|Year : 2019 | Volume
| Issue : 1 | Page : 97-102
The frequency and spectrum of HBB gene mutation in β-Thalassemia patients in Saudi Arabia
Raniah S Alotibi1, Eman Alharbi1, Bushra Aljuhani1, Bdoor Alamri1, Mohieldin Elsayid1, Naif M Alhawiti1, Fazal Hussain2, Fahad Almohareb2, Cherry Colcol2, Shoeb Qureshi3
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 Publication||4-Feb-2019|
Department of Research Methodology, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh
Source of Support: None, Conflict of Interest: None
| 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 16];10:97-102. Available from: http://www.jnsbm.org/text.asp?2019/10/1/97/251507
| Introduction|| |
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., 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., 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.
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., High prevalence of β-thalassemia is evident in the Mediterranean countries, Central Asia, India, and the Middle East among others. The diversified frequencies of 1%–11% are reported among the Arab nations. 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., 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. 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., The reduction or absence of β-globin chains increases the concentration of α-chain in the erythroblasts and the red blood cells and results in ineffective erythropoiesis, splenomegaly, and tissue hypoxia, eventually leading to increased deformation of the hemoglobin F and facial and skull bone marrows.,
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., The HBB genes are regulated by single-locus control region (LCR) which is situated in the short arm of chromosome 11., The LCR consists of four DNA hypersensitivity portions that influence the interaction among the erythroid-specific transcribing elements.,, 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. In Saudi Arabia, among other Arab nations, human β-globin gene mutation occurs along the LCR sites impacting on the production of β-globin., HBB genes consist of 5' and 3' untranslated regions, 146 amino acids, two introns, and three exons.
From clinical indications, β-thalassemia is classified as β-thalassemia major, β-thalassemia intermedia, and β-thalassemia minor. β-thalassemia major is caused by complete absence of β-globin formation due to several copies of HBB mutant gene. This form of β-thalassemia is severe and can appear within the initial 2 years of life with symptoms such as severe anemia, reduced growth, jaundice, and distended organs. 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.,, Similarly, β-thalassemia minor results from defect in one copy of HBB mutant gene, which leads to mild anemia. People with β-thalassemia minor are carriers and symptom free. 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. 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. 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|| |
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.
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.
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.
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.
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].
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.
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.
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|| |
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 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|| |
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., 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, 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., Individuals from the Mediterranean and Middle Eastern ethnicity are highly susceptible to β-thalassemia. 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., This mutation is more frequent in the eastern region of Saudi Arabia, especially in Al-Qatif and Al-Ahsa provinces. 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.,,, 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.,, 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., 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.,,,, 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., 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., 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. 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.
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,,,,,,,,,, and the variations in the distribution of these mutations can be accounted due to geographical factors., 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.,,, 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.,,,, 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.,,, Besides, molecular determination of patient phenotype and outcome can also be attributed to polymorphism in specific genes involved in β-thalassemia.,,,, 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., 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., 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.,, 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|| |
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.
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Conflicts of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2]