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Letter

Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair

¹ Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium; ² Human Genome Laboratory, Department of Human Genetics, K.U.Leuven, B-3000 Leuven, Belgium; ³ Department of Human Genetics, University Hospital Gasthuisberg, B-3000 Leuven, Belgium; ⁴ JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA; ⁵ Centre Hospitalier Universitaire, Clermont-FD, Génétique Humaine, F-63003 Clermont-Ferrand, France; ⁶ Institute of Human Genetics, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany; ⁷ Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, SP-05508-900 São Paulo, Brazil; ⁸ Department of Clinical Genetics, Oulu University Hospital and Oulu University, FIN-90221 Oulu, Finland; ⁹ Centre Hospitalier Universitaire de Tours, Service de Génétique, F-37044 Tours, France

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.

¹¹ Corresponding author.

E-mail guy.froyen{at}med.kuleuven.be; fax 32-16-347166.

[Supplemental material is available online at www.genome.org.]

Article is online at http://www.genome.org/cgi/doi/10.1101/gr.075903.107

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