Thalassaemia-like carriers not linked to the β-globin gene cluster

Abstract

This study describes the largest series reported to date, of individuals belonging to unrelated families carrying a β-thalassaemia-like phenotype in whom the β-globin gene was found to be structurally intact by sequence analysis. This genetic determinant appears haematologically heterogeneous, displaying either a silent β-thalassaemia-like phenotype or a typical β-thalassaemia carrier-like phenotype in different families. Compound heterozygosity for both β-thalassaemia-like determinant and typical β-thalassaemia allele resulted either in thalassaemia intermedia or thalassaemia major. By linkage analysis both the silent and the typical β-like determinants were found not to be linked to the β-globin cluster. Sequence analysis of the hypersensitive site cores of locus control region and of the genes coding for the transcription factors erythroid Kruppel-like factor and nuclear factor (erythroid-derived 2) were normal. β-globin mRNA levels determined by real-time polymerase chain reaction were reduced in both types of β-like carriers. These results indicate the existence of causative genetic determinants not yet molecularly defined, but most likely, resulting from either the reduction or loss of function of a gene coding for unknown transcriptional regulator(s) of the β-globin gene. The knowledge of these rare β-thalassaemia-like determinants have implications for clinical and, especially, prenatal diagnosis of β-thalassaemia. © 2006 Blackwell Publishing Ltd.