Molecular Genetics of the α‐Thalassaemias


α‐Thalassaemias are widespread disorders worldwide, with the exception of rare non‐α‐globin gene related forms and of acquired forms in patients with myelodysplasia. However, the most severe forms are found among the populations of Asian and Mediterranean ancestry. Clinical manifestations of α‐thalassaemia are highly variable, ranging from asymptomatic subjects to a more or less severe haemolytic anaemia. Haemoglobin Bart's hydrops foetalis (absence of functional α‐globin genes) leads to death in utero or at birth. Antenatal screening is available for couples at risk for this severe form, that is carriers of an α zero thalassaemia allele (absence of any functional α gene on one chromosome 16). Carrier detection is first based on red blood cell indices and confirmed by molecular analysis. Selective advantage against severe Plasmodium falciparum infection has been demonstrated for individuals with α‐thalassaemia. α‐Thalassaemia is also a genetic modifier in sickle cell syndromes and β‐thalassaemia.

Key Concepts

  • α‐Thalassaemia has become a widespread genetic disorder worldwide due to the relative protection it conferred against life‐threatening malarial anaemia.
  • There are four main forms of α‐thalassaemia depending on the number of remaining functional α globin gene(s) in the individual.
  • α‐Thalassaemia can be a severe condition: absence of three functional α‐globin genes results in chronic haemolytic anaemia of variable severity (haemoglobin H disease), whereas the total absence of functional α‐globin gene leads to haemoglobin Bart's hydrops foetalis, a usually lethal condition.
  • In utero transfusion therapy and stem cell transplantation may improve the outcome of foetuses and infants with Hb Bart's hydrops foetalis in very rare cases.
  • α‐Thalassaemia carriers are usually clinically asymptomatic; however, detection of carriers of an α zero thalassaemia allele is of utmost importance to allow preventing hydrops foetalis.
  • α‐Thalassaemia carriers may benefit from the diagnosis of their condition, as this may avoid unnecessary iron therapy due to the presence of microcytosis.
  • α‐Thalassaemia is a genetic modifier of sickle cell disease severity through the reduction of the haemolytic rate and higher haemoglobin levels.

Keywords: α‐thalassaemia; molecular genetics; prevention; malaria; sickle cell disease

Figure 1. α‐Globin gene cluster. The 30 kb α‐globin gene cluster is located on chromosome 16 (16 p13‐2pter). The locus name is HBA. It comprises three functional genes: ζ, α2, α1, 2 expressed genes with unknown function: μ and θ1 and 3 pseudogenes: ψζ, ψα1 and ψρ. The ζ gene is expressed during the embryonic period, rapidly followed by the expression of adult α genes, α1 (gene symbol HBA1) and α2 (gene symbol HBA2). Four conserved DnaseI Hypersensitive Sites (HS‐10, HS‐40, HS‐33 and HS40) are located upstream the α genes and are known to bind erythroid transcription factors.
Figure 2. AT, α‐thalassaemia; ATMDS, α‐thalassaemia myelodysplastic syndrome. Molecular mechanisms leading to either inherited or acquired forms of α‐thalassaemia have been found to be similar with mutations or deletions lying in the same genes.
Figure 3. Schematic relationship between α‐thalassaemia phenotype according to the number of active α‐globin genes. MCV, mean corpuscular volume; normal individuals have four functional α‐globin genes; this number decreases while the α‐thalassaemia phenotype worsens.


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Further Reading

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Steinberg MH, Forget BG, Higgs DR and Nagel RL (eds)1268 pp (2001) Disorders of Hemoglobin. Genetics, Pathophysiology, and Clinical Management, 1st edn. Cambridge University Press.

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Aguilar‐Martinez, Patricia, and Gulbis, Béatrice(Oct 2018) Molecular Genetics of the α‐Thalassaemias. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022439.pub2]