Beta-Thalassemia Intermedia: A Single Thalassemia Center Experience from Northeastern Iraq

Objective. To determine the molecular characterization and disease-associated complications of beta-thalassemia intermedia (β-TI) patients in Sulaymaniyah province, northeastern Iraq. Methods. A total of 159 β-TI patients from 114 families were enrolled. Detection of β-thalassemia mutations was done by reverse hybridization technique and direct gene sequencing. Also, the clinical and hematological data were collected through an electronic-based medical recording system using a designed comprehensive questionnaire. Results. Nineteen different β-globin gene mutations arranged in 37 various genotypes were determined. The most frequent were IVS-II-I (G>A) (47.2%), followed by IVS-I-6 (T>C) (23.3%) and IVS-I-110 (G>A) (5%). Among disease-related morbidities documented, bone disease amounted to 53% (facial deformity and osteoporosis), followed by endocrinopathies 17.6% (growth retardation and subclinical hypothyroidism), cholelithiasis 13.8%, pulmonary hypertension 11.3%, and abnormal liver function test 7.5%, whereas venous thrombosis, extramedullary hemopoiesis, and leg ulcer were less frequently observed. Age≥35 and female sex were risk factors for cholelithiasis, while age was an independent risk for hypothyroidism and female sex was associated with increased risk for osteoporosis. Mean serum ferritin of ≥1000 μg/L was associated with an increased risk of osteoporosis, whereas chelation therapy was protective for a multitude of other complications. Transfusion, on the other hand, increased the risk of osteoporosis, yet it was protective for cholelithiasis and hypothyroidism. Moreover, splenectomy was protective for cholelithiasis, although it was an independent risk for hypothyroidism. Finally, hydroxyurea was associated with an increased risk of osteoporosis, while it was protective for cholelithiasis. Discussion and Conclusion. β+-thalassemia mutation had contributed to 41.25 of families with a less severe β-thalassemia phenotype in the northeastern part of Iraq, justifying the need to investigate the contribution of genetic modifiers in ameliorating disease severity. In addition, the substantial number of β-TI patients developed disease-related morbidities, which necessitates the need for more appropriate clinical management with earlier intervention.

Download Full-text

Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations

Blood ◽

10.1182/blood.v77.6.1342.1342 ◽

1991 ◽

Vol 77 (6) ◽

pp. 1342-1347 ◽

Cited By ~ 49

Author(s):

S Murru ◽

G Loudianos ◽

M Deiana ◽

C Camaschella ◽

GV Sciarratta ◽

...

Keyword(s):

Blot Analysis ◽

Globin Gene ◽

Beta Thalassemia ◽

Italian Population ◽

Beta Globin ◽

Thalassemia Intermedia ◽

Dot Blot ◽

Beta Globin Gene ◽

Dot Blot Analysis ◽

Thalassemia Mutation

Abstract In this study, we have defined by dot-blot analysis with allelic specific oligonucleotide probes or direct sequencing on amplified DNA the beta-thalassemia mutations in a large group of patients (23) of Italian descent with thalassemia intermedia. These patients had one parent with either the silent beta-thalassemia carrier phenotype or borderline-normal hemoglobin A2 (HbA2) levels (2.5% to 3.5%). Nearly all were genetic compounds for a severe beta-thalassemia mutation and a beta-thalassemia mutation associated with high residual output of beta- globin chains (beta + intervening sequence [IVS]-I-nt6, beta -87, beta - 101), indicating that inheritance of a mild beta-thalassemia allele, even in a single dose, is the most common molecular mechanism producing thalassemia intermedia in the Italian population. In three cases, in whom we failed to define by dot-blot analysis the mutations, we sequenced the beta + globin gene and found three novel beta-thalassemia mutations, which are certainly very rare because they have been hitherto detected solely in a single patient. These mutations consist of: (1) a T-A substitution at position 2 of IVS-I, in a patient compound heterozygote for this mutation and the -87 promoter mutation; (2) a G-C substitution at position 844 of IVS-II, in a patient heterozygous for this mutation who showed normal sequences at the in trans beta-globin gene (The reason for the presence of clinical manifestations in a beta-thalassemia heterozygote has not been defined.); and (3) a deletion of one nucleotide (-T) at codon 126, resulting in a frameshift and readthrough of the 5′ untranslated region and most likely producing an elongated Hb molecule of 156 amino acid residues, in a patient heterozygous for this mutation with normal beta- globin gene sequences at the other locus.

Download Full-text

Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations

Blood ◽

10.1182/blood.v77.6.1342.bloodjournal7761342 ◽

1991 ◽

Vol 77 (6) ◽

pp. 1342-1347 ◽

Cited By ~ 1

Author(s):

S Murru ◽

G Loudianos ◽

M Deiana ◽

C Camaschella ◽

GV Sciarratta ◽

...

Keyword(s):

Blot Analysis ◽

Globin Gene ◽

Beta Thalassemia ◽

Italian Population ◽

Beta Globin ◽

Thalassemia Intermedia ◽

Dot Blot ◽

Beta Globin Gene ◽

Dot Blot Analysis ◽

Thalassemia Mutation

In this study, we have defined by dot-blot analysis with allelic specific oligonucleotide probes or direct sequencing on amplified DNA the beta-thalassemia mutations in a large group of patients (23) of Italian descent with thalassemia intermedia. These patients had one parent with either the silent beta-thalassemia carrier phenotype or borderline-normal hemoglobin A2 (HbA2) levels (2.5% to 3.5%). Nearly all were genetic compounds for a severe beta-thalassemia mutation and a beta-thalassemia mutation associated with high residual output of beta- globin chains (beta + intervening sequence [IVS]-I-nt6, beta -87, beta - 101), indicating that inheritance of a mild beta-thalassemia allele, even in a single dose, is the most common molecular mechanism producing thalassemia intermedia in the Italian population. In three cases, in whom we failed to define by dot-blot analysis the mutations, we sequenced the beta + globin gene and found three novel beta-thalassemia mutations, which are certainly very rare because they have been hitherto detected solely in a single patient. These mutations consist of: (1) a T-A substitution at position 2 of IVS-I, in a patient compound heterozygote for this mutation and the -87 promoter mutation; (2) a G-C substitution at position 844 of IVS-II, in a patient heterozygous for this mutation who showed normal sequences at the in trans beta-globin gene (The reason for the presence of clinical manifestations in a beta-thalassemia heterozygote has not been defined.); and (3) a deletion of one nucleotide (-T) at codon 126, resulting in a frameshift and readthrough of the 5′ untranslated region and most likely producing an elongated Hb molecule of 156 amino acid residues, in a patient heterozygous for this mutation with normal beta- globin gene sequences at the other locus.

Download Full-text

beta-thalassemia intermedia in a Brazilian patient with - 101(C > T) and codon 39 (C > T) mutations

Sao Paulo Medical Journal ◽

10.1590/s1516-31802003000100007 ◽

2003 ◽

Vol 121 (1) ◽

pp. 28-30

Author(s):

Sylvia Morais de Sousa ◽

Letícia Khater ◽

Luís Antônio Peroni ◽

Karine Miranda ◽

Marcelo Jun Murai ◽

...

Keyword(s):

Clinical Course ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Hypochromic Anemia ◽

Beta Thalassemia ◽

Beta Globin ◽

Thalassemia Intermedia ◽

Mean Cell Volume ◽

Molecular Alterations ◽

Brazilian Patient

CONTEXT: We verified molecular alterations in a 72-year-old Brazilian male patient with a clinical course of homozygous beta-thalassemia intermedia, who had undergone splenectomy and was surviving without regular blood transfusions. The blood cell count revealed microcytic and hypochromic anemia (hemoglobin = 6.5 g/dl, mean cell volume = 74 fl, mean cell hemoglobin = 24 pg) and hemoglobin electrophoresis showed fetal hemoglobin = 1.3%, hemoglobin A2 = 6.78% and hemoglobin A = 79.4%. OBJECTIVE: To identify mutations in a patient with the symptoms of beta-thalassemia intermedia. DESIGN: Molecular inquiry into the mutations possibly responsible for the clinical picture described. SETTING: The structural molecular biology and genetic engineering center of the Universidade Estadual de Campinas, Campinas, Brazil. PROCEDURES: DNA extraction was performed on the patient's blood samples. The polymerase chain reaction (PCR) was done using five specific primers that amplified exons and the promoter region of the beta globin gene. The samples were sequenced and then analyzed via computer programs. RESULTS: Two mutations that cause the disease were found: -101 (C > T) and codon 39 (C > T). CONCLUSIONS: This case represents the first description of 101 (C > T) mutation in a Brazilian population and it is associated with a benign clinical course.

Download Full-text

Beta zero-thalassemia in association with a gamma-globin gene quadruplication

Blood ◽

10.1182/blood.v68.6.1394.bloodjournal6861394 ◽

1986 ◽

Vol 68 (6) ◽

pp. 1394-1397

Author(s):

KG Yang ◽

JZ Liu ◽

F Kutlar ◽

A Kutlar ◽

C Altay ◽

...

Keyword(s):

Clinical Condition ◽

Globin Gene ◽

Normal Chromosome ◽

Gene Arrangement ◽

Beta Thalassemia ◽

Globin Genes ◽

Thalassemia Intermedia ◽

Gamma Globin ◽

Alpha Globin

We have studied the hematology, hemoglobin composition, and globin gene arrangements in one young Turkish boy with a beta zero-thalassemia homozygosity and in 11 of his relatives. Evidence is presented that the chromosome with the beta zero-thalassemia determinant carries a gamma- globin gene quadruplication, perhaps in a -G gamma-G gamma-G gamma-A gamma-gene arrangement. The eight gamma-globin genes in this patient produced G gamma and A gamma chains in a 95 to 5 ratio, and nearly 99% of the patient's hemoglobin was of the fetal type. The clinical condition resembled that of a thalassemia intermedia. HbF levels in eight beta-thalassemia heterozygotes varied between 0.5 and 4.2% and the percentages of G gamma in this HbF averaged at 87% or 95%; this level is to some extent related to the haplotype of the normal chromosome. All subjects carried four alpha-globin genes; a new BglII polymorphism was observed within the psi alpha-globin gene.

Download Full-text

BETA-GLOBIN GENE MUTATIONS IN TURKISH CHILDREN WITH BETA-THALASSEMIA: RESULTS FROM A SINGLE CENTER STUDY

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2013.055 ◽

2013 ◽

Vol 5 (1) ◽

pp. e2013055 ◽

Cited By ~ 13

Author(s):

Ali Fettah ◽

Cengiz Bayram ◽

Nese Yarali ◽

Pamir Isik ◽

Abdurrahman Kara ◽

...

Keyword(s):

Globin Gene ◽

Gene Mutations ◽

Thalassemia Major ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Thalassemia Intermedia ◽

Turkish Children ◽

Tertiary Center

Introduction: The beta thalassemias are common genetic disorders in Turkey and in this retrospective study our aim was to evaluate β-globin chain mutations and the phenotypic severity of β-thalassemia patients followed-up in our hospital, a tertiary center which serves patients from all regions of Turkey. Materials and Methods: 106 pediatric patients were analysed for β-globin gene mutations by using DNA analysis. Patients were classified as having β-thalassemia major or β-thalassemia intermedia based on age at diagnosis, transfusion frequency and lowest hemoglobin concentration in between transfusions. Results: There were 106 patients (52.8% female and 47.2% male) with a mean age of 11.2±5 years (1.6 – 22.3 years). Eighty-four (79.2%) patients had β-thalassemia major, whereas the remaining 22 patients (20.8%) were identified as having β-thalassemia intermedia. Overall, 18 different mutations were detected on 212 alleles. The most frequently encountered mutation was IVS I.110 (G>A) (35.3%), followed by Codon 8 del-AA (10.4%), IVS II.1 (G>A) (8%), IVS I.1 (G>A) (7.5%), Codon 39 (C>T) (7.1%) and Codon 5 (-CT) (6.6%), which made up 79.4% of observed mutations. According to present results, IVS I.110 (G>AA) was the most frequent mutation observed in this study, as in other results from Turkey. Evaluation of β-thalassemia mutations in 106 patients with 212 alleles, revealed the presence of homozygous mutation in 85 patients (80.2%) and compound heterozygous mutation in 21 patients (19.8%). The mutations detected in patients with homozygous mutation were IVS I.110 (G>A) (38.8%), Codon 8 del –AA (11.8%), IVS II.1 (G>A) (8.2%) and IVS I.1 (G>A) (8.2%). Observed mutations in the compound heterozygotes were Codon 39 (C>T)/Codon 41-42 (-CTTT) (14.3%), IVS I.110 (G>A)/Codon 39(C>T) (14.3%), IVS I.110 (G>A)/Codon 44(-C) (14.3%), and IVS II.745 (C>G)/ 5’UTR + 22 (G>A) (9.5%). Conclusion: Our hospital is a tertiary referral center that provides care to patients from all over the country, and thus the distribution of mutations observed in the current study is significant in term of representing that of the country as a whole.

Download Full-text

Molecular analysis of beta zero-thalassemia intermedia in Sardinia

Blood ◽

10.1182/blood.v74.2.823.823 ◽

1989 ◽

Vol 74 (2) ◽

pp. 823-827 ◽

Cited By ~ 42

Author(s):

R Galanello ◽

E Dessi ◽

MA Melis ◽

M Addis ◽

MA Sanna ◽

...

Keyword(s):

Nonsense Mutation ◽

Frameshift Mutation ◽

Globin Gene ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Beta Globin ◽

Thalassemia Intermedia ◽

Mild Phenotype ◽

Beta Globin Gene ◽

Alpha Thalassemia

Abstract In this study we have carried out alpha- and beta-globin gene analysis and defined the beta-globin gene polymorphisms in a group of patients with thalassemia intermedia of Sardinian descent. A group of patients (109) with thalassemia major of the same origin served as control. Characterization of the beta-thalassemia mutation showed either a frameshift mutation at codon 6 or a codon 39 nonsense mutation. We found that homozygotes for the frameshift mutation at codon 6 or compound heterozygotes for this mutation and for the codon 39 nonsense mutation develop thalassemia intermedia more frequently than thalassemia major. The frameshift mutation at codon 6 was associated with haplotype IX that contains the C-T change at position -158 5′ to the G gamma globin gene implicated in high gamma chain production and thus the mild phenotype. In patients' homozygotes for codon 39 nonsense mutation, those with thalassemia intermedia more frequently had the two- gene deletion form of alpha-thalassemia, or functional loss of the alpha 2 gene as compared with those with thalassemia major. In a few siblings with thalassemia major and intermedia, the thalassemia intermedia syndrome correlated with the presence of the -alpha/-alpha genotype. No cause for the mild phenotype was detected in the majority of patients who had not inherited either haplotype IX or alpha- thalassemia.

Download Full-text

Beta-Thalassemia in Iran: New Insight into the Role of Genetic Admixture and Migration

The Scientific World JOURNAL ◽

10.1100/2012/635183 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 16

Author(s):

Ali Reza Rezaee ◽

Mohammad Mehdi Banoei ◽

Elham Khalili ◽

Massoud Houshmand

Keyword(s):

Globin Gene ◽

Gene Mutations ◽

Genetic Admixture ◽

Beta Thalassemia ◽

The Caspian Sea ◽

Genetic Classification ◽

And Migration ◽

The Persian Gulf

Iran with an area of 1.648 million km2is located between the Caspian Sea and the Persian Gulf. The Iranian population consists of multiethnic groups that have been influenced by various invasions and migration throughout history. Studies have revealed the presence of more than 47 differentβ-globin gene mutations responsible forβ-Thalassemia in Iran. This paper is an attempt to study the origin ofβ-Thalassemia mutations in different parts of Iran. Distribution ofβ-Thalassemia mutations in Iran shows different patterns in different areas.β-Thalassemia mutations have been a reflection of people and area in correlation with migration and origin of ancestors. We compared the frequencies ofβ-globin mutations in different regions of Iran with those derived from neighboring countries. The analysis provided evidence of complementary information about the genetic admixture and migration of some mutations, as well as the remarkable genetic classification of the Iranian people and ethnic groups.

Download Full-text

Frequency of hereditary hemochromatosis gene mutations and their effects on iron overload among beta thalassemia patients of Chennai residents

AIMS Molecular Science ◽

10.3934/molsci.2021018 ◽

2021 ◽

Vol 8 (4) ◽

pp. 233-247

Author(s):

Bhuvana Selvaraj ◽

◽

Sangeetha Soundararajan ◽

Shettu Narayanasamy ◽

Ganesan Subramanian ◽

...

Keyword(s):

Iron Overload ◽

Iron Status ◽

Globin Gene ◽

Hereditary Hemochromatosis ◽

Gene Mutations ◽

Autosomal Recessive Disorder ◽

Thalassemia Major ◽

Organ Damage ◽

Beta Thalassemia ◽

Hemochromatosis Gene

<abstract> <p>Hereditary Hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism associated with <italic>HFE</italic> gene mutations, characterized by increased iron absorption and accumulation leading to multi-organ damage caused by iron overload toxicity. Beta thalassemia is caused by a mutation in the human beta globin gene. Imbalanced production of globin chain results in beta thalassemia, where the unpaired alpha chains precipitates in red cell precursors leading to ineffective erythropoiesis and reduced RBC survival. Both HH and beta thalassemia condition results in rapid accumulation of iron lead to iron overload in tissues and organs. The study aims to analyze the frequency of <italic>HFE</italic> variants among beta thalassemia cases and their effect on iron overload. The frequency of three <italic>HFE</italic> variants C282Y, H63D, S65C was analyzed by PCR RFLP method among Beta Thalassemia Trait (BTT) (n = 203), Beta Thalassemia Major (BTM) (n = 19) and age and sex-matched control samples (n = 200). The present study furnished allele frequency of H63D variant in BTT, BTM and controls 8.13, 15.8 and 6% respectively. Ten out of 33 heterozygous H63D variants exhibited iron overload with higher ferritin levels indicating <italic>HFE</italic> variant might aggravate the absorption of iron. The C282Y variant was present in heterozygous state in 1 case among beta thalassemia carriers. The C282Y variant was absent among BTM and control cases. S65C <italic>HFE</italic> variant was absent in the present study. Iron overload was completely absent in the control cases among all three <italic>HFE</italic> genotypes. Hence it is inferred from the present investigation, analysis of <italic>HFE</italic> genes and iron status will remarkably help to reason out the probable reason behind the iron status and support in proper management of beta thalassemia cases.</p> </abstract>

Download Full-text

Analysis of beta globin gene mutations in Diyarbakir

Turkish Journal of Biochemistry ◽

10.1515/tjb-2020-0546 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Selahaddin Tekeş ◽

Diclehan Oral ◽

Murat Söker ◽

Selda Şimşek ◽

Veysiye Hülya Uzel ◽

...

Keyword(s):

Globin Gene ◽

Molecular Genetic ◽

Point Mutations ◽

Gene Mutations ◽

Turkish Population ◽

University Hospital ◽

Beta Thalassemia ◽

Amplification Refractory Mutation System ◽

Compound Heterozygous ◽

Common Mutation

Abstract Objectives Hemoglobin disorders are quite heterogeneous in the Turkish population. Up to now, more than forty different beta thalassemia mutations and 60 hemoglobin variants have been characterized in the country. The aim of this study was to investigate genetic heterogeneity of HBB gene mutations in patients and their parents at Southeastern Anatolia in Turkey. Methods Genomic DNA was isolated from 145 thalassemic patients’ blood samples and their parents in this study. Ten different HBB gene mutations HBB:c.-80T>A, HBB:c.17_18delCT, HBB:c.25_26delAA, HBB:c.92+1G>A, HBB:c.92+5G>C, HBB:c.92+6T>C, HBB:c.93-21G>A, HBB:c.135delC, HBB:c.315+1G>A, HBB:c.316-106C>G were screened by amplification refractory mutation system. Four Hb variants and some rare beta thalassemia mutation were characterized by DNA sequencing. Results In this study, 97 homozygous and 48 compound heterozygous thalassemic patients were diagnosed by molecular genetic analyses. As a results, 18 β-thalassemia mutations and four abnormal hemoglobins; HBB:c.20A>T, HBB:c.364G>C, HBB:c.34G>A and HBB:c.208G>A were detected at Dicle University Hospital. Conclusions In the results, HBB:c.93-21G>A is the most common mutation in the region. Three mutations [(HBB:c.93-21G>A), (HBB:c.25_26delAA) and (HBB:c.135delC)] account for about 58 per cent of all the point mutations. Except HBB:c.20A>T and HBB:c.364G>C, two silent Hb variants (HBB:c.34G>A and HBB:c.208G>A) were detected in this study. Hb Hamilton [β11 (GTT>ATT) Val>Ile] was seen first time in Turkey.

Download Full-text

Rare double heterozygosity for poly A(A>G) and CD17(A>T) of beta thalassemia intermedia in a Chinese family

Hematology Reports ◽

10.4081/hr.2019.7911 ◽

2019 ◽

Vol 11 (3) ◽

Author(s):

Jianhong Xie ◽

Yuqiu Zhou ◽

Qizhi Xiao ◽

Ruoting Long ◽

Lianxiang Li ◽

...

Keyword(s):

Globin Gene ◽

Carrier State ◽

Beta Thalassemia ◽

Chinese Family ◽

Beta Globin ◽

Thalassemia Intermedia ◽

Wide Range ◽

Chain Synthesis ◽

Double Heterozygosity ◽

Globin Chain Synthesis

Beta thalassemia is a hereditary disorder resulted from mutations in the β globin gene leading to alpha/beta imbalance, ineffective erythropoiesis, and chronic anemia. Three types have been defined, based on the degree of reduced beta-globin chain synthesis and clinical phenotype: major, intermedia and minor (heterozygote carrier state). Beta thalassemia intermedia is characterized by heterogeneity for the wide clinical spectrum of various genotypes and a wide range of presentations. The genotypes of beta thalassemia intermedia are much complicated referring to β+/β+,β+/β0, Hb E/β0, β0/β0 compounding alpha thalassemia and so on. In this present case, we reported a rare beta thalassemia intermedia genotype of double heterozygosity for poly A (A>G) and CD17(A>T) indicated of β+/β0 in a Chinese family.

Download Full-text