Molecular characterization of a β⁰-thalassemia resulting from a 1.4 kilobase deletion

We report the characterization of a β⁰-thalassemia in an American Black with unusually high HbA₂ and HbF levels. Genomic southern analysis indicated that the individual was heterozygous for a deletion that began within the second intervening sequence of the β-globin gene and extended ~1.4 kb in the 5' direction. A clone spanning the breakpoint on the abnormal chromosome was isolated and further mapped, and the deletion joint was sequenced. Comparison of the normal β-globin gene and its 5' flanking region with the deletion joint sequence indicated that the 5' breakpoint for this deletion was 484 base pairs (bp) 5' to the transcriptional start site for the β-globin gene and the 3' breakpoint was 908 bp into the β-globin gene; the deletion removed a total of 1,393 bp. Comparison of the normal 5' and 3' breakpoint sequences indicated that this deletion was the result of a 'clean' nonhomologous breakage and reunion event; ie, no spurious bases were added during the recombinational event. Analysis of the breakpoints of this deletion together with the breakpoints of two other small deletions involving the β-globin gene suggests that the breakpoints may occur at DNA polymerase α pause sites.