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. Copy number variation (CNV) is a common source of genetic variation implicated in many genomic disorders. We evaluate the utility of WES 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. Of the 12 clinically relevant CNVs 11 were detected via read‐depth analysis of WES‐data. The combined detection of small mutations and CNVs makes WES an attractive diagnostic test for genetically heterogeneous disorders.