The Spectrum of α-Thalassemia Mutations in Syrian Patients.

α-Thalassemia (α-thal) is a globally prevalent genetic disorder of hemoglobin (Hb) structure where the rate of α-globin chain synthesis is reduced or absent due to the presence of α-globin mutation(s). The aim of this study is to define the spectrum of α-globin gene mutations and evaluate their allele frequency in a group of α-thal carriers. A total of 55 individuals with possible α-thal patients were referred from the thalassemia centers in Syria. They have unexplained hypochromia and microcytosis. All patients were genetically tested for 21 common α-globin gene mutations using reverse hybridization kit. Seven different α-globin gene mutations and 13 different genotypes were detected in 55 patients. The two most frequently encountered mutations were -α3.7 deletion (47.1%) and --MED mutation (21.4%). The most commonly observed genotype was -α3.7/αα (40%), followed by --MED/αα genotype (21.8%). We determined the most common α thalassemia mutations in the Syrian patients. α-Thalassemia mutations with deletions were mostly observed in our study.

Genotype/Phenotype Correlation of ß-Thalassemia in Syrian Patients: A Cross-Sectional Study.

ß-Thalassemia (ß-thal) is an inherited blood disorder caused by reduced or absent synthesis of ß-globin chains leading to imbalance of globin chain synthesis. ß0-Thalassemia (ß0-thal), refers to the complete absence of ß-globin chain production on the affected allele. ß+-Thalassemia (ß+-thal) refers to alleles with some residual production of ß-globin chain. We studied the correlation of genotype/phenotype of ß-thal disease in Syrian patients. A cross-sectional study was carried out on 260 patients with ß-thal. Genotyping was determined by a DNA sequencing technique. Routine investigations were performed to assess the complete blood count (CBC), serum ferritin, Hb A2 and Hb F levels. We found that the ß0/ß0 genotype was the most common in our patients followed by ß+/ß+ and ß0/ß+. Patients with ß0/ß0 received transfusions at an earlier age and more frequently when compared to those with ß0/ß+ and ß+/ß+ genotypes. Moreover, patients with ß0/ß0 had higher levels of Hb F and lower levels of Hb A2 compared to those with ß0/ß+ and ß+/ß+ genotypes. All patients with ß-thal intermedia (ß-TI) carry the ß+/ß+ genotype, while all patients with ß0/ß0 and ß0/ß+ genotypes presented with transfusion-dependent ß-thal major (ß-TM).

Description of a rare ß-globin gene mutation, IVS-II-848 (C>A) (HBB: c.316-3C>A) in association with IVS-I-1 (G>A) (HBB: c.92 + 1G>A), observed in a Syrian family: a case report.

ß-Thalassemia (ß-thal) is a hereditary and heterogeneous group of disorders caused by mutations on the ß-globin gene that result in the reduced or non production of ß-globin chains. We report a rare ß-globin mutation, IVS-II-848 (C>A) (HBB: c.316-3C>A), which was found in a female Syrian patient. This mutation was associated with the IVS-I-1 (G>A) (HBB: c.92+1G>A) mutation, and the genotype is a compound heterozygote for IVS-I-1(G>A)/IVS-II-848(C>A). This combination was found for the first time in Syria.

Compliance with Deferoxamine Therapy and Thyroid Dysfunction of Patients with ß-Thalassemia Major in Syria.

Hypothyroidism is one of the common endocrine complications described in patients with ß-thalassemia major (ß-TM). Studies have reported its incidence and severity depending on the region, quality of management and treatment protocols. The reported thyroid dysfunction includes overt hypothyroidism, subclinical hypothyroidism and rarely, central hypothyroidism. The main aims of this study were to identify the incidence of hypothyroidism in 82 patients with ß-TM in Syria, and also to evaluate the effect of compliance with deferoxamine (DFO) therapy on the patients' thyroid function. Out of the 82 patients included in this study, 24 had subclinical hypothyroidism (29.27%) and one patient had overt hypothyroidism (1.22%). It was demonstrated by this study that noncompliance with DFO therapy increases the risk of thyroid dysfunction 6.38-times compared to compliance with DFO [risk ratio (RR) = 6.385; 95% confidence interval (95% CI) 2.40-16.95)]. These results emphasize the importance of compliance with chelation therapy to minimize the burden of thyropathy on patients' quality of life, and also augment the rationale for a routine follow-up and endocrine evaluation for early detection and management of these complications.

Haplotype Analysis of Three Common ß-Thalassemia Mutations in Syrian Patients.

ß-Globin haplotypes were used to investigate the origin of three common ß-globin mutations, IVS-I-110 (G>A); HBB: c.93-21G>A, IVS-I-1 (G>A); HBB: c.92 + 1G>A and codon 39 (C>T); HBB: c.118C > T in Syrian patients. Haplotype analysis was done for 49 unrelated patients with ß-thalassemia (ß-thal) and 20 unrelated healthy subjects by polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) for the ß-globin gene cluster of the following polymorphic restriction sites: HincII 5' to ε, HindIII 5' to Gγ, HindIII 5' to Aγ, HincII in ψß, HincII 3' to ψß, AvaII in ß, and HinfI 3' to ß. The IVS-I-110 mutation was associated with three haplotypes: I [+ - - - - + +] (79.4%), V [+ - - - - + -] (5.9%) and VII [+ - - - - - +] (14.7%), while, the two mutations IVS-I-1 and codon 39 were be linked to a single haplotype V (100.0%) and II [- + + - + + +] (100.0%), respectively. The normal chromosomes (ßA/ßA) were associated with four haplotypes, I (50.0%), II (7.5%), V (32.5%) and VII (10.0%). In the Syrian population, the IVS-I-110 mutation was associated with multi haplotypes, whereas the IVS-I-1 and codon 39 mutations have a single origin. More studies for the other mutations will be very useful for genetic epidemiological studies in Syria.

Prenatal molecular diagnosis of ß-thalassemia and sickle cell anemia in the Syrian population.

Our objective was to evaluate the prenatal diagnosis (PND) of ß-thalassemia (ß-thal) and sickle cell anemia in Syria. Mutations detected from blood of at-risk couples and 55 amniotic fluid samples collected at the second trimester of pregnancy (14-22 weeks' gestation) were characterized. Molecular screening and direct DNA sequencing of the HBB gene was carried out. DNA analyses showed 14 affected fetuses (25.45%), 32 (58.18%) carriers and eight (14.54%) normal fetuses. It appears that 20.0% of individuals carried the sickle cell anemia mutation and 80.0% carried the ß-thal mutation. Thirteen different known mutations were detected in the fetuses. The most common mutations were: IVS-II-1 (G > A), codon 39 (C > T)], IVS-I-110 (G > A), IVS-I-1 (G > A) and IVS-I-5 (G > C). The Hb S [ß6(A3)Glu → Val; HBB: c.20A > T] mutation was the only abnormal hemoglobin (Hb) that was found. The results point to a successful future for PND of ß-thal and sickle cell anemia in Syria, using a rapid and accurate molecular method. We hope that this method will be used as a common application approach to decrease the incidence of ß-thal major (ß-TM).

Geographical distribution of ß-globin gene mutations in Syria.

OBJECTIVES: ß-Thalassemia disease is caused by mutations in the ß-globin gene. This is considered as one of the common genetic disorders in Syria. The aim of this study was to identify the geographical distribution of the ß-thalassemia mutations in Syria. METHODS: ß-Globin gene mutations were characterized in 636 affected patients and 94 unrelated carriers using the amplification refractory mutations system-polymerase chain reaction technique and DNA sequencing. RESULTS: The study has revealed the presence of 38 ß-globin gene mutations responsible for ß-thalassemia in Syria. Important differences in regional distribution were observed. IVS-I.110 [G > A] (22.2%), IVS-I.1 [G > A] (17.8%), Cd 39 [C > T] (8.2%), IVS-II.1 [G > A] (7.6%), IVS-I.6 [T > C] (7.1%), Cd 8 [-AA] (6%), Cd 5 [-CT] (5.6%) and IVS-I.5 [G > C] (4.1%) were the eight predominant mutations found in our study. The coastal region had higher relative frequencies (37.9 and 22%) than other regions. A clear drift in the distribution of the third common Cd 39 [C > T] mutation in the northeast region (34.8%) to the northwest region (2.5%) was noted, while the IVS-I.5 [G > C] mutation has the highest prevalence in north regions. The IVS-I.6 [T > C] mutation had a distinct frequency in the middle region. Ten mutations -86 [C > G], -31 [A > G], -29 [A > G], 5'UTR; +22 [G > A], CAP + 1 [A > C], Codon 5/6 [-TG], IVS-I (-3) or codon 29 [C > T], IVS-I.2 [T > A], IVS-I.128 [T > G] and IVS-II.705 [T > G] were found in Syria for the first time. CONCLUSIONS: These data will significantly facilitate the population screening, genetic counseling and prenatal diagnosis in Syrian population.