|Detection of clinically relevant copy number variants with whole-exome sequencing.
|Year of Publication
|de Ligt, J, Boone, PM, Pfundt, R, Vissers, LELM, Richmond, T, Geoghegan, J, O'Moore, K, de Leeuw, N, Shaw, C, Brunner, HG, Lupski, JR, Veltman, JA, Hehir-Kwa, JY
|Algorithms, DNA Copy Number Variations, Exome, Genetic Testing, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Intellectual Disability, Reproducibility of Results
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.
|U54 HG003273 / HG / NHGRI NIH HHS / United States