@article {348,
	title = {An Organismal CNV Mutator Phenotype Restricted to Early Human Development.},
	journal = {Cell},
	volume = {168},
	year = {2017},
	month = {2017 02 23},
	pages = {830-842.e7},
	abstract = {<p>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.</p>},
	keywords = {Chromosome Aberrations, Chromosome Breakpoints, Chromosome Duplication, DNA Copy Number Variations, DNA Replication, Embryonic Development, Female, Gametogenesis, Genetic Diseases, Inborn, Genomic Instability, Humans, Male, Mutation},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2017.01.037},
	author = {Liu, Pengfei and Yuan, Bo and Carvalho, Claudia M B and Wuster, Arthur and Walter, Klaudia and Zhang, Ling and Gambin, Tomasz and Chong, Zechen and Campbell, Ian M and Coban Akdemir, Zeynep and Gelowani, Violet and Writzl, Karin and Bacino, Carlos A and Lindsay, Sarah J and Withers, Marjorie and Gonzaga-Jauregui, Claudia and Wiszniewska, Joanna and Scull, Jennifer and Stankiewicz, Pawe{\l} and Jhangiani, Shalini N and Muzny, Donna M and Zhang, Feng and Chen, Ken and Gibbs, Richard A and Rautenstrauss, Bernd and Cheung, Sau Wai and Smith, Janice and Breman, Amy and Shaw, Chad A and Patel, Ankita and Hurles, Matthew E and Lupski, James R}
}
@article {30,
	title = {Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome.},
	journal = {Am J Hum Genet},
	volume = {99},
	year = {2016},
	month = {2016 Aug 04},
	pages = {318-36},
	abstract = {<p>Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5\%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture.</p>},
	keywords = {Adolescent, Adult, Alleles, Animals, Bardet-Biedl Syndrome, Child, Child, Preschool, Chromosome Breakpoints, Cytoskeletal Proteins, DNA Copy Number Variations, Exons, Female, Gastrulation, Genes, Recessive, Humans, Infant, Male, Mutation, Pedigree, Young Adult, Zebrafish, Zebrafish Proteins},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2015.04.023},
	author = {Lindstrand, Anna and Frangakis, Stephan and Carvalho, Claudia M B and Richardson, Ellen B and McFadden, Kelsey A and Willer, Jason R and Pehlivan, Davut and Liu, Pengfei and Pediaditakis, Igor L and Sabo, Aniko and Lewis, Richard Alan and Banin, Eyal and Lupski, James R and Davis, Erica E and Katsanis, Nicholas}
}
