Disclosing the hidden structure and underlying mutational mechanism of a novel type of duplication CNV responsible for hereditary multiple osteochondromas

Su, Peiqiang, Wang, Ye, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484, Zhu, Wenjuan, Huang, Dongsheng, Férec, Claude, Wang, Yiming and Chen, Jian-Min 2015. Disclosing the hidden structure and underlying mutational mechanism of a novel type of duplication CNV responsible for hereditary multiple osteochondromas. Human Mutation 36 (8) , pp. 758-763. 10.1002/humu.22815

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Abstract

The additional mutational complexity associated with copy number variation (CNV) can provide important clues as to the underlying mechanisms of CNV formation. Correct annotation of the additional mutational complexity is, however, a prerequisite for establishing the mutational mechanism. We illustrate this point through the characterization of a novel ∼230 kb EXT1 duplication CNV causing autosomal dominant hereditary multiple osteochondromas. Whole-genome sequencing initially identified the CNV as having a 22-bp insertion at the breakpoint junction and, unprecedentedly, multiple breakpoint-flanking micromutations on both sides of the duplication. Further investigation revealed that this genomic rearrangement had a duplication-inverted triplication–duplication structure, the inverted triplication being a 41-bp sequence synthesized from a nearby template. This permitted the identification of the sequence determinants of both the initiation (an inverted Alu repeat) and termination (a triplex-forming sequence) of break-induced replication and suggested a possible model for the repair of replication-associated double-strand breaks.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords:	Alu-mediated recombination;break-induced replication;hereditary multiple osteochondromas;whole-genome sequencing
Publisher:	Wiley-Blackwell
ISSN:	1059-7794
Date of Acceptance:	1 May 2015
Last Modified:	31 Oct 2022 10:13
URI:	https://orca.cardiff.ac.uk/id/eprint/84073

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