Mutational spectrum of delta-globin gene in the Portuguese population

The phenotype of increased Hb A2 typical of beta-thalassaemia (beta-thal) carriers can be reduced to normal or borderline values because of the co-inheritance of a delta-globin gene (HBD, MIM #142000) mutation, which may lead to misinterpretation of diagnostic results. To know the spectrum of delta-globin mutations in the Portuguese population we performed a mutational analysis of the delta-globin gene in a group of 51 Portuguese beta-thal carriers presenting microcytosis, hypochromia and a normal/borderline Hb A2 level and in another group of 15 individuals suspected to have delta-globin structural abnormalities. The heterozygosity for the beta+IVS-I-6T -> C (HBB:c. 92+6T > C) mutation was the main cause for the mentioned atypical beta-thal carrier phenotype. Furthermore, eight individuals were double heterozygous for one common beta-thal mutation and the delta(+)Cd27G -> T mutation (Hb A2-Yialousa; HBD:c.82G > T). One of them also presented a novel delta-globin gene promoter mutation,-80G -> A (HBD:c.-130G > A), responsible for about 25% decrease of the promoter activity in transient expression assays. One the other hand, in the other group of 15 individuals suspected to have delta-globin structural abnormalities observed by biochemical methods, some known Hb A2 variants were identified - Hb A2' (HBD:c.49G > C), Hb A2-Babinga (HBD:c.410G > A), and Hb A2-Wrens (HBD:c.295G > A), and the novel Hb A2-Fogo [delta 64(E8)(Gly -> Ser); (HBD:c.193G > A)]. This novel Hb A2 variant was observed segregating in linkage with Hb E (HBB:c.79G > A) in a three generation family. In conclusion, six different delta-globin mutations were found, being two of them new molecular defects. All delta-alleles identified were found linked to the expected beta-globin cluster haplotype. All mutations caused a low Hb A2 level and through this could lead to misdiagnosis when inherited together with a beta-thal allele.