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
1. Pignatti CB, Galanello R. Thalassemias and related
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.
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 20Apr.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
