title: Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching.
abstract: 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 approximately 250 kb to approximately 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Trilochan
authors.initials: T
authors.lastname: Sahoo
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.forename: Chad
authors.initials: C
authors.lastname: Shaw
authors.forename: Sandra
authors.initials: S
authors.lastname: Peacock
authors.forename: Amber
authors.initials: A
authors.lastname: Pursley
authors.forename: Y Jane
authors.initials: YJ
authors.lastname: Tavyev
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Ramocki
authors.forename: Magdalena
authors.initials: M
authors.lastname: Nawara
authors.forename: Ewa
authors.initials: E
authors.lastname: Obersztyn
authors.forename: Angela M
authors.initials: AM
authors.lastname: Vianna-Morgante
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski