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Nat Genet. 2016 Oct;48(10):1107-11. doi: 10.1038/ng.3638. Epub 2016 Aug 17.

Patterns of genic intolerance of rare copy number variation in 59,898 human exomes.

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Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.


Copy number variation (CNV) affecting protein-coding genes contributes substantially to human diversity and disease. Here we characterized the rates and properties of rare genic CNVs (<0.5% frequency) in exome sequencing data from nearly 60,000 individuals in the Exome Aggregation Consortium (ExAC) database. On average, individuals possessed 0.81 deleted and 1.75 duplicated genes, and most (70%) carried at least one rare genic CNV. For every gene, we empirically estimated an index of relative intolerance to CNVs that demonstrated moderate correlation with measures of genic constraint based on single-nucleotide variation (SNV) and was independently correlated with measures of evolutionary conservation. For individuals with schizophrenia, genes affected by CNVs were more intolerant than in controls. The ExAC CNV data constitute a critical component of an integrated database spanning the spectrum of human genetic variation, aiding in the interpretation of personal genomes as well as population-based disease studies. These data are freely available for download and visualization online.

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