Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation

Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show
a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)–gene clusters are located
close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the
OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic
exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and
8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom
both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced
translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments
with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both
4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23
were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly
heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms
in the evolution and pathology of the human genome.