences in the phenotypic expression of the disease in patients with Hb S-beta-thalassemia; patients with Hb S-beta(+)-thalassemia are less severely affected than those with Hb S-beta(0)-thalassemia. The five most frequent mutations have comparable distributions all over Sicily.

Phenotype–genotype correlation in Sicilian patients with Hb H

“…Environmental and genetic factors, which can be dif®cult to evaluate, can be determinant in the manifestation of the disease. This is an aspect that we have frequently found in the study of hemoglobinopathies in the Sicilian population (2,25). The characterization of a-thal alleles in couples at risk and during pregnancy at risk for a-thal diseases is determinant, but an adequate genetic counselling must provide information not only regarding potential medical signi®cance and social burden of disease, but also with regard to its variability.…”

“…The incidence of carriers of at least one structural haemoglobin (Hb) variant is 2.5%, while the frequency of b-thalassemia (b-thal) alleles is up to 5.9% (1). The high frequency is accompanied by a marked molecular heterogeneity: 26 Hb variants and 17 different b-thal mutations have so far been identi®ed (1,2). In this context the a-thalassemia (athal) mutations have long been considered as not being common, probably due to the observation of a limited number of cases of Hb H disease (--/-a) and due to the absence of hydrops fetalis (--/--).…”

A mild form of Hb S‐β‐thalassemia syndrome is assured in Sicilian patients by β+mutant IVS‐I nt 6(T→C)

“…The correlation between genotype and phenotype in hemoglobinopathies is a problem that is particularly felt in certain geographic areas such as Sicily, where the high frequency (5.9%) and the genetic heterogeneity of the P-thal mutations (3) are accompanied by a notable incidence of structural variants (2.5%) ( 5 ) and, particularly, Hb S (2%) (6). Up to the present, we have identified at least 15 different P-thal mutations among which IVS-1-6 occurs with a frequency of l6%, and is the most common after CD39 (34.5%) and IVS-1-110 (24%) (3). Our experience shows that in Sicilian patients 2 main features characterize the condition of compound heterozygous p"/P1"s-'-6.…”

Relative Levels of α-, β-, and γ-mRNA from Patients with Severe and Intermediate β-Thalassemia Major

“…the severe, transfusion-dependent type and the intermediate type, where transfusions are only occa sionally required. As none of the patients had an addition al a-thalassemia and their genotypes had been determined earlier [6], we placed our efforts mainly in comparing the relative levels of a-, P-, and y-mRNAs and the in vitro a-, ß-, and y-mRNA in ß-Thalassemia Major chain synthesis ratios. Unfortunately, the protein data were almost entirely limited to the untransfused patients, precluding any comparison between values obtained for the two groups of patients with different phenotypes.…”

“…They have been regularly attending the thalassemia clinic of the Division of Pediatric Hematology and Oncology at the University of Catania in Sicily for many years. Their gentoypes had been determined before and were reported in a previous publication [6]. Their phenotypes, i.e.…”