Co-heredity of silent CAP + 1570 T>C (HBB:c*96T>C) defect and severe β-thal mutation: a cause of mild β-thalassemia intermedia.

Summary Introduction During an intensive screening program aimed at identifying the healthy carriers of thalassemia and the couples at risk of bearing an affected fetus, a rare single nucleotide variation (SNV), CAP + 1570 T > C (HBB:c*96T > C), located 12 nucleotides upstream of the polyadenylation signal in 3'UTR of the beta globin gene was identified. It was previously reported as a β+ thalassemia mutation and later as a plain polymorphism. Methods Genotype identification of globin gene mutations was carried out using sequencing analysis, GAP-PCR, and MLPA methods. Results CAP + 1570 T > C (HBB:c*96T > C) was found in 39 heterozygotes, in one case in homozygous state and in thirteen cases of co-inheritance of this nucleotide substitution with other mutations in globin genes. Carriers of this mutation showed a ‘silent’ phenotype without appreciable microcytosis and hypochromia, so they cannot be differentiated from noncarrier individuals. Compound heterozygotes for this mutation and severe β-thal mutations showed a variable phenotype ranging from β-thal carrier to mild form of β-thalassemia intermedia, revealing new aspects and allowing to better understand the clinical implications of this nucleotide substitution that can be classified as a silent β-thalassemic defect. Conclusion Data reported in this study indicate the need of investigating partner of β-thalassemia carrier by complete sequencing analysis of β-globin gene and of providing an appropriate genetic counseling for couples at risk undergoing prenatal diagnosis.