title: Two classes of low-copy repeats comediate a new recurrent rearrangement consisting of duplication at 8p23.1 and triplication at 8p23.2.
abstract: We describe a new type of rearrangement consisting of the duplication of 8p23.1 and the triplication of 8p23.2 [dup trp(8p)] in two patients affected by mental retardation and minor facial dysmorphisms. Array-comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and genotyping of polymorphic loci allowed us to demonstrate that this rearrangement is mediated by the combined effects of two unrelated low-copy repeats (LCRs). The first set of LCRs consists of the two clusters of olfactory receptor genes (OR-REPs) lying at 8p23.1. The second type of LCRs consists of a 15-kb segmental duplication, lying in inverted orientation at 8p23.2 and enclosing a nonrepeated sequence of approximately 130 kb, named MYOM2-REP because of its proximity to the MYOM2 gene. The molecular characterization of a third case with a dicentric chromosome 8 demonstrated that the rearrangement had been generated by nonallelic homologous recombination between the two MYOM2-REPs. Based on our findings, we propose a model showing that a second recombination event at the level of the OR-REPs leads to the formation of the dup trp(8p) chromosome. This rearrangement can only arise during meiosis in heterozygous carriers of the polymorphic 8p23.1 inversion, whereas in subjects with noninverted chromosomes 8 or homozygous for the inversion only the dicentric chromosome can be formed. Our study demonstrates that nonallelic homologous recombination involving multiple LCRs can generate more complex rearrangements and cause a greater variety of genomic diseases.
authors.affiliation: E. Medea Scientific Institute, Bosisio Parini, Lecco, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giorda
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccone
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gimelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Pramparo
authors.forename: Silvana
authors.initials: S
authors.lastname: Beri
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Bonaglia
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Jesùs
authors.initials: J
authors.lastname: Argente
authors.forename: Mariano
authors.initials: M
authors.lastname: Rocchi
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002869:Chromosome Aberrations; D002898:Chromosomes, Human, Pair 8; D064211:Connectin; D004247:DNA; D005260:Female; D015321:Gene Rearrangement; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D009124:Muscle Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic
chemical_list: D064211:Connectin; C577287:MYOM2 protein, human; D009124:Muscle Proteins; D004247:DNA