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International Journal of Blood Research and Disorders





DOI: 10.23937/2469-5696/1410004



Diverse Genotype Presentation of the Saudi-Type Polya Signal Mutation (αTsaudiα) in the Population of Bahrain

Nabeel Al Moamen*, Fawzia Mahdi, Ahmed Thabet, Rugaya Abbas, Ebtihal Salman and Ahmed Al Alawi


Genetic Laboratory, Department of Pathology, Salmaniya Medical Complex, Kingdom of Bahrain


*Corresponding author: Nabeel Al Moamen, Genetic Laboratory, Department of athology, Salmaniya Medical Complex, Manama, Kingdom of Bahrain, E-mail: njassim@yahoo.com
Int J Blood Res Disord, IJBRD-2-004, (Volume 2, Issue 1), Letter to the Editor; ISSN: 2469-5696
Received: December 28, 2014 | Accepted: January 05, 2015 | Published: January 15, 2015
Citation: Al Moamen N, Mahdi F, Thabet A, Abbas R, Salman E, et al., (2015) Diverse Genotype Presentation of the Saudi-Type Polya Signal Mutation (aTsaudia) in the Population of Bahrain. Int J Blood Res Disord 2:004. 10.23937/2469-5696/1410004
Copyright: © 2015 Al Moamen N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Keywords

Bahrain, Alpha-thalassemia, HbH disease, TSaudi, poly A

α-Thalassemia is quite prevalent in the population of Bahrain reaching a frequency of 24.3% based on neonates screening of Hb Bart's in cord blood hemolysates [1]. In a preliminary report we found five different α-thalassemia determinants as the underlying molecular defects for α-thalassemia in our population [2]. The first most common α-thal determinant uncovered in that report was the Saudi-type polyadenylation signal mutation that is found in α2-globin gene (αTSaudiα) [AATAAA?AATAAG; c.*94A>G] [2,3,4]. In this letter we presented the diverse genotype combinations of the (αTSaudiα) haplotype in our population and their relevant phenotypes.

A total of 1187 patients with α-thalassemia phenotype presentation have been recruited for this investigation. Preliminary diagnosis of α-thalassemia was based on low hematological indices (MCV and MCH) of the red blood cells and/or persistently low hemoglobin levels, along with low or normal levels of HbA2 and absence of iron deficiency [5,6]. The molecular diagnosis of α-thalassemia was established by using a commercially available α-thalassemia strip assay (α-Globin StripAssay, ViennaLab Diagnostics GmbH) and direct nucleotide sequencing for further confirmation.

The spectrum of phenotype presentations for the (αTSaudiα) genotype combinations ranges between hemoglobin H (Hb H) disease and ??thalassemia trait phenotype with variable severity.

The first molecular defect causing HbH disease in our population is homozygosity for the (αTSaudiα) haplotype, i.e., the (αTSaudiα/αTSaudiα) genotype, which is by far the most common molecular basis of Hb H disease in this population. A total of 49 patients were uncovered with this genotype and a representative 15 patients are introduced in Table 1. These patients are presented with moderate to severe level of anemia (Hb ranges: 7.4-9.7g/dL). They persistently show Hb H peak fraction on HPLC of their RBC hemolysates with HbH level ranges from 7.5 to 27.2 % of total hemoglobin. In addition, most of these patients are presented with elevated level of reticulocytes (>3.0%), an indication of hematopoitic stress due to persistent anemia. Moreover, significant number of these patients is undergoing infrequent blood transfusion which is in line with variable phenotype presentation of Hb H disease in other populations [7-9]. Although this genotype is inactivating only two α-globin genes it gives rise to a severe form of Hb H disease whereas the inactivation of three α-globin genes is commonly encountered in Hb H disease [10]. This unusual effect of the (αTSaudiα) mutation is largely attributed to a down regulation effect of this mutation on the linked α1-globin gene as a result of transcriptional interference as was suggested before [11,12].



strong>Table 1: Hematological parameters in selected patients harboring the (αTSaudi(α/(αTSaudi(α) genotype strong>View Table 1



The second genotype underlying Hb H disease in this population is compound heterozygosity of the (αTSaudiα) haplotype in trans with the IVS I donor-site pentanucleotide deletion mutant in α2-globin gene on the other chromosome [(αHphα); c.95+2_95+6del TGAGG] [13]. This genotype combination [i.e.,(αTSaudiα/αHphα)] was discovered in a total of 25 patients and all are presented with relatively mild-to-moderate form of Hb H disease with total Hb levels ranging from 9.0 g/dL to 11.3 g/dL (Table 2). None of these patients require blood transfusion.



strong>Table 2: Hematological parameters in selected patients harboring the (αTSaudi(α/(αHph(α) genotype strong>View Table 2



Comparison of hematological parameters between the(αTSaudiα/αTSaudiα) genotype and the (αTSaudiα/αHphα) genotype by using the Student's T-test revealed highly significant difference (P< 0.001) in Hb levels (8.5 0.7 vs. 10 0.8), RBC counts (4.6 0.4 vs. 5.4 0.5) and HbA2 levels (1.7 0.3 vs. 2.3 0.2) [values are means SD for (αTSaudiTSaudi(α vs. (αTSaudi(αHph(α, respectively]. In contrast no difference was observed between these two genotypes in MCV (60 3.5 vs. 58.7 2.6) and MCH (18.1 0.5 vs. 18.3 0.9) (P>0.05) [n=33 for (αTSaudiTSaudi(α and n=25 for (αTSaudi(αHph(α]. In summary, these two genotypes are presented with the most severe phenotype of Hb H disease in this population.

Other genotype combination of the Saudi type poly a signal mutation that we uncovered includes the (-α3.7TSaudiα) genotype that we found in 52 patients (Table 3). In addition, we found 12 patients with the (-α4.2TSaudi) genotype. Indeed, both of these genotypes are presented, as expected, with the same level of hematological severity and mild presentation of Hb H disease (Table 3). Finally we uncovered 40 patients with the (αTSaudiα/αα) genotype?. These simple heterozygotes are consistently presented with α-thalassemia trait phenotype (Table 3).



Table 3: Average hematological values for patients harboring various combinationsof the (αTSaudia) genotype along with values for wild type genotype (αα/αα) in the population of Bahrain View Table 3



In summary, this report presents our findings in regard of the (αTSaudiα) genotype combinations in the population of Bahrain and their phenotypes. Further investigations in various developmental stages are warranted to clearly understand the natural history of αTSaudiα) genotype combinations.


References
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  12. Proudfoot NJ (1986) Transcriptional interference and termination between duplicated alpha-globin gene constructs suggests a novel mechanism for gene regulation. Nature 322: 562-565.

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