Detection of copy-number variations from NGS data using read depth information: a diagnostic performance evaluation

Olivier Quenez (1) , Kevin Cassinari (1) , Sophie Coutant (1) , Francois Lecoquierre (1) , Kilan Le Guennec (1) , Stéphane Rousseau (1) , Anne-Claire Richard (1) , Stéphanie Vasseur (2) , Emilie Bouvignies (2) , Jacqueline Bou (2) , Gwendoline Lienard (2) , Sandrine Manase (2) , Steeve Fourneaux (1) , Nathalie Drouot (2) , Virginie Nguyen-Viet (2) , Myriam Vezain (1) , Pascal Chambon (1) , Géraldine Joly-Helas (1) , Nathalie Le Meur (1) , Mathieu Castelain (1) , Anne Boland (3, 4) , Jean-François Deleuze (3, 4) , Isabelle Tournier (1) , Francoise Charbonnier (1) , Edwige Kasper (1) , Gaëlle Bougeard (1) , Thierry Frebourg (1) , Pascale Saugier-Veber (1) , Stephanie Baert-Desurmont (1) , Dominique Campion (1, 5) , Anne Rovelet-Lecrux (1) , Gael Nicolas (1)

1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 Service de génétique [Rouen]
3 CNRGH - Centre National de Recherche en Génomique Humaine
4 CEPH - Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris]
5 Centre Hospitalier du Rouvray

The detection of copy-number variations (CNVs) from NGS data is underexploited as chip-based or targeted techniques are still commonly used. We assessed the performances of a workflow centered on CANOES, a bioinformatics tool based on read depth information. We applied our workflow to gene panel (GP) and whole-exome sequencing (WES) data, and compared CNV calls to quantitative multiplex PCR of short fluorescent fragments (QMSPF) or array comparative genomic hybridization (aCGH) results. From GP data of 3776 samples, we reached an overall positive predictive value (PPV) of 87.8%. This dataset included a complete comprehensive QMPSF comparison of four genes (60 exons) on which we obtained 100% sensitivity and specificity. From WES data, we first compared 137 samples with aCGH and filtered comparable events (exonic CNVs encompassing enough aCGH probes) and obtained an 87.25% sensitivity. The overall PPV was 86.4% following the targeted confirmation of candidate CNVs from 1056 additional WES. In addition, our CANOES-centered workflow on WES data allowed the detection of CNVs with a resolution of single exons, allowing the detection of CNVs that were missed by aCGH. Overall, switching to an NGS-only approach should be cost-effective as it allows a reduction in overall costs together with likely stable diagnostic yields. Our bioinformatics pipeline is available at: https://gitlab.bioinfo-diag.fr/nc4gpm/canoes-centered-workflow.

Domaines: Sciences du Vivant [q-bio]

Olivier Quenez, Kevin Cassinari, Sophie Coutant, Francois Lecoquierre, Kilan Le Guennec, et al.. Detection of copy-number variations from NGS data using read depth information: a diagnostic performance evaluation. European Journal of Human Genetics, 2020, ⟨10.1038/s41431-020-0672-2⟩. ⟨hal-02883904⟩