Int J Med Biochem . 2021; 4(2): 91-96 | DOI: 10.14744/ijmb.2021.65477

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

Güven Toksoy¹, Nergis Akay², Agharza Aghayev¹, Volkan Karaman¹, Þahin Avcý¹, Tugba Kalayci¹, Umut Altunoðlu¹, Zeynep Karakaþ², Zehra Oya Uyguner^1
1Department of Medical Genetics, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
²Department of Pediatric Hematology-Oncology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey

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.

Keywords: Alpha-globin gene quadruplication, co-inheritance of HBA and HBB, multiplex ligation-dependent probe amplification, thalassemia intermedia

---

CITE