title: Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation.
abstract: The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. 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.
authors.affiliation: Biologia Generale e Genetica Medica, Università di Pavia, Via Forlanini 14, 27100 Pavia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.forename: Vladimiro
authors.initials: V
authors.lastname: Calvari
authors.forename: Giuliana
authors.initials: G
authors.lastname: Gregato
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gimelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Camanini
authors.forename: Roberto
authors.initials: R
authors.lastname: Giorda
authors.forename: Angela
authors.initials: A
authors.lastname: Ragusa
authors.forename: Silvana
authors.initials: S
authors.lastname: Guerneri
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Marcus
authors.initials: M
authors.lastname: Stumm
authors.forename: Holger
authors.initials: H
authors.lastname: Tonnies
authors.forename: Mario
authors.initials: M
authors.lastname: Ventura
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: John
authors.initials: J
authors.lastname: Barber
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Mariano
authors.initials: M
authors.lastname: Rocchi
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D007446:Chromosome Inversion; D002894:Chromosomes, Human, Pair 4; D002898:Chromosomes, Human, Pair 8; D005260:Female; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D005810:Multigene Family; D018035:Receptors, Odorant / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic
chemical_list: D018035:Receptors, Odorant