title: Detection of clinically relevant copy number variants with whole-exome sequencing.
abstract: Copy number variation (CNV) is a common source of genetic variation that has been implicated in many genomic disorders. This has resulted in the widespread application of genomic microarrays as a first-tier diagnostic tool for CNV detection. More recently, whole-exome sequencing (WES) has been proven successful for the detection of clinically relevant point mutations and small insertion-deletions exome wide. We evaluate the utility of short-read WES (SOLiD 5500xl) to detect clinically relevant CNVs in DNA from 10 patients with intellectual disability and compare these results to data from two independent high-resolution microarrays. Eleven of the 12 clinically relevant CNVs were detected via read-depth analysis of WES data; a heterozygous single-exon deletion remained undetected by all algorithms evaluated. Although the detection power of WES for small CNVs currently does not match that of high-resolution microarray platforms, we show that the majority (88%) of rare coding CNVs containing three or more exons are successfully identified by WES. These results show that the CNV detection resolution of WES is comparable to that of medium-resolution genomic microarrays commonly used as clinical assays. The combined detection of point mutations, indels, and CNVs makes WES a very attractive first-tier diagnostic test for genetically heterogeneous disorders.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, 6500 HB, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.forename: Philip M
authors.initials: PM
authors.lastname: Boone
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Todd
authors.initials: T
authors.lastname: Richmond
authors.forename: Joel
authors.initials: J
authors.lastname: Geoghegan
authors.forename: Kathleen
authors.initials: K
authors.lastname: O'Moore
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.forename: Christine
authors.initials: C
authors.lastname: Shaw
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
mesh_terms: D000465:Algorithms; D056915:DNA Copy Number Variations; D059472:Exome; D005820:Genetic Testing / Q000379:methods; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D015203:Reproducibility of Results
keywords: clinical; copy number variation; whole exome sequencing