Table of Contents    
REVIEW ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 1  |  Page : 97-102  

The frequency and spectrum of HBB gene mutation in β-Thalassemia patients in Saudi Arabia


1 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
2 King Faisal Specialists Hospital and Research Center, Riyadh, Saudi Arabia
3 Department of Research Methodology, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

Date of Web Publication4-Feb-2019

Correspondence Address:
Shoeb Qureshi
Department of Research Methodology, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsbm.JNSBM_62_18

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   Abstract 


Background: β-thalassemia is an autosomal disorder of the blood caused by mutations in HBB gene responsible for the production of β-globin. The HBB mutations reduce the synthesis of β-globin which results in severe anemia. A high frequency of β-thalassemia is reported in Saudi Arabia, and hence this study assessed the most frequent β-thalassemia mutations in Saudi Arabia. Materials and Methods: Data of preimplantation genetic diagnosis and gene sequencing for 59 β-thalassemia patients and carriers were collected from the electronic medical record system at KFSH and RC and were analyzed using SPSS version 19. Results: Twelve mutations were confirmed in the five regions investigated in this study. Cd39 was identified as the most frequent mutation with a frequency of 22.7%, with high prevalence in the central parts of Saudi Arabia. IVS-II-1 G > A was the second frequent mutation observed with a frequency of 21.2%, while IVS-I-1 (G-A) and IVS I-130G>C mutations were observed to be least frequent in the study. Of the 12 gene mutations, 85% were frequently observed in Saudi Arabia, while 15% were less frequent. The regional distribution of HBB gene mutations varied considerably. Conclusion: The population diversity in Saudi Arabia contributes to the variability in the prevalence rates of HBB gene mutations. Nevertheless, this study identifies Cd39 and IVS-II-1 G > A as the predominant mutations in HBB gene in Saudi Arabia.

Keywords: β-thalassemia, HBB gene mutations, thalassemia


How to cite this article:
Alotibi RS, Alharbi E, Aljuhani B, Alamri B, Elsayid M, Alhawiti NM, Hussain F, Almohareb F, Colcol C, Qureshi S. The frequency and spectrum of HBB gene mutation in β-Thalassemia patients in Saudi Arabia. J Nat Sc Biol Med 2019;10:97-102

How to cite this URL:
Alotibi RS, Alharbi E, Aljuhani B, Alamri B, Elsayid M, Alhawiti NM, Hussain F, Almohareb F, Colcol C, Qureshi S. The frequency and spectrum of HBB gene mutation in β-Thalassemia patients in Saudi Arabia. J Nat Sc Biol Med [serial online] 2019 [cited 2019 Feb 17];10:97-102. Available from: http://www.jnsbm.org/text.asp?2019/10/1/97/251507




   Introduction Top


β-thalassemia appears to be endemic in areas associated with the previous prevalence of malaria in Saudi Arabia in addition to the frequency of variations in the parasitic carriers.[1],[2] β-thalassemia syndrome consists of hereditary disorders that are influenced by genetic mutations, which can cause absence or deficiency in the synthesis of β-globin chains.[1],[3] The state of homozygosis or compound heterozygosis can project the development of severe, transfusion-dependent anemia, where β-thalassemia trait (heterozygous type) results in mild or moderate anemia. Such a scenario indicates that the molecular bases of β-thalassemia are heterozygous due to variations in the coding areas of β-globin (HBB) genes induced by point mutation.[4]

Globally, about 3% of the population are carriers of β-thalassemia. Over 300 mutations of the HBB genes are reported, with 40 mutations being responsible for cases of β-thalassemia.[5],[6] High prevalence of β-thalassemia is evident in the Mediterranean countries, Central Asia, India, and the Middle East among others.[7] The diversified frequencies of 1%–11% are reported among the Arab nations.[8] In Saudi Arabia, prevalence varies across different parts of the country, where Eastern provinces, such as Jubail, and along the Red Sea coastal strip show the highest prevalence.[9],[10] Gene mutations, such as frameshift, deletion, initiation-codon, and splicing enhance the complete inactivation of β-globin genes that prevent the creation of β-globulin chains causing β-thalassemia.[11] Other mutations can also enable partial inactivation of the HBB genes reducing the β-globin chain to β+ or β++ that is necessary for β-globin production.[12],[13] The reduction or absence of β-globin chains increases the concentration of α-chain in the erythroblasts and the red blood cells[14] and results in ineffective erythropoiesis, splenomegaly, and tissue hypoxia, eventually leading to increased deformation of the hemoglobin F and facial and skull bone marrows.[15],[16]

The severity of β-thalassemia condition is dependent on the ratio of α-globin or non-α-globin synthesis to excess of free α-chains.[17],[18] The HBB genes are regulated by single-locus control region (LCR) which is situated in the short arm of chromosome 11.[18],[19] The LCR consists of four DNA hypersensitivity portions that influence the interaction among the erythroid-specific transcribing elements.[19],[20],[21] The most prevalent types of β-thalassemia mutations are enacted from the abnormal processing of the messenger-RNA or possible blockage in the process of transcription.[22] In Saudi Arabia, among other Arab nations, human β-globin gene mutation occurs along the LCR sites impacting on the production of β-globin.[23],[24] HBB genes consist of 5' and 3' untranslated regions, 146 amino acids, two introns, and three exons.[25]

From clinical indications, β-thalassemia is classified as β-thalassemia major, β-thalassemia intermedia, and β-thalassemia minor.[14] β-thalassemia major is caused by complete absence of β-globin formation due to several copies of HBB mutant gene.[15] This form of β-thalassemia is severe and can appear within the initial 2 years of life[16] with symptoms such as severe anemia, reduced growth, jaundice, and distended organs.[16] A regular blood transfusion should be adopted in the treatment of β-thalassemia major to provide them with sufficient volume of mature red blood cells.[17],[18],[19] Similarly, β-thalassemia minor results from defect in one copy of HBB mutant gene, which leads to mild anemia.[20] People with β-thalassemia minor are carriers and symptom free.[20] People whose clinical manifestation is between the severe signs of β-thalassemia major and the mild symptoms of β-thalassemia minor are considered to have β-thalassemia intermedia.[21] HBB gene mutations can cause β-thalassemia which has a high prevalence in the Middle East. Understating the profile of HBB mutations in a specific population is essential to make the clinical diagnosis efficient, simple, and cost-effective.[26] Hence, this study aimed to identify the more frequent HBB mutations of β-thalassemia that are related to the Saudi Arabian population at King Faisal Specialists Hospital and Research Center (KFSH and RC). The results of the study will be utilized by national health awareness programs to improve the outcomes of genetic risk profiling.


   Materials and Methods Top


Study area

The selected areas under investigation were based on the raw data collected at KFSH and RC in Riyadh, Saudi Arabia, to lay emphasis on the significant regions affected by β-thalassemia. Such a consideration provided a practical choice of the affected area in Saudi Arabia to address the research objective.

Study subjects

The participants for the research were randomly selected from the targeted population to avoid bias. Both genders were included in the study, yet the selection was based on the inclusion and exclusion criteria. For example, individuals with β-thalassemia who had undergone HBB gene sequencing and appeared at KFSH and RC from 2002 to 2017 were included in the study. On the other hand, people without β-thalassemia or β-thalassemia patients who had not undergone HBB gene sequencing and are not registered patients at KFSH and RC were excluded from the study.

Study design

The research utilized an exploratory and descriptive design to deliberate on the situation of β-thalassemia and investigate the issue based on the available data. In such a move, a retrospective chart review quantitative study was used in the identification of the frequent HBB mutations in β-thalassemia patients that are related to the Saudi population at KFSH and RC, Saudi Arabia.

Sample size

A sample size of 59 β-thalassemia patients was registered in the research. The number was achieved through calculation using the Check Market online calculator, providing a marginal error of 5% at 95% confidence level. However, the required sample size was 51, which represented cases from across the targeted regions in Saudi Arabia.

Demographic data

The demographic information of the 59 participants in the study included both children and adults from Saudi Arabia. The family backgrounds were also assessed for history of the condition. The data are summarized in [Table 1].
Table 1: Demographic data of study participants

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Sampling technique

Through continuous sampling, the samples were selected followed by molecular screening for β-thalassemia. The results of preimplantation genetic diagnosis and gene sequencing were collected from the electronic medical record system in the institution. The different HBB gene mutations in Mediterranean and Middle East regions and their detection rates are highlighted in [Table 2].
Table 2: Different HBB gene mutations in Mediterranean and Middle East regions and their detection rates

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HBB gene testing and analysis

Heterozygous or carrier detection is performed through hematologic and molecular genetic tests. However, molecular genetic testing of HBB is preferred, especially when hematologic analysis shows abnormality. The procedure is performed to identify pathogenic variants in addition to mild and silent β-thalassemia mutation. At-risk population is often screened due to high carrier rate of HBB pathogenic variants, which relies on hematologic evaluation. The HBB pathogenic variants are responsible for the mutation.

Data analysis

The collected data were tabulated in Microsoft Excel and then submitted for analysis using Statistical Package for the Social Sciences (SPSS) software version 19 (IBM, armonk, NY, USA). The analyzed data were expressed as percentages. The categorical is variables were represented by frequencies and percentiles, while mean and standard deviation were used for continuous variables.

Ethical considerations

The study was reviewed and approved by the KFSH and RC Ethical Committee and the Research Advisory Council. Informed consent was demonstrated among the study participants while ensuring confidentiality of the collected and retrieved data.


   Results Top


Twelve mutations were identified from the 59 Saudi β-thalassemia carriers and patients at KFSH and RC in Riyadh. The 12 cases were abstracted from five different Saudi regions (central, northern, southern, eastern, and western parts).

The frequency of the individual mutations is shown in [Figure 1], while the regional distribution of the identified mutations in the Saudi population is represented in [Figure 2]. Cd39 was the most frequent mutation observed with a rate of 22.7% and higher prevalence rate was recorded in the central region. IVS II-1 G > A was the second most common mutation observed with a frequency of 21.2%. However, the IVS II-1 G > A was more frequent in the eastern region. The third most common mutation was IVS I-110 G > A with a frequency of 13.6%. The IVS I-110 G > A had higher distribution rate in the western region of Saudi Arabia which was followed by the central region.
Figure 1: Frequency of HBB mutations in Saudi populations

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Figure 2: Regional distribution of the 12 β-thalassemia mutations in Saudi populations

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Apart from the dominant mutations, other mutations observed include IVS I-5 G > C with a frequency of 10.6%, IVSI-3' end 25 bp with a rate of 9.1%, and Cd8/9 (+G) with a rate of 7.6%, which had higher distribution in the eastern region. Nearly 85% of the cases had mutations in Cd39, IVS II-1 G > A, IVS I-110 G > A, IVS I-5 G > C, IVSI-3' end 25 bp, and Cd8/9 (+G) regions of HBB gene.


   Discussion Top


Cd39 was the most frequent HBB gene mutation observed in our study. This mutation is reported to have the highest distribution in the Arabian Peninsula.[13],[27] It is distributed in most of the Saudi regions, with a higher rate in the central region. Although β-thalassemia is likely to affect primarily people of Saudi Arabia regardless of the provinces,[28] the variations in the percentage of people with β-thalassemia are due to the possible β-globin gene mutations in various areas and diversity in the ethnic groups in the country.[27],[29] Individuals from the Mediterranean and Middle Eastern ethnicity are highly susceptible to β-thalassemia.[27] This is supported by the consistency in reported cases over the region, where IVS II-1 G > A is the second most common mutation in the East Mediterranean origin.[13],[30] This mutation is more frequent in the eastern region of Saudi Arabia, especially in Al-Qatif and Al-Ahsa provinces.[31] The highest prevalence rate of IVS II-1 G > A mutation was found in Iran, hence the dominance of this mutation in the eastern region of Saudi Arabia.[13],[29],[32],[33] IVS II-1 G > A was more frequent in the northern region, while IVS I-5 G > C had the highest rate in the southeastern part. Such variations in the distribution outline the significance of migration in the population, causing the variable HBB gene mutation as opposed to ethnic background.[29],[33],[34] IVS I-110 G > A was the third most common mutation, with a higher distribution rate in the western region of Saudi Arabia followed by the central region. The origin of IVS I-110 G > A mutation in the Mediterranean basin is reported to be from Turkey and is thought to have spread in Arabian Peninsula during the Ottoman Empire.[13],[34] In such a consideration, IVS I-110 G > A mutation is common along the coastal strip of the Red Sea. Nevertheless, the other common mutations such as IVS I-5 G > C, IVSI-3' end 25 bp, and Cd8/9 (+G) are distributed in more than one region, with higher distribution rates in the eastern region of Saudi Arabia. Recent studies on the prevalence of β-thalassemia provide figures on the frequencies of occurrence in Saudi Arabia, with a high incidence in the highlighted areas.[4],[29],[35],[36],[37] From this study, seven β-globin gene mutations are identified as common, i.e., IVS II-5 G > C, while 16 other mutations were less prevalent. The origin of the less frequent HBB gene mutations is of Asian Indian.[13],[38] Consequently, the distribution of HBB mutations in eastern Arabian Peninsula is related to the historical migration and trade routes used by the caravans originating from India.[13],[39] The other six mutations in this study, namely Cd26 (G-A) Hb E, IVS-II-848 C > A, Cd 82/83 (-G), -88C > A, IVS-I-1 (G-A), and IVS I-130G>C had the lowest frequency of 15%. From the findings, the following two novel mutations were observed: IVS I-130 (G-C) and IVS I-110 (G-A), and these are previously not reported in the Eastern Province.[40] Out of the identified mutations, Cd 82/83 (-G), -88C > A, and IVS I-130G > C are considered to be rare mutations in the Arab countries.[23]

Based on the present and past researches, Saudi Arabia has never encountered situations of FSC 20/21 mutation or possible correlation to β-thalassemia. This study finding was consistent with previous studies,[9],[13],[22],[40],[41],[42],[43],[44],[45],[46] and the variations in the distribution of these mutations can be accounted due to geographical factors.[13],[45] This retrospective report shows that 12 mutations are evident in the Saudi Arabian population, which justifies the accuracy of the frequencies and range of mutations reported in HBB genes.[47],[48],[49],[50] Nevertheless, the novel mutations that have been reported in the Saudi population were not heightened in this investigation, possibly due to the size of the sample, which is a limitation of the study. Hence, further research on the number of novelty mutations in HBB gene is necessary in the future. Within the limitations of this study, the central region was observed to have the highest prevalence of β-thalassemia. HBB gene mutations of Asian Indian origin had higher rates in Oman, the UAE, Bahrain, and east of Saudi Arabia.[13],[51],[52],[53],[54] However, the most widespread mutation among Arabs was found to be IVS I-110 G > A. In the Arab countries, the admixture of people from different ethnic backgrounds and geographical locations is responsible for the variations in the HBB gene mutation.[31],[33],[55],[56] Besides, molecular determination of patient phenotype and outcome can also be attributed to polymorphism in specific genes involved in β-thalassemia.[7],[50],[33],[57],[58] In adults, studies have shown that molecular targets are used as effectors of silencing the expression of γ-globin genes, which is the principal mediator in polymorphism or modifier of β-thalassemia phenotype. Despite the recognition of gamma gene, its appearance in HBB mutation has not been clarified and is subject to further research.

From the variables in the percentages of β-thalassemia, it is clear that geographical differences contribute to the significant variations in the HBB gene mutations. This diversity is attributed to the unique positioning of Saudi Arabia between the southeast Asian and Mediterranean regions. The range of mutations likely to be evident in Saudi Arabia includes c. 315 + 1G > A, c. 118 C > T, and c. 92 + 5 G > C.[57],[58] The clinical significance of c. 315 + 1G > A and c. 118 C > T mutations is linked to the production of β0 thalassemia phenotypes. These phenotypes are likely to occur in most of the Mediterranean and Gulf regions.[24],[59] On the other hand, c. 92 + 5 G > C has the capacity of developing β+-thalassemia phenotype, which can be demonstrated in the Asian Indian region.[46],[57],[59] These observations can help in facilitating the diagnosis of β-thalassemia by minimizing the mutations of interest and saving time, efforts, and cost spent on gene sequencing.


   Conclusion Top


From the research, it can be concluded that 85% of the identified HBB mutations were highly distributed in Saudi Arabia. Twelve HBB mutations with varying prevalence were observed in the five regions of Saudi Arabia. The prevalence rates of these mutations among the Saudi regions were wide ranging due to the diversity of its geographic boundaries. Nevertheless, C39 and IVS II-1 G > A mutations were the most frequent contributors to the prevalence of β-thalassemia in Saudi Arabia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Thein SL. The molecular basis of β-thalassemia. Cold Spring Harb Perspect Med 2013;3:a011700.  Back to cited text no. 1
    
2.
Cao A, Galanello R. Beta-thalassemia. Genet Med 2010;12:61-76.  Back to cited text no. 2
    
3.
Boonyawat B, Monsereenusorn C, Traivaree C. Molecular analysis of beta-globin gene mutations among Thai beta-thalassemia children: Results from a single center study. Appl Clin Genet 2014;7:253-8.  Back to cited text no. 3
    
4.
Hamamy HA, Al-Allawi NA. Epidemiological profile of common haemoglobinopathies in Arab countries. J Community Genet 2013;4:147-67.  Back to cited text no. 4
    
5.
Kountouris P, Kousiappa I, Papasavva T, Christopoulos G, Pavlou E, Petrou M, et al. The molecular spectrum and distribution of haemoglobinopathies in Cyprus: A 20-year retrospective study. Sci Rep 2016;6:26371.  Back to cited text no. 5
    
6.
Manning LR, Russell JE, Padovan JC, Chait BT, Popowicz A, Manning RS, et al. Human embryonic, fetal, and adult hemoglobins have different subunit interface strengths. Correlation with lifespan in the red cell. Protein Sci 2007;16:1641-58.  Back to cited text no. 6
    
7.
Ribeiro DM, Sonati MF. Regulation of human alpha-globin gene expression and alpha-thalassemia. Genet Mol Res 2008;7:1045-53.  Back to cited text no. 7
    
8.
Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood 2008;112:3927-38.  Back to cited text no. 8
    
9.
Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Rev 2012;26 Suppl 1:S3-6.  Back to cited text no. 9
    
10.
Leung WC, Leung KY, Lau ET, Tang MH, Chan V. Alpha-thalassaemia. Semin Fetal Neonatal Med 2008;13:215-22.  Back to cited text no. 10
    
11.
Karim MF, Ismail M, Hasan AM, Shekhar HU. Hematological and biochemical status of beta-thalassemia major patients in Bangladesh: A comparative analysis. Int J Hematol Oncol Stem Cell Res 2016;10:7-12.  Back to cited text no. 11
    
12.
Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010;5:11.  Back to cited text no. 12
    
13.
Hamamy H, Al-Allawi N. Epidemiological profile of common hemoglobinopathies in Arab countries. J Community Genet 2012;4:147-67.  Back to cited text no. 13
    
14.
Kohne E. Hemoglobinopathies: Clinical manifestations, diagnosis, and treatment. Dtsch Arztebl Int 2011;108:532-40.  Back to cited text no. 14
    
15.
Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med 2005;353:1135-46.  Back to cited text no. 15
    
16.
Grow K, Vashist M, Abrol P, Sharma S, Yadav R. Beta thalassemia in India: Current status and the challenges ahead. Int J Pharm Pharm Sci 2014;6:28-33.  Back to cited text no. 16
    
17.
Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004;89:1187-93.  Back to cited text no. 17
    
18.
Fung EB, Harmatz PR, Lee PD, Milet M, Bellevue R, Jeng MR, et al. Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Br J Haematol 2006;135:574-82.  Back to cited text no. 18
    
19.
Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol 2007;138:291-304.  Back to cited text no. 19
    
20.
Marengo-Rowe AJ. The thalassemia and related disorders. Bayl Univ Med Cent Proc 2007;20:27-31.  Back to cited text no. 20
    
21.
Khalifa AS, Salem M, Mounir E, El-Tawil MM, El-Sawy M, Abd Al-Aziz MM, et al. Abnormal glucose tolerance in Egyptian beta-thalassemic patients: Possible association with genotyping. Pediatr Diabetes 2004;5:126-32.  Back to cited text no. 21
    
22.
Haj Khelil A, Laradi S, Miled A, Omar Tadmouri G, Ben Chibani J, Perrin P, et al. Clinical and molecular aspects of haemoglobinopathies in Tunisia. Clin Chim Acta 2004;340:127-37.  Back to cited text no. 22
    
23.
Nahla H, Nada A, Robert TJ. Iron deficiency is an important contributor to anemia among reproductive age women in Lebanon. Ecol Food Nutr 2004;43:77-92.  Back to cited text no. 23
    
24.
Al-Ali AK, Al-Ateeq S, Imamwerdi BW, Al-Sowayan S, Al-Madan M, Al-Muhanna F, et al. Molecular bases of beta-thalassemia in the Eastern Province of Saudi Arabia. J Biomed Biotechnol 2005;2005:322-5.  Back to cited text no. 24
    
25.
Teebi AS, Teebi SA. Genetic diversity among the Arabs. Community Genet 2005;8:21-6.  Back to cited text no. 25
    
26.
Al-Obaidli A, Hamodat M, Fawzi Z, Abu-Laban M, Gerard N, Krishnamoorthy R, et al. Molecular basis of thalassemia in Qatar. Hemoglobin 2007;31:121-7.  Back to cited text no. 26
    
27.
Jiffri EH, Bogari N, Zidan KH, Teama S, Elhawary NA. Molecular updating of β-thalassemia mutations in the upper Egyptian population. Hemoglobin 2010;34:538-47.  Back to cited text no. 27
    
28.
Zakaria MA, Mona HS, Ahmed MT, Mohammed AZ, Abdul RS. Experience with combination therapy of deferiprone and desferrioxamine in β-thalassemia major patients with iron overload at maternity and children hospital, Al Madinah Al Munawarah, Saudi Arabia. J Taibah Univ Med Sci 2010;5:27-35.  Back to cited text no. 28
    
29.
Al-Allawi NA, Hassan KM, Sheikha AK, Nerweiy FF, Dawood RS, Jubrael J, et al. B-thalassemia mutations among transfusion-dependent thalassemia major patients in Northern Iraq. Mol Biol Int 2010;2010:479282.  Back to cited text no. 29
    
30.
Jalal SD, Al-Allawi NA, Bayat N, Imanian H, Najmabadi H, Faraj A, et al. B-thalassemia mutations in the Kurdish population of Northeastern Iraq. Hemoglobin 2010;34:469-76.  Back to cited text no. 30
    
31.
Abuzenadah AM, Hussein IM, Damanhouri GA, A-Sayes FM, Gari MA, Chaudhary AG, et al. Molecular basis of β-thalassemia in the Western Province of Saudi Arabia: Identification of rare β-thalassemia mutations. Hemoglobin 2011;35:346-57.  Back to cited text no. 31
    
32.
Akhavan-Niaki H, Derakhshandeh-Peykar P, Banihashemi A, Mostafazadeh A, Asghari B, Ahmadifard MR, et al. Acomprehensive molecular characterization of beta thalassemia in a highly heterogeneous population. Blood Cells Mol Dis 2011;47:29-32.  Back to cited text no. 32
    
33.
Al-Sultan A, Phanasgaonkar S, Suliman A, Al-Baqushi M, Nasrullah Z, Al-Ali A, et al. Spectrum of β-thalassemia mutations in the Eastern Province of Saudi Arabia. Hemoglobin 2011;35:125-34.  Back to cited text no. 33
    
34.
Terreros MC, Rowold DJ, Mirabal S, Herrera RJ. Mitochondrial DNA and Y-chromosomal stratification in Iran: Relationship between Iran and the Arabian Peninsula. J Hum Genet 2011;56:235-46.  Back to cited text no. 34
    
35.
Bhowmick S, Das DK, Maiti AK, Chakraborty C. Computer-aided diagnosis of thalassemia using scanning electron microscopic images of peripheral blood: A morphological approach. J Med Imag Health Infor 2012;2:215-21.  Back to cited text no. 35
    
36.
López-Escribano H, Parera MM, Guix P, Serra JM, Gutierrez A, Balsells D, et al. Balearic archipelago: Three Islands, three beta-thalassemia population patterns. Clin Genet 2013;83:175-80.  Back to cited text no. 36
    
37.
Sahli CA, Bibi A, Ouali F, Siala H, Fredj SH, Othmani R, et al. Δ0-thalassemia in cis of βKnossos globin gene:First homozygous description in thalassemia intermedia libyans and first combination with codon 39 (C → T) in thalassemia intermedia Tunisian patients. Clin Chem Lab Med 2012;50:1743-8.  Back to cited text no. 37
    
38.
Rezaee AR, Banoei MM, Khalili E, Houshmand M. Beta-thalassemia in Iran: New insight into the role of genetic admixture and migration. ScientificWorldJournal 2012;2012:635183.  Back to cited text no. 38
    
39.
Sirdah MM, Sievertsen J, Al-Yazji MS, Tarazi IS, Al-Haddad RM, Horstmann RD, et al. The spectrum of β-thalassemia mutations in Gaza strip, Palestine. Blood Cells Mol Dis 2013;50:247-51.  Back to cited text no. 39
    
40.
Garcia-Bertrand R, Simms TM, Cadenas AM, Herrera RJ. United Arab emirates: Phylogenetic relationships and ancestral populations. Gene 2014;533:411-9.  Back to cited text no. 40
    
41.
Reading NS, Sirdah MM, Tarazi IS, Prchal JT. Detection of nine Mediterranean β-thalassemia mutations in Palestinians using three restriction enzyme digest panels: A reliable method for developing countries. Hemoglobin 2014;38:39-43.  Back to cited text no. 41
    
42.
Qari MH, Wali Y, Albagshi MH, Alshahrani M, Alzahrani A, Alhijji IA, et al. Regional consensus opinion for the management of beta thalassemia major in the Arabian Gulf area. Orphanet J Rare Dis 2013;8:143.  Back to cited text no. 42
    
43.
Borgio JF, AbdulAzeez S, Al-Nafie AN, Naserullah ZA, Al-Jarrash S, Al-Madan MS, et al. Anovel HBA2 gene conversion in cis or trans: “α12 allele” in a Saudi population. Blood Cells Mol Dis 2014;53:199-203.  Back to cited text no. 43
    
44.
Jarjour RA, Murad H, Moasses F, Al-Achkar W. Molecular update of β-thalassemia mutations in the Syrian population: Identification of rare β-thalassemia mutations. Hemoglobin 2014;38:272-6.  Back to cited text no. 44
    
45.
Murad H, Moassas F, Jarjour R, Mukhalalaty Y, Al-Achkar W. Prenatal molecular diagnosis of β-thalassemia and sickle cell anemia in the Syrian population. Hemoglobin 2014;38:390-3.  Back to cited text no. 45
    
46.
Warsy AS, El-Hazmi MA, Aleem A, Al-Hazmi AM, Al-Momin AK. Genetic basis of Saudi beta thalassemia identification of Mediterranean and Asian mutations. Biosci Biotechnol Res Asia 2012;9:97-104.  Back to cited text no. 46
    
47.
Kumar R, Sagar C, Sharma D, Kishor P. B-globin genes: Mutation hot-spots in the global thalassemia belt. Hemoglobin 2015;39:1-8.  Back to cited text no. 47
    
48.
Nasouhipur H, Banihashemi A, Youssefi Kamangar R, Akhavan-Niaki H. Hb knossos: HBB: c. 82G>T associated with HBB: c. 315+1G>A beta zero mutation causes thalassemia intermedia. Indian J Hematol Blood Transfus 2014;30:243-5.  Back to cited text no. 48
    
49.
Elena C. Genetics and racial difference in contemporary Brazil: Haemoglobinopathies, whiteness, and admixture in biomedical literature. Bull Latin Am Res 2016;35:165-77.  Back to cited text no. 49
    
50.
Ozkinay F, Onay H, Karaca E, Arslan E, Erturk B, Ece Solmaz A, et al. Molecular basis of β-thalassemia in the population of the Aegean region of Turkey: Identification of A novel deletion mutation. Hemoglobin 2015;39:230-4.  Back to cited text no. 50
    
51.
Cherry L, Calo C, Talmaci R, Perrin P, Gavrila L. B-thalassemia haplotypes in Romania in the context of genetic mixing in the Mediterranean area. Hemoglobin 2016;40:85-96.  Back to cited text no. 51
    
52.
Adly AA, Ebeid FS. Cultural preferences and limited public resources influence the spectrum of thalassemia in Egypt. J Pediatr Hematol Oncol 2015;37:281-4.  Back to cited text no. 52
    
53.
Elmezayen AD, Kotb SM, Sadek NA, Abdalla EM. B-globin mutations in Egyptian patients with β-thalassemia. Lab Med 2015;46:8-13.  Back to cited text no. 53
    
54.
Mokhtar GM, El Alfy MS, Ebeid SE, El Sawi MA, Fayek MH, Adly AA, et al. Hemochromatosis C282Y gene mutation as a potential susceptibility factor for iron-overload in Egyptian beta-thalassemia patients. Egypt J Med Hum Genet 2017;19:103-6.  Back to cited text no. 54
    
55.
AlFadhli S, Salem M, Shome DK, Mahdi N, Nizam R. The effects of HFE polymorphisms on biochemical parameters of iron status in Arab beta-thalassemia patients. Indian J Hematol Blood Transfus 2017;33:545-51.  Back to cited text no. 55
    
56.
De Sanctis V, Kattamis C, Canatan D, Soliman AT, Elsedfy H, Karimi M, et al. B-thalassemia distribution in the old world: An ancient disease seen from a historical standpoint. Mediterr J Hematol Infect Dis 2017;9:e2017018.  Back to cited text no. 56
    
57.
El-Hazmi MA, Warsy AS. Appraisal of sickle-cell and thalassaemia genes in Saudi Arabia. East Mediterr Health J 1999;5:1147-53.  Back to cited text no. 57
    
58.
Hasounah FH, Sejeny SA, Omer JA, Old JM, Oliver RW. Spectrum of beta-thalassaemia mutations in the population of Saudi Arabia. Hum Hered 1995;45:231-4.  Back to cited text no. 58
    
59.
El-Harth EH, Kühnau W, Schmidtke J, Stuhrmann M, Nasserallah Z, Al-Shahiri A, et al. Identification and clinical presentation of beta thalassaemia mutations in the Eastern region of Saudi Arabia. J Med Genet 1999;36:935-7.  Back to cited text no. 59
    


    Figures

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    Tables

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