An Organismal CNV Mutator Phenotype Restricted to Early Human Development

Pengfei Liu, Bo Yuan, Claudia M.B. Carvalho, Arthur Wuster, Klaudia Walter, Ling Zhang, Tomasz Gambin, Zechen Chong, Ian M. Campbell, Zeynep Coban Akdemir, Violet Gelowani, Karin Writzl, Carlos A. Bacino, Sarah J. Lindsay, Marjorie Withers, Claudia Gonzaga-Jauregui, Joanna Wiszniewska, Jennifer Scull, Paweł Stankiewicz, Shalini N. JhangianiDonna M. Muzny, Feng Zhang, Ken Chen, Richard A. Gibbs, Bernd Rautenstrauss, Sau Wai Cheung, Janice Smith, Amy Breman, Chad A. Shaw, Ankita Patel, Matthew E. Hurles, James R. Lupski

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)830-842.e7
Issue number5
StatePublished - Feb 23 2017
Externally publishedYes


  • CNV
  • DNA replication
  • cancer
  • de novo
  • duplication
  • genomic instability
  • germline
  • mutator

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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