Co-heredity of silent CAP + 1570 T>C (HBB:c96T>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.