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

Summary 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.