Spectrum ofα-Thalassemia Mutations in Transfusion-Dependent β-Thalassemia Patients from the Eastern Province of Saudi Arabia

Abstract

Both α- and β-thalassemia (α- and β-thal) are highly prevalent in the population of the Al-Qatif and Al-Ahsa regions in the Eastern Province of Saudi Arabia. This study provides a more precise picture of the α-thal mutations prevalent in 104 transfusion-dependent β-thal patients in the Eastern Province. Detection of α-thal mutations was carried out using the α-globin StripAssay kit. A total of 12 α-thal mutations (21 genotypes) were identified in 33.7% of the chromosomes (46 patients). The heterozygous and homozygous -α(3.7) (α(+)) deletion mutations were the most prevalent in the β-thal patients (21.7%). We identified three α(0) deletions [- -(MED), - -(FIL) and -(α)20.5] that have not been previously reported for the population of Saudi Arabia. The seven point mutations identified in the β-thal patients were: codon 14 [TGG>TAG (α1)], codon 59 [GGC>GAC (α1)] (Hb Adana), polyadenylation signal site (polyA1) [AATAAA>AATAAG (α2)], codon 142 [TAA>TCA (α2)] (Hb Koya Dora), codon 59 [GGC>GAC (α2)] (Hb Adana), initiation codon [ATG>ACG (α2)] and the ααα(anti 3.7) gene triplication. The Hb Koya Dora mutation occurred at the highest frequency (15.38%). Comparison of the clinical phenotype of β-thal patients, with and without an α-thal mutation, showed that patients with β-thal alone had a significantly elevated level of alanine transaminase (ALT) (mean 72.5 IU/L) and aspartate transaminase (AST) (mean 71.8 IU/L) (p <0.005). In addition, the β-thal patients without an α-thal mutation had a higher percentage of osteoporosis (16.6%), fractures (12.5%), and splenectomies (58.3%). This confirms previous data that the co-inheritance of α-thal in β-thal patients results in the amelioration of the clinical phenotype of β-thal patients. Moreover, the high frequency of α- and β-thal in the Eastern Province of Saudi Arabia and their coinheritance, necessitates the inclusion of α-thal testing in the current pre marital testing program to highlight the risk to the offspring of affected individuals.

Co-inheritance of novel ATRX gene mutation and globin (α & β) gene mutations in transfusion dependent beta-thalassemia patients

“…Sickle cell disease, α-thalassemia and β-thalassemia are the most common monogenic disorders in the oasis of Qatif and Al-Ahsa in the Eastern Province of Saudi Arabia [5][6][7]17,18]. In our previous study of the prevalence of these disorders in the Eastern Province of Saudi Arabia, we confirmed the widespread coinheritance of α-thalassemia mutation in transfusion dependent β-thalassemia patients [6,7].…”

“…In our previous study of the prevalence of these disorders in the Eastern Province of Saudi Arabia, we confirmed the widespread coinheritance of α-thalassemia mutation in transfusion dependent β-thalassemia patients [6,7]. The characteristics of the transfusion dependent β-thalassemia patients indicated that some of these subjects have a family history of mental retardation, the cause of which is unknown.…”

“…The study was approved by the University of Dammam Institutional Review Board and written informed consent was obtained from all participating subjects. All mutations in the transfusion dependent β-thalassemia patients had previously been identified and these patients were requested to donate an additional blood sample for the purpose of this study [5][6][7]. Accordingly, blood samples (5 mL) from all participating subjects were collected in EDTA vacutainers and analyzed using the α-globin StripAssays (cat for α 4-160, Vienna Lab Diagnostics GmbH, Vienna, Austria) to identify the α-thalassemia mutations.…”

“…Some of these subjects have a family history of mental retardation, the cause of which is unknown. β-thalassemia is caused by reduced or absent synthesis of the β-globin chains coded by two β-globin genes, one on each of chromosome 11 and α-thalassemia is caused by decreased or absent synthesis of the α-globin chains coded by four α genes, two on each chromosome 16 [5][6][7]. Although some of the patients with transfusion dependent β-thalassemia have a family history of mental retardation, to our knowledge, a study of ATRX gene mutations in β-thalassemia has not been previously conducted on this population [8].…”

Modifying effect of XmnI, BCL11A, and HBS1L-MYB on clinical appearances

“…The phenotypic diversity of these conditions are related to the influencing genetic factors, such as the presence of mild/silent b-thal alleles, and co-inheritance with a-thalassemia (a-b-thalassemia). Milder clinical symptoms are allegedly caused by a better balance ratio between the a-chain and the non-a-chain [7]. In particular, increasing fetal hemoglobin (HbF) level in many studies was shown to affect the clinical outcome of patients with sickle cell disease (SCD), b-thal, or HbE/b-thal [8,9].…”