Human Molecular Genetics Advance Access originally published online on March 26, 2009
Human Molecular Genetics 2009 18(12):2188-2203; doi:10.1093/hmg/ddp151
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Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching
1 Department of Molecular and Human Genetics 2 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA 3 Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, 05508-900 São Paulo, Brazil 4 Department of Medical Genetics, Institute of Mother and Child, Warsaw 01-211, Poland 5 Texas Children’s Hospital, Houston, TX 77030, USA
* To whom correspondence should be addressed at: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, TX 77030, USA. Tel: +1 7137983723; Fax: +1 7137985073; Email: jlupski{at}bcm.tmc.edu
Received November 10, 2008; Accepted March 24, 2009
Duplication at the Xq28 band including the MECP2 gene is one of the most common genomic rearrangements identified in neurodevelopmentally delayed males. Such duplications are non-recurrent and can be generated by a non-homologous end joining (NHEJ) mechanism. We investigated the potential mechanisms for MECP2 duplication and examined whether genomic architectural features may play a role in their origin using a custom designed 4-Mb tiling-path oligonucleotide array CGH assay. Each of the 30 patients analyzed showed a unique duplication varying in size from 
250 kb to 2.6 Mb. Interestingly, in 77% of these non-recurrent duplications, the distal breakpoints grouped within a 215 kb genomic interval, located 47 kb telomeric to the MECP2 gene. The genomic architecture of this region contains both direct and inverted low-copy repeat (LCR) sequences; this same region undergoes polymorphic structural variation in the general population. Array CGH revealed complex rearrangements in eight patients; in six patients the duplication contained an embedded triplicated segment, and in the other two, stretches of non-duplicated sequences occurred within the duplicated region. Breakpoint junction sequencing was achieved in four duplications and identified an inversion in one patient, demonstrating further complexity. We propose that the presence of LCRs in the vicinity of the MECP2 gene may generate an unstable DNA structure that can induce DNA strand lesions, such as a collapsed fork, and facilitate a Fork Stalling and Template Switching event producing the complex rearrangements involving MECP2.
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