Wolf–Hirschhorn syndrome-associated chromosome changes are not mediated by olfactory receptor gene clusters nor by inversion polymorphism on 4p16

Abstract

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.

Prenatal diagnosis of Wolf-Hirschhorn syndrome confirmed by comparative genomic hybridization array: report of two cases and review of the literature

“…Unbalanced translocations involving the short arms of chromosomes 4 and 8 appear with high frequency in several large series of WHS patients [40-43]. These rearrangements usually arise as a result of a) a homologous non-allelic recombination mediated by olfactory receptors (OR)-gene clusters in both 4p and 8p, or b) a parental inversion polymorphism on 4p16 [44,45]. Recent studies point to a multigenic profile of WHS that contributes to the complex phenotype though two critical regions (WHSCR1 and -2) have been implicated in the pathogenesis of the syndrome [8,46,47].…”

Epilepsy and chromosomal abnormalities

“…Its frequency is estimated as one per 50000 births with a female predilection of 2:1 [16-18]. The syndrome is characterized by typical cranio-facial anomalies consisting of microcephaly, ocular hypertelorism, epicanthic folds, coloboma of the iris, prominent glabella with a "Greek warrior elmet" appearance, cleft lip and/or palate, severe mental retardation and high prevalence of seizures (80-90%) that include alternate hemiconvulsion, febrile seizures, infantile spasms frequently drug resistant [19-21].…”

Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf‐Hirschhorn syndrome–associated seizures disorder

“…WHS is a contiguous gene syndrome characterized by great variability of the basic genomic defect. [2][3][4]12 Although the associated clinical phenotype varies greatly in individual patients, depending mainly on the size of the 4p deletion, there is a consensus in considering the core WHS phenotype as defined by the association of severe growth delay, ID, typical facial appearance featuring the well-known Greek warrior helmet profile, and seizures (or EEG anomalies). 2,3 All these signs were mapped within the terminal 1.9 Mb region on 4p16.3, where the critical region, WHSCR-2, was described.…”