title: Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder.
abstract: Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease-associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene.
authors: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors: Julia
authors: J
authors: Vogt
authors: Tanja
authors: T
authors: Mussotter
authors: Kathrin
authors: K
authors: Bengesser
authors: Kathleen
authors: K
authors: Claes
authors: Josef
authors: J
authors: Högel
authors: Nadia
authors: N
authors: Chuzhanova
authors: Chuanhua
authors: C
authors: Fu
authors: Jenneke
authors: J
authors: van den Ende
authors: Victor-Felix
authors: VF
authors: Mautner
authors: David N
authors: DN
authors: Cooper
authors: Ludwine
authors: L
authors: Messiaen
authors: Hildegard
authors: H
authors: Kehrer-Sawatzki
mesh_terms: D001483:Base Sequence; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D053960:DNA Breaks; D056915:DNA Copy Number Variations; D016514:Genes, Neurofibromatosis 1; D059765:Homologous Recombination; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007859:Learning Disabilities / Q000235:genetics*; D008938:Mitosis / Q000235:genetics; D008969:Molecular Sequence Data; D009030:Mosaicism; D060885:Multiplex Polymerase Chain Reaction; D009363:Neoplasm Proteins; D017253:Neurofibromatoses / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D011544:Pseudogenes; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors
chemical_list: D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2