Int J Blood Res Disord ISSN: 2469-5696

• Keywords
• Table 1
• Table 2
• Table 3
• References

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International Journal of Blood Research and Disorders

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

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 (α^TSaudiα) [AATAAA?AATAAG; c.*94A>G] [2,3,4]. In this letter we presented the diverse genotype combinations of the (α^TSaudiα) 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 (α^TSaudiα) 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 (α^TSaudiα) haplotype, i.e., the (α^TSaudiα/α^TSaudiα) 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 (α^TSaudiα) 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].

The second genotype underlying Hb H disease in this population is compound heterozygosity of the (α^TSaudiα) haplotype in trans with the IVS I donor-site pentanucleotide deletion mutant in α2-globin gene on the other chromosome [(α^Hphα); c.95+2_95+6del TGAGG] [13]. This genotype combination [i.e.,(α^TSaudiα/α^Hphα)] 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.

Comparison of hematological parameters between the(α^TSaudiα/α^TSaudiα) genotype and the (α^TSaudiα/α^Hphα) 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 (α^TSaudi(α^TSaudi(α vs. (α^TSaudi(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 (α^TSaudi(α^TSaudi(α and n=25 for (α^TSaudi(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 (-α^3.7/α^TSaudiα) genotype that we found in 52 patients (Table 3). In addition, we found 12 patients with the (-α^4.2/α^TSaudi) 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 (α^TSaudiα/αα) genotype?. These simple heterozygotes are consistently presented with α-thalassemia trait phenotype (Table 3).

In summary, this report presents our findings in regard of the (α^TSaudiα) 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 α^TSaudiα) genotype combinations.

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