Detection of clinically relevant copy number variants with whole-exome sequencing.

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 ap- plication of genomic microarrays as a first-tier diagnostic tool for CNV detection. More recently, whole-exome se- quencing (WES) has been proven successful for the de- tection of clinically relevant point mutations and small insertion-deletions exome wide. We evaluate the utility of short-read WES (SOLiD 5500xl) to detect clinically rel- evant CNVs in DNA from 10 patients with intellectual disability and compare these results to data from two in- dependent high-resolution microarrays. Eleven of the 12 clinically relevant CNVs were detected via read-depth anal- ysis of WES data; a heterozygous single-exon deletion re- mained 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 con- taining three or more exons are successfully identified by WES. These results show that the CNV detection reso- lution 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. Hum Mutat 34:1439-1448, 2013. C � 2013 Wiley Periodicals, Inc.