Detection of Complex Hemoglobinopathies: Recommendations on Screening and DNA Testing

The following recommendations should be taken into account during the evaluation and elucidation of the complex hemoglobinopathies: (a) in complex hemoglobinopathies performing DNA studies on all family members might be essential; (b) complex gene-gene interactions offer major diagnostic challenges both at the technical and clinical level; (c) hematological & DNA analyses must be run in parallel. Some cases may be straight forward but others may require indepth DNA work-up; (d) co-inheritance of α-thalassemia offers added challenge as it may affect phenotype significantly; (e) sickle cell anemia (SS), co-inherited with a-thal, can be a phenocopy of Sβ⁰-thal. The HbA₂ increase can be mistaken for Sβ-thal. DNA Sequencing is imperative; (f) only a selected number of normal MCV, MCH, borderline HbA₂ cases must be referred for DNA analysis. However, in certain cases, following hematological and family evaluation, the β and δ genes may need to be sequenced; (g) DNA Sequencing will increasingly become the method of choice for screening and DNA mutation analysis. However, new methods like MLPA-which analyzes gene dosage- must be used more commonly to rule out deletion mutants to avoid false negative sequencing results; (h) these recommendations should be reviewed every 2–3 years reflecting new methods, new findings and new findings from ethnic groups.