Genetic modifiers in hemoglobinopathies.
ABSTRACT Hereditary anemias show considerable variation in their clinical presentation. In some cases, the causes of these variations are easily apparent. In thalassemia (or in HbE/thalassemia), genetic variation is primarily caused by the severity of the thalassemia mutation. However, not uncommonly, there is variation unexplained by the globin gene mutations themselves, which may be caused by genetic modifiers. In sickle cell disease, the primary mutation is the same in all patients. Therefore, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving beta globin, the most clearcut influence on phenotype results from elevated fetal hemoglobin levels. In addition, alpha globin gene number can influence disease phenotype. In thalassemia major or intermedia, reduction in the number of alpha globin genes can ameliorate the disease phenotype; conversely, excess alpha globin genes can convert beta thalassemia trait to a clinical picture of thalassemia intermedia. In sickle cell disease, the number of alpha globin genes has both ameliorating and exacerbating effects, depending on which disease manifestation is being examined. Unlinked genetic factors have substantial effects on the phenotype of hereditary anemias, both on the anemia and other disease manifestations. Recently, studies using genome-wide techniques, particularly studying QTLs causing elevated HbF, or affecting HbE/thalassemia, have revealed other genetic elements whose mechanisms are under study. The elucidation of genetic modifiers will hopefully lead to more rational and effective management of these diseases.
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ABSTRACT: The frequency of hemoglobinopathies is still high in Adana, the biggest city of the Cukurova Region that is located in the southern part of Turkey. Our aim was to identify the concomitant mutations in α- and β-globin genes which lead to complex hemoglobinopathies and to establish an appropriate plan of action for each subject, particularly when prenatal diagnosis is necessary. We studied the association between the β-globin gene and α-thalassemia genotypes. The reverse hybridization technique was employed to perform molecular analysis, and the results were confirmed by amplification refractory mutation system (ARMS) or restriction fragment length polymorphism (RFLP) technique. We evaluated 36 adult subjects (28 female and 8 male; age range: 18-52 years) with concomitant mutations in their α- and β-globin genes. The -α(3.7)/αα deletion was the commonest defect in the α-chain as expected, followed by α(3.7)/-α(3.7) deletion. Twenty-five of 36 cases were sickle cell trait with coexisting α-thalassemia, while seven Hb S/S patients had concurrent mutations in their α-genes. The coexistence of α(PolyA-2)α/αα with Hb A/D and with Hb S/D, which is very uncommon, was also detected. There was a subject with compound heterozygosity for β-globin chain (-α(3.7)/αα with IVSI.110/S), and also a case who had -α(3.7)/αα deletion with IVSI.110/A. Although limited, our data suggest that it would be valuable to study coexisting α-globin mutations in subjects with sickle cell disease or β-thalassemia trait during the screening programs for premarital couples, especially in populations with a high frequency of hemoglobinopathies.Archives of medical science : AMS. 09/2012; 8(4):644-9.
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ABSTRACT: To study the ß-gene mutations spectrum, the genotype/phenotype correlation, the modulatory effect of co-inherited factors such as α-gene mutations and of Xmn1 polymorphism in a large cohort of Malaysian patients. A total of 264 cases clinically diagnosed as Thalassemia major (TM) (111), Thalassemia intermedia (21), HbE-β Thalassemia (131), and 1 HbE homozygous were studied. The detection of α and ß gene mutations and characterization of Xmn1 polymorphism were performed by multiplex PCR, amplification refractory mutation system (ARMS), DNA sequencing, and restriction fragment length polymorphism (RFLP)-PCR. A total of 19 ß Thalassemia mutations were characterized. CD26 and CD41/42 were the most common found in the Malay and Chinese population, respectively. The sensitivity of the clinical diagnosis for β TM, thalassemia intermedia, and HbE/β thalassemia was 94.0%, 15.2%, and 89.2%, respectively. Patients with Xmn1 heterozygosity [+/-] required less frequent transfusion compared with those without the polymorphism. Co-inheritance of α-thalassemia alleviates the severity of HbE-β thalassemia in our cohort. Molecular analysis should be used for a better diagnosis and management of β thalassemia.International journal of laboratory hematology 02/2012; 34(4):377-82. · 1.30 Impact Factor
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ABSTRACT: López-Escribano H, Parera MM, Guix P, Serra JM, Gutierrez A, Balsells D, Oliva-Berini E, Castro JA, Ramon MM, Picornell A. Balearic archipelago: three islands, three beta-thalassemia population patterns. The mutation spectrum of 175 β-thalassemia (β-thal) carriers, identified in pilot carrier screening on 22,713 individuals from Balearic Islands (Spain), is reported. The β(0) CD39 (C>T) mutation is the most frequent (61.1%), followed by β(+) IVS-I-110 (G>A) (12.0%), β(+) IVS-I-6 (T>C) and β(0) IVS-1-1 (G>A) (3.4% both) and eight other rare mutations (2.9-0.6%); with a distinct prevalence and distribution between islands. Minorca shows the highest prevalence in Iberian populations, with a single mutation, CD39 (C>T), present in most β-thal carriers. Ibiza is the only Western Mediterranean population where the most frequent β-thal mutation is IVS-I-110 (G>A). These results can be explained by a combination of historical-demographic characteristics together with evolutionary forces such as founder effect, genetic drift and probably selection by malaria. Knowledge of the mutational spectrum in the Balearic Islands will enable to optimize mutation detection strategy for genetic diagnosis of β-thal in these islands.Clinical Genetics 02/2012; · 4.25 Impact Factor