The C–T substitution in the distal CACCC box of the β‐globin gene promoter is a common cause of silent β thalassaemia in the Italian population

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Abstract
This paper describes four families of Italian descent in each of which the propositus had the clinical phenotype of thalassaemia intermedia, resulting from the compound heterozygous state for high HbA2β thalassaemia and type I silent β thalassaemia. Direct sequencing on amplified DNA and/or oligonucleotide analysis detected, in all families but one, the compound heterozygous state for codon 39 nonsense mutation and the C-T substitution at position – 101 in the distal CACCC box of the β-globin gene promoter (βth–101). Members of these families who are heterozygous for high HbA2β thalassaemia showed the codon 39 nonsense mutation, while those with the clinical phenotype of silent β thalassaemia had the βth–101 mutation. In the remaining family, the propositus and one of his siblings had the compound heterozygous state for a molecularly undefined high HbA2β thalassaemia and the βth–101 mutation in combination with the triple α globin gene arrangement. These patients showed a more severe thalassaemia intermedia like clinical phenotype as compared to those with the same β-globin genotype and a normal α-globin gene arrangement. In the families investigated the βth–101 was always associated with haplotype I. A group of patients with thalassaemia intermedia from Southern Italy, either homozygous or heterozygous for haplotype I and in whom previous studies had failed to define the mutation in one of the β thalassaemia globin genes, were screened by oligonucleotide analysis for the presence of the βth–101. Three out of nine were positive. These results indicate that the βth–101 mutation is a common cause of the type I silent β thalassaemia phenotype in the Southern Italian population.