Beta-thalassemia: from genotype to phenotype

“…The clinical presentation is widely variable because the amount of unbound a-globin chains can be modified by both the capacity to produce a-globin chains (HBA genes variants) and the capacity to produce g-globin chains (HBG2 gene modulators) that can bind available a-globin chains to form effective fetal hemoglobin (HBF). 1,2 The severity of mutations in the HBB gene and defects of the HBA genes were the first determinants of the phenotype variability of b-thalassemia to be discovered. The third determinant to be identified was the XmnI polymorphism of the HBG2 promoter (HBG2:g.-158C>T) which is widely included in the diagnostic workup for thalassemia patients.…”

Section: Introductionmentioning

confidence: 99%

A genetic score for the prediction of beta-thalassemia severity

et al. 2014

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Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the amelioration of beta-thalassemia phenotype, to build a predictive score of severity using a representative cohort of 890 β-thalassemic patients. Using Cox proportional hazard analysis on a training set, we assessed the effect of these loci on the age at which patient started regular transfusions, built a Thalassemia Severity Score, and validated it on a testing set. Discriminatory power of the model was high (C-index=0.705; R(2)=0.343) and the validation conducted on the testing set confirmed its predictive accuracy with transfusion-free survival probability (P<0.001) and with transfusion dependency status (Area Under the Receiver Operating Characteristic Curve=0.774; P<0.001). Finally, an automatized on-line calculation of the score was made available at http://tss.unica.it. Besides the accurate assessment of genetic predictors effect, the present results could be helpful in the management of patients, both as a predictive score for screening and a standardized scale of severity to overcome the major-intermedia dichotomy and support clinical decisions

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“…Moreover, transfusion therapy is able to control the majority of underlying pathophysiologic mechanisms while also contributing to a great deal to secondary morbidity [8][9][10][11]. Today, for management purposes, the thalassemia patients are commonly categorized into transfusion dependent (TDT: those who are not capable to produce sufficient amount of Hb to survive without blood transfusion) or non-transfusion-dependent (NTDT) [12,13] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Laboratory diagnosis of thalassemia

Brancaleoni

Pierro

Motta

et al. 2016

Int J Lab Hematology

160

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Summary The thalassemias can be defined as α‐ or β‐thalassemias depending on the defective globin chain and on the underlying molecular defects. The recognition of carriers is possible by hematological tests. Both α‐ and β‐thalassemia carriers (heterozygotes) present with microcytic hypochromic parameters with or without mild anemia. Red cell indices and morphology followed by separation and measurement of Hb fractions are the basis for identification of carriers. In addition, iron status should be ascertained by ferritin or zinc protoporphyrin measurements and the iron/total iron‐binding capacity/saturation index. Mean corpuscular volume and mean corpuscular hemoglobin are markedly reduced (mean corpuscular volume: 60–70 fl; MCH: 19–23 pg) in β‐thalassemia carriers, whereas a slight to relevant reduction is usually observed in α‐carriers. HbA2 determination is the most decisive test for β‐carrier detection although it can be disturbed by the presence of δ‐thalassemia defects. In α‐thalassemia, HbA2 can be lower than normal and it assumes significant value when iron deficiency is excluded. Several algorithms have been introduced to discriminate from thalassemia carriers and subjects with iron‐deficient anemia; because the only discriminating parameter is the red cell counts, these formulas must be used consciously. Molecular analysis is not required to confirm the diagnosis of β‐carrier, but it is necessary to confirm the α‐thalassemia carrier status. The molecular diagnosis is essential to predict severe transfusion‐dependent and intermediate‐to‐mild non‐transfusion‐dependent cases. DNA analysis on chorionic villi is the approach for prenatal diagnosis and the methods are the same used for mutations detection, according to the laboratory facilities and expertise.

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Beta-thalassemia: from genotype to phenotype

Cited by 104 publications

References 18 publications

Novel Βeta (β)-Thalassemia Mutation in Turkish Children

Novel Βeta (β)-Thalassemia Mutation in Turkish Children

A genetic score for the prediction of beta-thalassemia severity

Laboratory diagnosis of thalassemia

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