The discovery of fetal DNA (f-DNA) opens the possibility of early non-invasive procedure for detection of paternally inherited mutation of beta-thalassemia. Since 2002, some studies have examined the sensitivity and specificity of this method for detection of paternally inherited mutation of thalassemia in pregnant women at risk of having affected babies. We conducted a systematic review of published articles that evaluated using this method for early detection of paternally inherited mutation in maternal plasma. A sensitive search of multiple databases was done in which nine studies met our inclusion criteria. The sensitivity and specificity was 99 and 99 %, respectively. The current study found that detection of paternally inherited mutation of thalassemia using analysis of cell-free fetal DNA is highly accurate. This method could replace conventional and invasive methods.
α-Thalassemia (α-thal) is the most common monogenic disease that is caused by the absence or reduced expression of α-globin genes. The aim of this study was to investigate common α-globin mutations and their associated haplotypes in four northern provinces of Iran (Gilan, Mazandaran, Golestan, Khorasan). One thousand, one hundred and ninety-one persons were tested for α-thal mutations by gap-polymerase chain reaction (PCR), reverse dot-blot hybridization, restriction fragment length polymorphism (RFLP) analysis and sequencing. Of the nine different mutations found, the most frequent were -α (rightward deletion) (45.6%), polyadenylation site (α°α) (α2) (AATAAA>AATGAA; HBA2: c.*92 A>G) (15.27%), - - (Mediterranean deletion) (6.86%), -α (leftward deletion), (6.17%), αα [Hb Constant Spring (Hb CS) (HBA2: c.427 T>C)] (4.62%), -α (HBA2: c.95+2_95+6delTGAGG) (3.70%). All chromosomes bearing an α-globin point mutation [α°α, -αα, αα, α°α (AATAAA> AATAAG; HBA2: c.*94 A>G)] showed only one haplotype that was present in most normal chromosomes, while the -α deletion was associated with three distinct haplotypes. Our results indicate that α-thal mutations are heterogeneous and -α and α°α are the most prevalent mutations in this region. The presence of -α with three different haplotypes suggests an older history for this mutation. The high prevalence of α°α in Mazandaran Province, Iran compared to other parts of the country and the world, suggests a founder effect. Altogether, we here provide further data confirming the heterogeneity of the northern population of Iran. These data may contribute to the establishment of a national mutation database, more accurate genetic counseling and prenatal diagnosis (PND).
β-thalassemia is the most common single gene disorder worldwide and in Iran. In the present study we report for the first time a rare variant of hemoglobin HBB:c.82G>T; Codon 27 GCC→TCC (Ala→Ser), Hb Knossos, using sequencing and reverse dot blot hybridization, in members of a family from North Iran. The family has a 16 years-old compound heterozygous thalassemia intermedia male child presenting this variant together with HBB:c.315+1G>A (IVSII-I) mutation. The father, heterozygous for Hb Knossos, showed borderline hematological indices. To our knowledge, this is the first report of Hb Knossos in trans with the β(O) IVSII-I allele leading to thalassemia intermedia. Our data also highlight the necessity of deep molecular characterization of subjects presenting normal HbA2 level associated with abnormal or borderline red cell indices.
Hb Constant Spring (Hb CS, codon 142, TAA>CAA, α2) (HBA2:c.427T>C) and α2 IVS-I donor site (GAGGTGAGG>GAGG - - - - -) (HBA2:c.95+2_95+6delTGAGG) are nondeletional α-thalassemia (α-thal) mutations found all over the world. Identification of α-thal genotypes in at-risk couples for severe anemia or in highly heterogeneous populations requires rapid, accurate and cost-effective genotyping methods. In this study, a pair of primers were used to specifically amplify an 883 bp fragment from the α2-globin gene in order to simultaneously identify these two mutations by a PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method. We determined the genotypic frequencies of Hb CS and the α2 IVS-I donor site mutations after amplification and enzymatic digestion with Tru9I in 238 northern Iranian samples referred for α-thal testing. Hb CS and the α2 IVS-I donor site mutations accounted for 21 (8.8%) and 29 (12.2%) of the nondeletional cases. This genotyping assay has proven to be a rapid, reliable and useful diagnostic tool for simultaneous detection of these two anomalies for genetic counseling or further prenatal diagnosis.
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