The basic genomic defect in Wolf-Hirschhorn syndrome (WHS), including isolated 4p deletions and various unbalanced de novo 4p;autosomal translocations and above all t(4p;8p), is heterogeneous. Olfactory receptor gene clusters (ORs) on 4p were demonstrated to mediate a group of WHS-associated t(4p;8p)dn translocations. The breakpoint of a 4-Mb isolated deletion was also recently reported to fall within the most distal OR. However, it is still unknown whether ORs mediate all 4p-autosomal translocations, or whether they are involved in the origin of isolated 4p deletions. Another unanswered question is whether a parental inversion polymorphism on 4p16 can act as predisposing factor in the origin of WHS-associated rearrangements. We investigated the involvement of the ORs in the origin of 73 WHS-associated rearrangements. No hotspots for rearrangements were detected. Breakpoints on 4p occurred within the proximal or the distal olfactory receptor gene cluster in 8 of 73 rearrangements (11%). These were five t(4p;8p) translocations, one t(4p;7p) translocation and two isolated terminal deletions. ORs were not involved in one additional t(4p;8p) translocation, in a total of nine different 4p;autosomal translocations and in the majority of isolated deletions. The presence of a parental inversion polymorphism on 4p was investigated in 30 families in which the 4p rearrangements, all de novo, were tested for parental origin (7 were maternal and 23 paternal). It was detected only in the mothers of 3 t(4p;8p) cases. We conclude that WHS-associated chromosome changes are not usually mediated by low copy repeats. The 4p16.3 inversion polymorphism is not a risk factor for their origin.