|Title||Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Chiang, T, Liu, X, Wu, T-J, Hu, J, Sedlazeck, FJ, White, S, Schaid, D, de Andrade, M, Jarvik, GP, Crosslin, D, Stanaway, I, Carrell, DS, Connolly, JJ, Hakonarson, H, Groopman, EE, Gharavi, AG, Fedotov, A, Bi, W, Leduc, MS, Murdock, DR, Jiang, Y, Meng, L, Eng, CM, Wen, S, Yang, Y, Muzny, DM, Boerwinkle, E, Salerno, WJ, Venner, E, Gibbs, RA|
|Date Published||2019 Mar 20|
PURPOSE: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs.
METHODS: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap).
RESULTS: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA).
CONCLUSION: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.
|Alternate Journal||Genet. Med.|
|Grant List||U01HG8664 / / National Human Genome Research Institute / |
HG008898 / / National Human Genome Research Institute /
HG006542 / / National Human Genome Research Institute /