Two classes of low-copy repeats comediate a new recurrent rearrangement consisting of duplication at 8p23.1 and triplication at 8p23.2

• Published in: Human mutation 2007-05, Vol.28 (5), p.459-468
• Main Authors: Giorda, Roberto, Ciccone, Roberto, Gimelli, Giorgio, Pramparo, Tiziano, Beri, Silvana, Bonaglia, Maria Clara, Giglio, Sabrina, Genuardi, Maurizio, Argente, Jesùs, Rocchi, Mariano, Zuffardi, Orsetta
• Format: Article
• Language: English
• Subjects: Adolescent; Base Sequence; chromosome 8; Chromosome Aberrations; chromosome duplication; chromosome triplication; Chromosomes, Human, Pair 8; Connectin; DNA; Female; Gene Rearrangement; Genetic Carrier Screening; Genotype; Humans; In Situ Hybridization, Fluorescence; Infant; low-copy repeats; Male; Muscle Proteins - genetics; nonallelic homologous recombination; Polymerase Chain Reaction; Recombination, Genetic; recurrent rearrangement
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.20465

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. Hum Mutat 28(5), 459–468, 2007. © 2007 Wiley‐Liss, Inc.