Genotype-Phenotype Relationship of the δ-Thalassemia and Hb A₂ Variants: Observation of 52 Genotypes

Abstract

The increase of Hb A₂ (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 A₂ 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 A₂ values of ≤2.0% or were β-thal heterozygotes with normal Hb A₂ levels. Hb A₂ 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 A₂ was extremely heterogeneous. Nineteen δ-globin alleles (Hb A₂-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 α⁰-thal traits, are the most important factors in decreasing the Hb A₂ percentage. These results are extremely useful in addressing the molecular diagnosis of hemoglobinopathies and thalassemias.

• Diagnosis of hemoglobinopathies and thalassemias
• β-Thalassemia (β-thal) prevention
• δ-Thalassemia (δ-thal)
• Hb A₂ variants
• Hb A₂-S.N. Garganico
• Genotype-phenotype relationship