Phenotypic diversity in beta-HbE thalassemia patients
Keywords:
thalassemia, phenotype, mutation
Abstract
Background 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 β-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/
α 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 β-thalassemia mutations and the ameliorating
factors (alpha-globin genes deletions and Xmn1 restriction site poly-
morphism at position –158 upstream of the G γ-globin gene) which
were already known.
Results Thirty patients with HbE/β thalassemia (4 to 29 years old)
were recruited. IVS1-nt5 (G>C) severe β + 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 á-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 γ polymor-
phism can explain the phenotypic variation. Other ameliorating
determinants or genetic modifications responsible for the variable
clinical severity remain to be explored.
References
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thalassemia in Thailand: Application to prenatal di-
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Haematologica. 2005;90:649-60.
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thalassaemia major. Br J Haematol 1989;72:73-80.
11. Cao A, Galanello R, Rosatelli MC. Genotype-pheno-
type correlations in β-thalassemias. Blood Rev
1994;8:1-12.
12. Galanello R, Cao A. Relationship between genotype
and phenotype: Thalassemia intermedia. Ann N Y
Acad Sci 1998;850:325-33.
disorders: Quantitative disorders of hemoglobin syn-
thesis. In: Greer JP, Foerster J, Lukens JN, Rodgers GM,
Paraskevas F, Gladeer B, editors. 11th ed. Wintrobe’s
clinical hematology. Philadelphia: Lippincott Williams
& Wilkins; 2004. p. 1319-65.
2. Weatherall D. The molecular basis for phenotypic vari-
ability of the common thalassaemias. Mol Med Today
1995;1:15-20.
3. Winichagoon P, Thonglairoam V, Fucharoen S, Wilairat
P, Fukumaki Y, Wasi P. Severity differences in β-thalas-
semia/haemoglobin E syndromes: Implication of genetic
factors. Br J Haematol 1993;83:633-9.
4. Winichagoon P, Fucharoen S, Chen P, Wasi P. Genetic
factors affecting clinical severity in [beta]-thalassemia
syndromes. J Paedtr Hem Onc 2000;22(6):573-80.
5. Ho PJ, Hall GW, Luo LY, Weatherhall DJ, Thein SL.
β-thalassemia intermedia: Is it possible consistently to
predict phenotype from genotype?. Br J Hematol
1998;100:70-8.
6. Setianingsih I. β-thalassemia in Indonesia: Molecular
basis and phenotype-genotype correlation [disserta-
tion]. Melbourne (Australia): The Murdoch Institute
Child Health Department, Univ. of Melbourne; 2000.
7. Thein SL, Winichagoon P, Hesketh C, Best S,
Fucharoen S, Wasi P, et al. The molecular basis of β-
thalassemia in Thailand: Application to prenatal di-
agnosis. Am J Hum Genet 1990;47:369-75.
8. Rees DC, Styles L, Vichinsky EP, Clegg JB, Weatherall
DJ. The hemoglobin E syndromes. Ann N Y Acad Sci
1998;850:334-43.
9. Thein SL. Genetic modifiers of beta-thalassemia.
Haematologica. 2005;90:649-60.
10. Yang KG, Kutlar F, George E, Wilson JB, Kutlar A, Stoming
TA, et al. Molecular characterization of β-globin gene
mutations in Malay patients with HbE-β-thalassemia and
thalassaemia major. Br J Haematol 1989;72:73-80.
11. Cao A, Galanello R, Rosatelli MC. Genotype-pheno-
type correlations in β-thalassemias. Blood Rev
1994;8:1-12.
12. Galanello R, Cao A. Relationship between genotype
and phenotype: Thalassemia intermedia. Ann N Y
Acad Sci 1998;850:325-33.
Published
2016-10-18
How to Cite
1.
Wahidiyat P, Gatot D, Tjitrasari T, Ringoringo H, Marzuki N, Taufani R, Setianingsih I, Harahap A. Phenotypic diversity in beta-HbE thalassemia patients. PI [Internet]. 18Oct.2016 [cited 25Nov.2024];46(2):82-. Available from: https://paediatricaindonesiana.org/index.php/paediatrica-indonesiana/article/view/906
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Received 2016-10-13
Accepted 2016-10-13
Published 2016-10-18
Accepted 2016-10-13
Published 2016-10-18
