The alpha globin genotypes of 55 beta thalassaemia heterozygotes have been determined by restriction endonuclease analysis to identify those with interacting alpha thalassaemia genes.
On the other hand, the combination of the homozygous state for the triple alpha-globin gene loci and the heterozygous state for beta-thalassemia produced a clinical picture of thalassemia intermedia with a very mild clinical course, minor increase of fetal hemoglobin (HbF) levels, and a pronounced imbalance of globin chain synthesis.
In the remaining family, the propositus and one of his siblings had the compound heterozygous state for a molecularly undefined high HbA2 beta thalassaemia and the beta th-101 mutation in combination with the triple alpha globin gene arrangement.
Identification of deletion and triple alpha-globin gene haplotypes in the Montreal beta-thalassemia screening program: implications for genetic medicine.
Identification of the genetic variants modifying fetal hemoglobin (HbF) production in combination with α globin genotype provide some prediction of disease severity for β thalassemia but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered.
The phenotype of increased Hb A2 typical of beta-thalassaemia (beta-thal) carriers can be reduced to normal or borderline values because of the co-inheritance of a delta-globin gene (HBD, MIM #142000) mutation, which may lead to misinterpretation of diagnostic results.
There are few studies investigating alpha globin gene triplications in beta-thalassemia in Asian Indians and its effect on phenotype, which was the primary aim of this study.
Other variant hemoglobins including beta thalassemia are rare, but alpha thalassemia occurs in 39% (32% with 3 alpha-globin genes; 7% with 2 alpha-globin genes).
In this paper we report that the combination of a triplicated alpha globin locus with heterozygous beta-thalassaemia produces a clinical phenotype of thalassaemia intermedia in five Italian subjects from four unrelated families, while in two other cases the phenotype was thalassaemia minor.
A wide heterogeneity of the delta-globin alleles was detected; seven known alleles in trans to the beta-globin gene defects were revealed in 17 out of 18 families, while a new allele in cis to a beta-thalassemia allele was detected in one family.
These indicated that the fetus was heterozygous for beta thalassaemia and had deletion of three alpha globin structural genes, while the mother, heterozygous for beta thalassaemia, also had deletion of two alpha globin structural genes.
Based on the molecular analysis of beta-thalassemia intermedia, beta-thalassemia homozygotes or compound heterozygotes combined with alpha-thalassemia, as well as the conjunctive abnormalities of beta-thalassemia heterozygote with triplicated haplotype of alpha-globin genes, were the most common cause of thalassemia intermedia in China.
Approximately 80% of α-thalassemia mutations are deletions in the α-globin cluster on chromosome 16 and about 10% of β-thalassemia mutations are deletions in the β-globin gene cluster on chromosome 11.
In a study of nine anaemic patients who were heterozygous for beta-thalassaemia and also heterozygous for the triplicated alpha-globin gene (alpha alpha alpha/alpha alpha), frequency of the shorter homopolymer was higher than expected.
These findings support the theory that coinheritance of alpha-thalassemia mitigates the severity of beta-thalassemia and suggest that the protection is most pronounced when two alpha-globin genes are deleted.
This could be a direct result of the gene defect producing beta-thalassemia or be due to differences in the delta-globin gene linked to this beta-thalassemia gene.
From these results, we may conclude that the inheritance of a mild beta-thalassemia allele such as the beta+ IVS-I nt 6 mutation, in the homozygous or heterozygous state, the coinheritance with homozygous beta zero-thalassemia of the -158 (C----T) G gamma gene promoter mutation and the presence of heterozygous beta-thalassemia/triple alpha-globin gene arrangement are the most common reasons accounting for the development of attenuated forms of beta-thalassemia in Puglia.
The preferential removal of the mutant alpha-globin explains the reduced level of haemoglobin Hasharon found in subjects carrying the gene for beta-thalassaemia (Alberti et al, 1975).
Our study showed that in most of the alpha thalassemia carriers just one copy of alpha globin gene was absent and they are not at risk of having children with Hb H disease or hydrops fetalis; however, up to 2.2% of neonates were carriers for ααα(anti3.7) triplication and they will be at risk for having a child with thalassemia intermediate if they marry a person which is a carrier of beta thalassemia.