Molecular Genetics of the α‐Thalassaemias

Abstract

AbstractWith the exception of rare non‐α‐globin gene‐related forms and of acquired forms in patients with myelodysplasia, α‐thalassaemias are very widespread worldwide. However, the most severe forms are found among 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. The most severe form, haemoglobin (Hb) Bart's hydrops fetalis (absence of functional α‐globin genes), leads to deathin uteroor 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 severePlasmodium falciparuminfection has been demonstrated for individuals with α‐thalassaemia. α‐Thalassaemia is also a genetic modifier in sickle cell syndromes.Key Concepts:α‐Thalassaemia has become a widespread genetic disorder worldwide due to the relative protection it confers 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 α genes results in chronic haemolytic anaemia of variable severity (Hb H disease), whereas the total absence of functional α‐globin gene leads to haemoglobin Bart's hydrops fetalis, a usually lethal condition.In uterotransfusion therapy and stem cell transplantation may improve the outcome of fetuses and infants with Hb Bart's hydrops fetalis in very rare cases.α‐Thalassaemia carriers are usually clinically asymptomatic; however, detection of carriers of α zero thalassaemia is of utmost importance to prevent hydrops fetalis.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 in the haemolytic rate and a higher haemoglobin level.