PT  - JOURNAL ARTICLE
AU  - Evan K. Maxwell
AU  - Jonathan S. Packer
AU  - Colm O’Dushlaine
AU  - Shane E. McCarthy
AU  - Abby Hare-Harris
AU  - Jeffrey Staples
AU  - Claudia Gonzaga-Jauregui
AU  - Samantha N. Fetterolf
AU  - W. Andrew Faucett
AU  - Joseph B. Leader
AU  - Andres Moreno-De-Luca
AU  - Giusy Della Gatta
AU  - Margaret Scollan
AU  - Trikaldarshi Persaud
AU  - John Penn
AU  - Alicia Hawes
AU  - Xiaodong Bai
AU  - Sarah Wolf
AU  - Alexander E. Lopez
AU  - Rick Ulloa
AU  - Christopher Sprangel
AU  - Rostislav Chernomorsky
AU  - Ingrid B. Borecki
AU  - Frederick E. Dewey
AU  - Aris N. Economides
AU  - John D. Overton
AU  - H. Lester Kirchner
AU  - Michael F. Murray
AU  - Marylyn D. Ritchie
AU  - David J. Carey
AU  - David H. Ledbetter
AU  - George D. Yancopoulos
AU  - Alan R. Shuldiner
AU  - Aris Baras
AU  - Omri Gottesman
AU  - Lukas Habegger
AU  - Christa Lese Martin
AU  - Jeffrey G. Reid
TI  - Profiling copy number variation and disease associations from 50,726 DiscovEHR Study exomes
AID  - 10.1101/119461
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 119461
4099  - http://biorxiv.org/content/early/2017/03/22/119461.short
4100  - http://biorxiv.org/content/early/2017/03/22/119461.full
AB  - Copy number variants (CNVs) are a substantial source of genomic variation and contribute to a wide range of human disorders. Gene-disrupting exonic CNVs have important clinical implications as they can underlie variability in disease presentation and susceptibility. The relationship between exonic CNVs and clinical traits has not been broadly explored at the population level, primarily due to technical challenges. We surveyed common and rare CNVs in the exome sequences of 50,726 adult DiscovEHR study participants with linked electronic health records (EHRs). We evaluated the diagnostic yield and clinical expressivity of known pathogenic CNVs, and performed tests of association with EHR-derived serum lipids, thereby evaluating the relationship between CNVs and complex traits and phenotypes in an unbiased, real-world clinical context. We identified CNVs from megabase to exon-level resolution, demonstrating reliable, high-throughput detection of clinically relevant exonic CNVs. In doing so, we created a catalog of high-confidence common and rare CNVs and refined population frequency estimates of known and novel gene-disrupting CNVs. Our survey among an unselected clinical population provides further evidence that neuropathy-associated duplications and deletions in 17p12 have similar population prevalence but are clinically under-diagnosed. Similarly, adults who harbor 22q11.2 deletions frequently had EHR documentation of neurodevelopmental/neuropsychiatric disorders and congenital anomalies, but not a formal genetic diagnosis (i.e., deletion). In an exome-wide association study of lipid levels, we identified a novel five-exon duplication within LDLR segregating in a large kindred with features of familial hypercholesterolemia. Exonic CNVs provide new opportunities to understand and diagnose human disease.