Non-deletional alpha thalassaemia: a review

Abstract

Background: Defective synthesis of the α-globin chain due to mutations in the alpha-globin genes and/or its regulatory elements leads to alpha thalassaemia syndrome. Complete deletion of the 4 alpha-globin genes results in the most severe phenotype known as haemoglobin Bart's, which leads to intrauterine death. The presence of one functional alpha gene is associated with haemoglobin H disease, characterised by non-transfusion-dependent thalassaemia phenotype, while silent and carrier traits are mostly asymptomatic.Main body: Clinical manifestations of non-deletional in alpha thalassaemia are varied and have more severe phenotype compared to deletional forms of alpha thalassaemia. Literature for the molecular mechanisms of common non-deletional alpha thalassaemia including therapeutic measures that are necessarily needed for the understanding of these disorders is still in demand. This manuscript would contribute to the better knowledge of how defective production of the α-globin chains due to mutations on the alpha-globin genes and/or the regulatory elements leads to alpha thalassaemia syndrome. Conclusion:Since many molecular markers are associated with the globin gene expression and switching over during the developmental stages, there is a need for increased awareness, new-born and prenatal screening program, especially for countries with high migration impact, and for improving the monitoring of patients with αthalassaemia.

Molecular basis and diagnosis of thalassemia

“…In addition, non-deletional variants lead to a greater reduction in α-globin chain expression than the single α-globin gene deletion form of thalassemia [ 12 , 13 ]. The most common forms that occur in the α2-globin gene are α IVS1(-5nt) α (Mediterranean, 5 nucleotide deletion in IVS1), α PA(AATAAG) α (Middle East Asia, 3′ untranslated region [UTR] polyadenylation site variant), and α CS α (South Asia, stop codon variant resulting in protein extension by an additional 32 amino acids) [ 14 ]. Table 2 presents the distribution of the α-thalassemia genotypes identified in the Seoul National University Hospital, South Korea.…”

Applications of next generation sequencing in the screening and diagnosis of thalassemia: A mini-review

“…Furthermore, 47 carriers of the large – SEA deletion, the second most abundant α-thalassemia mutation in China, were also missed by routine Hb electrophoresis. This increases the risk of HbH formation or even Hydrops fetalis if the other partner is also a carrier of the α + or α 0 determinants, respectively ( 29 , 30 ). Another group that designed the TCS gene panel to cover all the eight globin genes and four gene modifiers (KFL1, BCL11A, HBS1L, and MYB) to screen newlyweds also demonstrated similar enhanced detection rates by detecting 35 at-risk couples initially missed by routine analysis ( 25 ).…”

Accurate genotype diagnosis of Hong Kongαα thalassemia based on third-generation sequencing

“…The most common type of α-thalassemia is caused by deletions of different lengths in the α-globin genes, with -α 3.7 and -α 4.2 variants being the more common forms ( 5 , 6 ). The reciprocal recombination between Z segments during meiosis leads to the -α 3.7 and ααα anti 3.7 chromosomes.…”