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

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 ß+ 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 ß-thal mutations showed a variable phenotype ranging from ß-thal carrier to mild form of ß-thalassemia intermedia, revealing new aspects and allowing to better understand the clinical implications of this nucleotide substitution that can be classified as a silent ß-thalassemic defect. CONCLUSION: Data reported in this study indicate the need of investigating partner of ß-thalassemia carrier by complete sequencing analysis of ß-globin gene and of providing an appropriate genetic counseling for couples at risk undergoing prenatal diagnosis.