title: Disclosing the Hidden Structure and Underlying Mutational Mechanism of a Novel Type of Duplication CNV Responsible for Hereditary Multiple Osteochondromas.
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.
authors.affiliation: Department of Orthopedics, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Peiqiang
authors.initials: P
authors.lastname: Su
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine and Center for Genome Research, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Huang
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.|Etablissement Français du Sang (EFS)-Bretagne, Brest, France.|Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France.|Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine and Center for Genome Research, Sun Yat-Sen University, Guangzhou, China.|Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.|Etablissement Français du Sang (EFS)-Bretagne, Brest, France.|Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
mesh_terms: D020087:Alu Elements; D002681:China; D056915:DNA Copy Number Variations; D005097:Exostoses, Multiple Hereditary / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010375:Pedigree
keywords: Alu-mediated recombination; break-induced replication; hereditary multiple osteochondromas; whole-genome sequencing