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

INTRODUCTION: Alpha (α) and beta (β) thalassemia are the most prevalent genetic hematological disorders. The co-occurrence of 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 hemoglobin subunit alpha 1 (HBA1) and HBA2 gene alterations in 32 patients. Deletion, duplication, and other findings were analyzed 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) mutation was inherited from his mother. Notably, the mother did not demonstrate any thalassemia phenotype. Further investigation showed that the mother was carrying a single copy HBA gene deletion in the trans allele that explained her clinical condition.
DISCUSSION AND 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 is not very rare condition. Patients with clinical findings incompatible with their HBB genotypes should be investigated for small and gross α-globin gene variants in order to provide genetic counseling and prenatal diagnosis follow-up, as appropriate.