Heterozygosity for the Novel HBA2: c.*91_*92delTA Polyadenylation Site Variant on the α2-Globin Gene Expanding the Genetic Spectrum of α-Thalassemia in Iran.

There are four copy numbers of α-globin genes (16p13.3) in the human genome and the number of defective α-globin genes dictates the severity of α-thalassemia (α-thal). Mutations that occur in the 3' untranslated region (3'UTR), and especially at the polyadenylation (polyA) sites, affect the translation, stability and export of mRNA. A patient with hypochromic microcytic anemia was referred to the Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran by the health network. Molecular analysis of genomic DNA for the evaluation of mutations on the α- and ß-globin genes was performed. Direct sequencing of the hemoglobin (Hb) subunit α2 (HBA2) gene revealed a two nucleotide deletion between +816 and +817 in the 3'UTR, located at the polyA site, which seems to be a novel pathogenic variant. This novel variant expands the genetic spectrum of α-thal in the 3'UTR of the HBA2 gene.

Frequency of α-Globin Gene Triplications and Coinheritance with ß-Globin Gene Mutations in the Iranian Population.

Numerical variation in α-globin genes is very important due to their roles as an effective factor for phenotype presentation. An unequal crossover from misalignment of a homologous sequence of an α-globin gene during meiosis can produce a numerical alteration. A single α-globin gene deletion is the most frequent mutation in α-thalassemia (α-thal) worldwide, while the additional α-globin chain is relatively common. The excess α-globin gene plays a critical role in pathophysiology of thalassemia, especially when in coinherited with ß-thalassemia (ß-thal). α-Globin triplication leads to an imbalanced ratio between α- and ß-globin chains, thus, it can exacerbate the clinical and hematological features of ß-thal. Different studies have been performed in various countries to determine the frequency of α-globin triplication and its genotype-phenotype correlation with ß-thal. In this study, we focused on the frequency of α-globin gene triplication and its characterization, either solely or in coexistence with ß-globin gene mutations in Iranian populations. We have investigated the α-globin gene rearrangements in 4010 individuals from different provinces of Iran with normal to abnormal hematological parameters. In total, the frequency of the αααanti 3.7 triplication was 1.7% and phenotype aggravation was observed in α-globin triplication patients who were carriers of ß-thal. Therefore, identification of genotype-phenotype correlation of α-globin triplication with ß-thal can be very useful for predicting the severity of clinical manifestations during genetic counseling.

Identification of Mutations Causing Aberrant Termination and Deficient Splice Donor Site on the HBA1 Gene.

α-Thalassemia (α-thal) is a common genetic disorder in Iran and many parts of the world. Genetic defects on the α-globin gene cluster can result in α-thal that may develop a clinical phenotype varying from almost asymptomatic to a lethal hemolytic anemia. In the present study, four Iranian individuals with hypochromic microcytic anemia, who revealed none of the known mutations responsible for α-thal, were subjected for further investigations. The thalassemic phenotype of these patients resulted from abnormal RNA splicing sites owing to a missense at the splice donor site, a truncated protein or hemoglobin (Hb) variants as a result of two different substitutions on the α1-globin gene. The clinical presentation of mild anemia in these individuals showed the contribution of these novel mutations in α-thal in spite of the dominantly expressed α2-globin gene. This study describes hematological manifestations of subjects carrying some novel mutations comparable to the reported phenotype of α(+)-thal trait.