title: An Organismal CNV Mutator Phenotype Restricted to Early Human Development.
abstract: De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA. Electronic address: pengfei.liu@bcm.edu.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Claudia M B
authors.initials: CMB
authors.lastname: Carvalho
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Wuster
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Walter
authors.affiliation: Collaborative Innovation Center of Genetics and Development, Institute of Reproduction and Development, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zechen
authors.initials: Z
authors.lastname: Chong
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Coban Akdemir
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Violet
authors.initials: V
authors.lastname: Gelowani
authors.affiliation: Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Karin
authors.initials: K
authors.lastname: Writzl
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lindsay
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Withers
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wiszniewska
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Scull
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Collaborative Innovation Center of Genetics and Development, Institute of Reproduction and Development, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Medical Genetics Center, Bayerstrasse 3-5, 80335 Munich, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Rautenstrauss
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Smith
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Breman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D002869:Chromosome Aberrations; D056905:Chromosome Breakpoints; D058674:Chromosome Duplication; D056915:DNA Copy Number Variations; D004261:DNA Replication; D047108:Embryonic Development; D005260:Female; D005718:Gametogenesis; D030342:Genetic Diseases, Inborn / Q000196:embryology* / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D008297:Male; D009154:Mutation
keywords: CNV; DNA replication; cancer; de novo; duplication; genomic instability; germline; mutator