Copy number variations of six and seven α-globin genes in a family with intermedia and major thalassemia phenotypes

Abstract

Background: Copy number variations in α-globin genes are results of unequal crossover between homologous segments in the α-globin gene cluster that misalign during the meiosis phase of the gametogenesis process. Reduction or augmentation of α-globin genes leads to imbalance of α/β chains in hemoglobin tetramer and consequently attenuate or worsen the β-thal clinical symptoms, respectively. Objective: Multiplications in α-globin genes have been found in some populations, justifying unexpected severe phenotype of β-thal carriers. Study design: Unexpected severe phenotype in the family members may result from coexistence of extra α-globin genes, which is an important factor in the causation of thalassemia intermedia and major in heterozygous β-thalassemia. Results: We described different multiplications in α-globin locus in an Iranian family with one, two or three extra α-globin genes (ααα/αα, αααα/αα and αααα/ααα). Conclusion: The excess α-globin gene/genes cause increment in β/α chain imbalance and leads to worsening pathophysiology and clinical severity of β-thalassemia carriers.

Keywords:

• copy number variation
• gametogenesis
• Iranian
• α-globin gene cluster
• β-thalassemia carrier

Acknowledgments

We are grateful to all our colleagues, Department of Molecular Genetics at Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran for valuable technical assistance and also appreciate the cooperation of all the patients took part in this study.

Financial & competing interests disclosure

The authors were supported by the Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The unequal crossover mechanism generating −α^3.7 kb deletion leaves a set of three active α-globin genes (α triplication) on the other allele that will be inherited just like the −α^3.7 kb deletion and known as ααα^{anti 3.7} triplication.

• Dosage imbalance in the β/α ratio HbA is an important consequence of numerical alteration (copy number variations) in α-globin locus.

• Coinheritance of α-globin gene multiplications and heterozygosity for β-globin gene intensifies clinical symptoms.

• The genotype and phenotype characteristics of the patients described here indicate the need to consider the possibility of a duplicated α-globin allele or even locus in patients with a β-thal heterozygosity who show an unexpectedly severe phenotype in the Iranian population.

• The risk of possible pregnancies of a fetus inherited both α-globin gene multiplication and heterozygosity for β-thal, ought to be considered in Iranian population.

• Identification of the α-globin gene multiplications definitely would help physicians in Iran or other populations with high prevalent thalassemia to provide appropriate genetic counseling to choose the appropriate treatment and management.

Notes