TY  - JOUR
A1  - Bauters, Marijke
A1  - Van Esch, Hilde
A1  - Friez, Michael J.
A1  - Boespflug-Tanguy, Odile
A1  - Zenker, Martin
A1  - Vianna-Morgante, Angela M.
A1  - Rosenberg, Carla
A1  - Ignatius, Jaakko
A1  - Raynaud, Martine
A1  - Hollanders, Karen
A1  - Govaerts, Karen
A1  - Vandenreijt, Kris
A1  - Niel, Florence
A1  - Blanc, Pierre
A1  - Stevenson, Roger E.
A1  - Fryns, Jean-Pierre
A1  - Marynen, Peter
A1  - Schwartz, Charles E.
A1  - Froyen, Guy
T1  - Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair
Y1  - 2008/06/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 847 
EP  - 858 
DO  - 10.1101/gr.075903.107 
VL  - 18 
IS  - 6 
UR  - http://genome.cshlp.org/content/18/6/847.abstract 
N2  - 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. 
ER  -