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Detection of Clinically Relevant Copy Number Variants with Whole‐Exome Sequencing
Author(s) -
Ligt Joep,
Boone Philip M.,
Pfundt Rolph,
Vissers Lisenka E.L.M.,
Richmond Todd,
Geoghegan Joel,
O'Moore Kathleen,
Leeuw Nicole,
Shaw Christine,
Brunner Han G.,
Lupski James R.,
Veltman Joris A.,
HehirKwa Jayne Y.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22387
Subject(s) - copy number variation , biology , indel , exome sequencing , genetics , microarray , dna microarray , exome , comparative genomic hybridization , computational biology , copy number analysis , exon , dna sequencing , bioinformatics , mutation , gene , genome , single nucleotide polymorphism , genotype , gene expression
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 ( SOL i D 5500xl) to detect clinically relevant CNV s 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 CNV s 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 CNV s currently does not match that of high‐resolution microarray platforms, we show that the majority (88%) of rare coding CNV s 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 CNV s makes WES a very attractive first‐tier diagnostic test for genetically heterogeneous disorders.