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Atlas-CNV: a validated approach to call Single-Exon CNVs in the eMERGESeq gene panel

By Theodore Chiang, Xiuping Liu, Tsung-Jung Wu, Jianhong Hu, Fritz J Sedlazeck, Simon White, Daniel Schaid, Mariza de Andrade, Gail P Jarvik, David Crosslin, Ian Stanaway, David S Carrell, John J Connolly, Hakon Hakonarson, Emily E Groopman, Ali G Gharavi, Alexander Fedotov, Weimin Bi, Magalie S Leduc, David R. Murdock, Yunyun Jiang, Linyan Meng, Christine M Eng, Shu Wen, Yaping Yang, Donna Muzny, Eric Boerwinkle, William J. Salerno, Eric Venner, Richard A. Gibbs

Posted 27 Sep 2018
bioRxiv DOI: 10.1101/422337 (published DOI: 10.1038/s41436-019-0475-4)

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 midpool batch, when the target log2 ratio of the sample to the midpool 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 multi-exon and 29 single-exon CNVs with high C-scores were assessed by MLPA. Conclusions: 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 proposed guidelines and criteria to identify high confidence single-exon CNVs. Key Words: Atlas-CNV; copy number variation; CNV; single exon deletion duplication; targeted gene panel clinical sequencing;

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