Phenotypic diversity in beta-HbE thalassemia patients

Abstract

Background Thalassemia is a monogenic disease, yet the clini-cal manifestations (phenotype) are variable although they havethe same genotype. The clear-cut correlation between genotypeand phenotype in β-thalassaemia/HbE patients remains unex-plained. There are several factors that play a role in the severity ofthe 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/α thalassemia and to determine whether it is possible to predictphenotypic severity from genetic factors.Methods A descriptive study on clinical presentations and hema-tological data of beta-HbE thalassemia patients. DNA analysis wasperformed to detect β-thalassemia mutations and the amelioratingfactors (alpha-globin genes deletions and Xmn1 restriction site poly-morphism at position –158 upstream of the G γ-globin gene) whichwere already known.Results Thirty patients with HbE/β thalassemia (4 to 29 years old)were recruited. IVS1-nt5 (G>C) severe β + mutation was detectedin 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 á-globingene deletion. Almost all patients (19/20) with positive IVS1-nt5mutation group required regular transfusions, yet the mean age atfirst blood transfusion was older in negative IVS1-nt5 mutation groupthan that of positive IVS1-nt5 mutation group (5.7 vs 4 years). Meanhemoglobin 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 lowerin 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 betathalassemia mutation (IVS1-nt5) show remarkable clinical diver-sity. Neither two alpha-gene deletion, nor the Xmn1- G γ polymor-phism can explain the phenotypic variation. Other amelioratingdeterminants or genetic modifications responsible for the variableclinical severity remain to be explored.

The Hemoglobin, Rdw, and Mean Corpuscular Values in Patients With Beta-Thalassemia/Hemoglobin E Disease and Beta-Thalassemia Trait

“…HbA2 in beta0 thalassemia/hemoglobin E. In Indonesia, the most common beta-globin gene mutations are IVS1-nt5 (G C), IVS1-nt1 (G T), (AAC AGC ). Study from Semarang transfusion unit on a β thalassemic patient with routine transfusion the most common mutation is HbE/IVS1-nt5 (55.3%) followed by IVS1-nt5/IVS1-nt5 7,8 and HbE/Cd35 each as much as 13.2%.…”

Genetic Background of β Thalassemia Modifier: Recent Update

“…41 The data from Indonesia reported that genotypes (-/-) and (+/) of the XmnI locus is not related with the absolute amount of HbF in HbE/ β thalassemia patients. 42 The same group reported that β thalaseemia mutation type is not a factor that influence clinical manifestation, apartfrom the IVSl-nt 5 (G>C) that is related to severe clinical features, co-inheritance of a globin deletion type 3,7 kb (co/o-) is related to mild clinical manifestation, while αglobin chain triplication did not exist both mild and severe groupsand therefore its relation with clinical manifestation could not be assessed. Study also showed that Xmnl heterozygote polymorphisms (polymorphism in-150°y globin gene, C>T) werefound both in the mild and severe groups, therefore this kind of polymorphism is not afactor that influences clinical manifestations.…”

Genetics and genomic medicine in Indonesia

“…Therefore, carrier screening protocol and prenatal testing have to be designed on a regional basis (Wahidiyat et al. ).…”

“…This variation resulted to unequal anticipated carrier testing and prenatal testing workload. Therefore, carrier screening protocol and prenatal testing have to be designed on a regional basis (Wahidiyat et al 2006 (Ariani et al 2014).…”