Association of HBA gene copy number gains with pathogenic HBB gene variants

Abstract

8]. Four alleles of 2 structurally similar genes, HBA1 and HBA2 are responsible for α-globin gene expression and are critically important when establishing genotype-phenotype relationships in patients with β-thalassemia. Although the HBA1 gene Objectives: 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. 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.

The association between plasma IL-6 levels and several thalassemia-related clinical features in Iraqi patients

“…From the age of 6 months, HbA is the predominant type of hemoglobin in humans and accounts for 95-98% of the total hemoglobin molecules [43]. Simllar to our study finding, a previous investigation showed a signifcant decrease in HbA level in thalassemia patients [44]. Low HbA levels were related to a decline in physical function in beta-thalassemia patients, which was associated with elevated IL-6 levels [45].…”