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

IntroductionDuring 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 + thalassemia mutation and later as a plain polymorphism. MethodsGenotype identification of globin gene mutations was carried out using sequencing analysis, GAP-PCR, and MLPA methods. ResultsCAP + 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 -thal mutations showed a variable phenotype ranging from -thal carrier to mild form of -thalassemia intermedia, revealing new aspects and allowing to better understand the clinical implications of this nucleotide substitution that can be classified as a silent -thalassemic defect. ConclusionData reported in this study indicate the need of investigating partner of -thalassemia carrier by complete sequencing analysis of -globin gene and of providing an appropriate genetic counseling for couples at risk undergoing prenatal diagnosis.