Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching

摘要: Duplication at the Xq28 band including MECP2 gene is one of 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 potential mechanisms for duplication examined whether architectural features may play role their origin using custom designed 4-Mb tiling-path oligonucleotide array CGH assay. Each 30 patients analyzed showed unique varying size from 250 kb to 2.6 Mb. Interestingly, 77% these nonrecurrent duplications, distal breakpoints grouped within 215 interval, located 47 telomeric gene. The architecture this region contains both direct inverted low-copy repeat (LCR) sequences; same undergoes polymorphic structural variation general population. Array revealed complex eight patients; six contained an embedded triplicated segment, other two, stretches non-duplicated sequences occurred duplicated region. Breakpoint junction sequencing was achieved four inversion patient, demonstrating further complexity. propose that presence LCRs vicinity generate unstable DNA structure induce strand lesions, such as collapsed fork, facilitate Fork Stalling Template Switching event producing involving MECP2.