@article{ef59e1bfca0048ccb6a602f53f49e0c4,
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.",
keywords = "CNV, DNA replication, cancer, de novo, duplication, genomic instability, germline, mutator",
author = "Pengfei Liu and Bo Yuan and Carvalho, {Claudia M.B.} and Arthur Wuster and Klaudia Walter and Ling Zhang and Tomasz Gambin and Zechen Chong and Campbell, {Ian M.} and {Coban Akdemir}, Zeynep and Violet Gelowani and Karin Writzl and Bacino, {Carlos A.} and Lindsay, {Sarah J.} and Marjorie Withers and Claudia Gonzaga-Jauregui and Joanna Wiszniewska and Jennifer Scull and Pawe{\l} Stankiewicz and Jhangiani, {Shalini N.} and Muzny, {Donna M.} and Feng Zhang and Ken Chen and Gibbs, {Richard A.} and Bernd Rautenstrauss and Cheung, {Sau Wai} and Janice Smith and Amy Breman and Shaw, {Chad A.} and Ankita Patel and Hurles, {Matthew E.} and Lupski, {James R.}",
note = "Funding Information: We thank all the family members and collaborators who participated in this study. This work was supported in part by grants from the US National Institute of Neurological Disorders and Stroke (https://www.ninds.nih.gov/, R01NS058529), the National Human Genome Research Institute (NHGRI https://www.genome.gov/, U54HG003273), a joint NHGRI (https://www.genome.gov/)/National Heart Blood and Lung Institute (https://www.nhlbi.nih.gov/) grant (U54HG006542) to the Baylor Hopkins Center for Mendelian Genomics, and the BCM Intellectual and Developmental Disabilities Research Center, IDDRC grant number 5P30HD024064-23, from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The work was also partially supported by the Wellcome Trust (WT098051). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, the Wellcome Trust, or the National Institutes of Health. Baylor College of Medicine (BCM) and Miraca Holdings have formed a joint venture with shared ownership and governance of the Baylor Genetics (BG), which performs clinical microarray analysis and clinical exome sequencing. P.L., C.A.B., J. Scull, P.S., S.W.C., J. Smith, A.B., C.S., A.P., and J.R.L. are employees of BCM and derive support through a professional services agreement with the BG. J.R.L. serves on the Scientific Advisory Board of the BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. R.A.G. reports consulting fees from GE-Clarient. A.W. is an employee of Genentech. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = feb,
day = "23",
doi = "10.1016/j.cell.2017.01.037",
language = "English (US)",
volume = "168",
pages = "830--842.e7",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}