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

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Toksoy G., Akay N., Aghayev A., Karaman V., Avcı Ş., Kalaycı T., ...More

INTERNATIONAL JOURNAL OF MEDICAL BIOCHEMISTRY, vol.4, no.2, pp.91-95, 2021 (Peer-Reviewed Journal)


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


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

amplification, thalassemia intermedia