title: Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair.
abstract: Recurrent submicroscopic genomic copy number changes are the result of nonallelic homologous recombination (NAHR). Nonrecurrent aberrations, however, can result from different nonexclusive recombination-repair mechanisms. We previously described small microduplications at Xq28 containing MECP2 in four male patients with a severe neurological phenotype. Here, we report on the fine-mapping and breakpoint analysis of 16 unique microduplications. The size of the overlapping copy number changes varies between 0.3 and 2.3 Mb, and FISH analysis on three patients demonstrated a tandem orientation. Although eight of the 32 breakpoint regions coincide with low-copy repeats, none of the duplications are the result of NAHR. Bioinformatics analysis of the breakpoint regions demonstrated a 2.5-fold higher frequency of Alu interspersed repeats as compared with control regions, as well as a very high GC content (53%). Unexpectedly, we obtained the junction in only one patient by long-range PCR, which revealed nonhomologous end joining as the mechanism. Breakpoint analysis in two other patients by inverse PCR and subsequent array comparative genomic hybridization analysis demonstrated the presence of a second duplicated region more telomeric at Xq28, of which one copy was inserted in between the duplicated MECP2 regions. These data suggest a two-step mechanism in which part of Xq28 is first inserted near the MECP2 locus, followed by breakage-induced replication with strand invasion of the normal sister chromatid. Our results indicate that the mechanism by which copy number changes occur in regions with a complex genomic architecture can yield complex rearrangements.
authors.affiliation: Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium.
authors.forename: Marijke
authors.initials: M
authors.lastname: Bauters
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Friez
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Angela M
authors.initials: AM
authors.lastname: Vianna-Morgante
authors.forename: Carla
authors.initials: C
authors.lastname: Rosenberg
authors.forename: Jaakko
authors.initials: J
authors.lastname: Ignatius
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.forename: Karen
authors.initials: K
authors.lastname: Hollanders
authors.forename: Karen
authors.initials: K
authors.lastname: Govaerts
authors.forename: Kris
authors.initials: K
authors.lastname: Vandenreijt
authors.forename: Florence
authors.initials: F
authors.lastname: Niel
authors.forename: Pierre
authors.initials: P
authors.lastname: Blanc
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X; D019295:Computational Biology; D004260:DNA Repair; D004261:DNA Replication; D020440:Gene Duplication; D015894:Genome, Human; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2