Genotype-phenotype relationship of the δ-thalassemia and Hb A(2) variants: observation of 52 genotypes

• Published in: Hemoglobin Vol. 34; no. 5; pp. 407 - 423
• Main Authors: Lacerra, Giuseppina, Scarano, Clelia, Lagona, Laura F, Testa, Rosario, Caruso, Daniela G, Medulla, Emilia, Friscia, Maria G, Mastrullo, Lucia, Caldora, Mercedes, Prezioso, Romeo, Gaudiano, Carlo, Magnano, Carmelo, Romeo, Maria A, Musollino, Gennaro, Di Noce, Francesca, Carestia, Clementina
• Format: Journal Article
• Language: English
• Published: England 2010
• Subjects: alpha-Globins - genetics; Base Sequence; beta-Globins - genetics; Chromatography, High Pressure Liquid; delta-Globins - genetics; delta-Thalassemia - blood; delta-Thalassemia - diagnosis; delta-Thalassemia - genetics; DNA Mutational Analysis - methods; DNA Primers; Family Health; Female; Genetic Association Studies; Genetic Variation; Genotype; Hemoglobin A2 - analysis; Hemoglobin A2 - genetics; Humans; Male; Mutation; Phenotype
• ISSN: 1532-432X
• DOI: 10.3109/03630269.2010.511586

The increase of Hb A(2) (α2δ2) beyond the upper limit [2.0-2.2/3.3-3.4% of the total hemoglobin (Hb)] is an invaluable tool in the hematological screening of β-thalassemia (β-thal) carriers. Factors decreasing Hb A(2) percentages can hinder correct diagnosis. In order to analyze the genotype-phenotype relationship, we characterized δ-, β- and α-globin genotypes in 190 families where the probands had Hb A(2) values of ≤2.0% or were β-thal heterozygotes with normal Hb A(2) levels. Hb A(2) was measured with cation exchange high performance liquid chromatography (HPLC). Mutations were detected with allele-specific methods or DNA sequencing; two multiplex-ARMS (amplification refractory mutation system) assays were set up. The molecular basis underlying the decrease in Hb A(2) was extremely heterogeneous. Nineteen δ-globin alleles (Hb A(2)-S.N. Garganico was new) were detected; their interaction with α- or β-globin alleles (10 and eight, respectively) led us to observe 52 genotypes in 261 carriers. The type of δ-globin mutations, the relative genotypes, the interaction with α(0)-thal traits, are the most important factors in decreasing the Hb A(2) percentage. These results are extremely useful in addressing the molecular diagnosis of hemoglobinopathies and thalassemias.