Identification of recurrent type-2NF1microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder

Vogt, Julia, Mussotter, Tanja, Bengesser, Kathrin, Claes, Kathleen, Högel, Josef, Chuzhanova, Nadia, Fu, Chuanhua, van den Ende, Jenneke, Mautner, Victor-Felix, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484, Messiaen, Ludwine and Kehrer-Sawatzki, Hildegard 2012. Identification of recurrent type-2NF1microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder. Human Mutation 33 (11) , pp. 1599-1609. 10.1002/humu.22171

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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. Hum Mutat 33:1599–1609, 2012. © 2012 Wiley Periodicals, Inc.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > R Medicine (General)
Uncontrolled Keywords:	nonallelic homologous recombination; NF1 microdeletions; mosaicism; hotspot
Publisher:	Wiley-Blackwell
ISSN:	1059-7794
Last Modified:	21 Oct 2022 10:48
URI:	https://orca.cardiff.ac.uk/id/eprint/41416

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