Occurrence of common and rare δ-globin gene defects in two multiethnic populations: thirteen new mutations and the significance of δ-globin gene defects in β-thalassemia diagnostics.

Introduction: The aim of this review is to study the frequency of common and the occurrence of rare and novel mutations of the delta-globin gene and of Hb Lepore defects that might interfere with thalassemia diagnostics and to report the rationale of HbA2 estimation in the presence of delta- or alpha-gene mutations.

Methods: A total of 135 cases suspected to have a delta-globin gene defect collected in a diagnostic center in the USA and in a reference laboratory in the Netherlands were characterized by molecular analysis.

Results: Hb B2 was found at a frequency of at least 0.5% in the USA and 0.87% in the Netherlands. Known variants such as Hb A2-Babinga, Hb A2-Sphakia, Hb A2-Fitzroy, Hb A2-Flatbush, Hb A2-NYU, Hb A2-Grovetown, HbA2-Yialousa, Hb A2-Indonesia and several delta-thalassemia mutations were found together with 13 new mutations and two new polymorphisms, while Hb Lepores were regularly observed.

Conclusion: HbA2 mutations either structurally stable and visible or undetectable because of a thalassemia effect or instability are clinically asymptomatic but may compromise the diagnosis of beta-thalassemia minor. Stable mutations result in two HbA2 fractions of about half of the expected value. Expression defects are undetectable as a protein fraction but reduce the amount of HbA2 by half.