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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, W, Venner, E, Gibbs, RA |
Journal | Genet Med |
Volume | 21 |
Issue | 9 |
Pagination | 2135-2144 |
Date Published | 2019 Sep |
ISSN | 1530-0366 |
Abstract | 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. |
DOI | 10.1038/s41436-019-0475-4 |
Alternate Journal | Genet. Med. |
PubMed ID | 30890783 |
PubMed Central ID | PMC6752313 |
Grant List | U01 HG008666 / HG / NHGRI NIH HHS / United States U01 HG008684 / HG / NHGRI NIH HHS / United States U01 HG008685 / HG / NHGRI NIH HHS / United States U01 HG008679 / HG / NHGRI NIH HHS / United States U01HG8664 / HG / NHGRI NIH HHS / United States U01 HG008676 / HG / NHGRI NIH HHS / United States U01 HG008672 / HG / NHGRI NIH HHS / United States HG008898 / HG / NHGRI NIH HHS / United States U01 HG006379 / HG / NHGRI NIH HHS / United States U01 HG008657 / HG / NHGRI NIH HHS / United States U01 HG008664 / HG / NHGRI NIH HHS / United States U01 HG008701 / HG / NHGRI NIH HHS / United States U01 HG008680 / HG / NHGRI NIH HHS / United States U01 HG008673 / HG / NHGRI NIH HHS / United States HG006542 / HG / NHGRI NIH HHS / United States |