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

α-Thalassemia X-linked mental retardation syndrome is a rare inherited intellectual disability disorder due to mutations in the ATRX gene. In our previous study of the prevalence of ß-thalassemia mutations in the Eastern Province of Saudi Arabia, we confirmed the widespread coinheritance of α-thalassemia mutation. Some of these subjects have a family history of mental retardation, the cause of which is unknown. Therefore, we investigated the presence or absence of mutations in the ATRX gene in these patients. Three exons of the ATRX gene and their flanking regions were directly sequenced. Only four female transfusion dependent ß-thalassemia patients were found to be carriers of a novel mutation in the ATRX gene. Two of the ATRX gene mutations, c.623delA and c.848T>C were present in patients homozygous for IVS I-5(G→C) and homozygous for Cd39(C → T) ß-thalassemia mutation, respectively. While the other two that were located in the intronic region (flanking regions), were present in patients homozygous for Cd39(C → T) ß-thalassemia mutation. The two subjects with the mutations in the coding region had family members with mental retardation, which suggests that the novel frame shift mutation and the missense mutation at coding region of ATRX gene are involved in ATRX syndrome.

The ­α3.7 deletion in α­globin genes increases the concentration of fetal hemoglobin and hemoglobin A2 in a Saudi Arabian population.

The regions of Al­Qatif and Al­Ahssa in the Eastern Province of Saudi Arabia are known for their high prevalence of hemoglobinopathies, including ß­thalassemia and sickle cell anemia. Previously, the α­gene deletion has been demonstrated as highly prevalent among populations residing in these two regions. The present study was conducted in order to investigate the implications of the α­globin gene deletion on fetal hemoglobin (HbF) and hemoglobin α2 (HbA2) concentrations in patients with transfusion­dependent ß­thalassemia. A total of 166 Saudi patients with transfusion­dependent ß­thalassemia and 337 healthy Saudi patients were included in the study. The ­α3.7, ­α4.2, -­FIL, -­SEA, -­MED and -­(20.5) gene deletions were identified using multiplex α­globin deletion polymerase chain reaction. The present study revealed that the ­α3.7 gene deletion is the most prevalent (43.5%) in the Saudi populations that were analyzed and is characterized by the deletion of 3,804 base pairs. Numerous genotypes, namely ­3.7α2/α1α2, ­3.7α2/α1α12, ­3.7α2/­3.7α2, ­3.7α2HphI/α1α2HphI, ­3.7α2/α1­4.2, ­3.7α2/α1polyA­1α2, ­3.7α12/α1α12, ­­FIL/­3.7α2 and ­3.7α2/­3.7α2Hb Villiers le Bel were also identified in the investigated population. Furthermore, a gradual increase in the concentration of HbF and HbA2 in patients with ß­thalassemia and the number of α­gene deletions was demonstrated; whereas in healthy patients the level of HbA2 was demonstrated to decrease as the number of α­gene deletions increased. Therefore, it can be concluded that the high HbF concentration in the present study is predominantly associated with other mutations associated with ß­thalassemia rather than α­globin deletions. Furthermore, the results of the present study also revealed novel α­gene deletion genotypes prevalent in the population studied, namely α1α2/α1α2HphI, α1α2HphI/α1α2HphI, α1α2/α1α2Hb Handsworth, ­3.7α2HphI/α1α2HphI, ­3.7α2/­3.7α2Hb Villiers le Bel and ­-MED/α1α2HphI.