15 years of hemoglobinopathies and thalassemias: from a textbook example in biochemistry to an everyday diagnostic challenge

Abstract

Abstract Objectives Hemoglobinopathies are among the most common monogenic disorders worldwide and are a significant global health problem. However, diagnosing these disorders, especially those involving complex genotypes (HBA/HBB), is challenging. This issue must be addressed, even in regions with historically low disease prevalence. Methods 565 patients were tested for hemoglobinopathies using functional and genetic methods. In addition to a complete blood count, clinical chemistry parameters, and hemoglobin high-performance liquid chromatography, Sanger sequencing and MLPA were performed to detect pathogenic variants in the HBA and HBB gene cluster. Results As part of our routine diagnostic procedures, we have tested 565 patients for hemoglobin abnormalities between 2010 and 2025. 374 (66.2 %) carried at least one pathogenic variant, 88 (15.6 %) had a combined disorder, which is a combination of qualitative and quantitative globin chain defects or defects in the HBA and HBB gene clusters. 20 retrospectively selected cases are presented here. Conclusions Molecular hemoglobinopathy/thalassemia diagnostics should always be performed alongside functional tests such as a complete blood count, testing for iron deficiency, and hemoglobin analysis. However, a functional evaluation without genetic confirmation of the abnormalities is equally insufficient, particularly with regard to assessing the severity of the condition and providing genetic counseling for the family. Consistent findings in functional and molecular analyses ensure high sensitivity and specificity of the testing strategy even in complex syndromes.