Unusual Rearrangement of the α-Globin Gene Cluster Containing Both the −α3.7 and αααanti-4.2 Crossover Junctions: Clinical Diagnostic Implications and Possible Mechanisms

Misalignment of the homologous regions of the α-globin gene cluster and unequal crossover during meiosis produce single α-globin gene deletions (−α) and reciprocal α-globin gene triplications (ααα). Further unequal crossover of such recombinant alleles with wild-type alleles may produce more complex derivative alleles, such as quadruplicated alleles (1)(2)(3). Complex crossover events producing “patchwork” genes have also been reported at the human α- and β-globin gene cluster (4)(5)(6). In this report, we describe the identification of a novel rearrangement of the α-globin gene cluster containing both the −α3.7 and αααanti-4.2 crossover junctions. This allele was identified in 2 unrelated individuals and a parent in the course of screening by Southern analysis of patients with β-thalassemia major and minor for α-globin gene deletions (Table 1⇓ ). For patient 1, a routine α-globin gene configuration Southern analysis was performed to screen for the presence of the −\-SEA α-thalassemia deletion, a common amelioration factor of severe β-thalassemia (7). In the case of patient 2, Southern analysis was performed to rule out the presence of the −\-SEA α-thalassemia deletion, because hemoglobin H inclusion bodies typically present in α-thalassemia are absent when there is concurrent β-thalassemia (8). Southern analysis was performed by hybridizing [32P]dATP-labeled α- or ζ-globin gene probes to Bam HI- or Bgl II-digested genomic DNA. With an α-globin probe, an αααanti-4.2 triplication contributes an 18.2-kb hybridizing Bam HI band and 16.8- and 7.4-kb Bgl II bands, whereas a −α3.7 deletion contributes a 10.3-kb Bam HI band and a 16.3-kb Bgl II band. With a ζ-globin probe, both the αααanti-4.2 and −α3.7 alleles contribute 5.9-kb and 10.8/11.3-kb Bam HI bands, whereas αααanti-4.2 contributes 11.3/12.6-kb and 16.8-kb Bgl II bands, and −α3.7 contributes 11.3/12.6-kb …