Association between HBA locus copy number gains and pathogenic HBB gene variants

Abstract

Objectives: Alpha (α) and beta (β) thalassemia are the most prevalent genetic hematological disorders. The co-occurrenceof silent β-thalassemia with excess α-globin gene copies is associated with the thalassemia intermedia phenotype.This study was an investigation of the α-globulin gene dosage and sequence variations in thalassemia patients.Methods: Multiplex ligation-dependent probe amplification and Sanger sequencing were used to identify the hemoglobinsubunit alpha 1 (HBA1) and HBA2 gene alterations in 32 patients. Deletion, duplication, and other findings wereanalyzed in the index cases and family members.Results: Four of the 32 cases (12.5%) were found to have gross duplications. Two cases demonstrated α-globin triplication,and 2 had a quadruplicated HBA1/2 genes. Affected family members revealed genotype-phenotype correlation.In 1 patient, it was observed that quadruplicated HBA genes co-occurrence with hemoglobin subunit beta (HBB) mutationwas inherited from his mother. Notably, the mother did not demonstrate any thalassemia phenotype. Furtherinvestigation showed that the mother was carrying a single copy HBA gene deletion in the trans allele that explainedher clinical condition.Conclusion: This study examined the effect of increased copies of the HBA gene in HBB gene pathogenic variant carriers.The results indicated that β-thalassemia mutations with a co-occurrence of increased α-globin gene dosage isnot very rare condition. Patients with clinical findings incompatible with their HBB genotypes should be investigatedfor small and gross α-globin gene variants in order to provide genetic counseling and prenatal diagnosis follow-up, asappropriate.Keywords: Alpha-globin gene quadruplication, co-inheritance of HBA and HBB, multiplex ligation-dependent probeamplification, thalassemia intermedia