Phenotypic diversity in beta-HbE thalassemia patients
AbstractBackground Thalassemia is a monogenic disease, yet the clini-
cal manifestations (phenotype) are variable although they have
the same genotype. The clear-cut correlation between genotype
and phenotype in Î²-thalassaemia/HbE patients remains unex-
plained. There are several factors that play a role in the severity of
the clinical manifestations, i.e. two alpha-gene deletion, homozy-
gote Xmn1 polymorphism +/+, -+-++, ++-++ haplotype, and hemo-
globin Constant Spring.
Objective To understand the clinical diversity of patients with HbE/
Î± thalassemia and to determine whether it is possible to predict
phenotypic severity from genetic factors.
Methods A descriptive study on clinical presentations and hema-
tological data of beta-HbE thalassemia patients. DNA analysis was
performed to detect Î²-thalassemia mutations and the ameliorating
factors (alpha-globin genes deletions and Xmn1 restriction site poly-
morphism at position â€“158 upstream of the G Î³-globin gene) which
were already known.
Results Thirty patients with HbE/Î² thalassemia (4 to 29 years old)
were recruited. IVS1-nt5 (G>C) severe Î² + mutation was detected
in 20 patients. Eighteen of 20 patients with positive IVS1-nt5 mu-
tation group were heterozygous for Xmn1 restriction site polymor-
phism and none of the patients was co-inherited with two Ã¡-globin
gene deletion. Almost all patients (19/20) with positive IVS1-nt5
mutation group required regular transfusions, yet the mean age at
first blood transfusion was older in negative IVS1-nt5 mutation group
than that of positive IVS1-nt5 mutation group (5.7 vs 4 years). Mean
hemoglobin before initial transfusion was higher in negative IVS1-
nt5 mutation group than that of positive IVS1-nt5 mutation group
(5.88 vs 5.39 g/dl). The mean total transfusion per year was lower
in the negative IVS1-nt5 mutation group than that of positive IVS1-
nt5 mutation group (190.6 vs 215.1 ml/year).
Conclusions Beta-HbE thalassemia patients with identical beta
thalassemia mutation (IVS1-nt5) show remarkable clinical diver-
sity. Neither two alpha-gene deletion, nor the Xmn1- G Î³ polymor-
phism can explain the phenotypic variation. Other ameliorating
determinants or genetic modifications responsible for the variable
clinical severity remain to be explored.
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