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Original research
Exome sequencing as a first-tier test for copy number variant detection: retrospective evaluation and prospective screening in 2418 cases
  1. Quentin Testard1,2,3,
  2. Xavier Vanhoye1,
  3. Kevin Yauy3,4,
  4. Marie-Emmanuelle Naud1,
  5. Gaelle Vieville2,
  6. Francis Rousseau1,
  7. Benjamin Dauriat5,
  8. Valentine Marquet5,
  9. Sylvie Bourthoumieu5,
  10. David Geneviève6,7,
  11. Vincent Gatinois6,
  12. Constance Wells6,
  13. Marjolaine Willems6,
  14. Christine Coubes6,
  15. Lucile Pinson6,
  16. Rodolphe Dard8,
  17. Aude Tessier8,
  18. Bérénice Hervé8,
  19. François Vialard8,
  20. Ines Harzallah9,
  21. Renaud Touraine9,
  22. Benjamin Cogné10,
  23. Wallid Deb10,
  24. Thomas Besnard10,
  25. Olivier Pichon10,
  26. Béatrice Laudier11,
  27. Laurent Mesnard12,
  28. Alice Doreille12,
  29. Tiffany Busa13,
  30. Chantal Missirian13,
  31. Véronique Satre2,3,
  32. Charles Coutton2,3,
  33. Tristan Celse2,
  34. Radu Harbuz2,
  35. Laure Raymond1,
  36. Jean-François Taly1,
  37. Julien Thevenon2,3
  1. 1Service de Génétique, Eurofins Biomnis, Lyon, France
  2. 2Service de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France
  3. 3CNRS UMR 5309, INSERM, U1209, Université Grenoble Alpes, Institute for Advanced Bioscience, Grenoble, France
  4. 4SeqOne Genomics, Montpellier, France
  5. 5Service de Cytogénétique, Génétique Médicale et Biologie de la Reproduction, CHU Limoges, Limoges, France
  6. 6Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU Montpellier, Montpellier, France
  7. 7Unité INSERM U1183, University Montpellier 1, Montpellier, France
  8. 8Département de Génétique, CHI Poissy-Saint-Germain-en-Laye, Saint-Germain-en-Laye, France
  9. 9Service de génétique clinique, chromosomique et moléculaire, CHU Saint-Étienne, Saint-Etienne, France
  10. 10Service de Génétique Médicale, CHU Nantes, Nantes, France
  11. 11Laboratoire d'Immunologie et Neurogénétique Expérimentales et Moléculaires INEM UMR7355, CHR d'Orléans, Orléans, France
  12. 12Sorbonne Université, Urgences Néphrologiques et Transplantation Rénale, APHP, Hôpital Tenon, Paris, France
  13. 13Département de génétique médicale, AP HM, Hôpital de la Timone Enfant, Marseille, France
  1. Correspondence to Dr Jean-François Taly, Eurofins Biomnis Lyon, Lyon 69007, France; JeanFrancoisTaly{at}; Dr Julien Thevenon; jthevenon{at}


Background Despite the availability of whole exome (WES) and genome sequencing (WGS), chromosomal microarray (CMA) remains the first-line diagnostic test in most rare disorders diagnostic workup, looking for copy number variations (CNVs), with a diagnostic yield of 10%–20%. The question of the equivalence of CMA and WES in CNV calling is an organisational and economic question, especially when ordering a WGS after a negative CMA and/or WES.

Methods This study measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNVs on a retrospective cohort of 615 unrelated individuals. A prospective detection of WES-CNV on a cohort of 2418 unrelated individuals, including the 615 individuals from the validation cohort, was performed.

Results On the retrospective validation cohort, every CNV detectable by the method (ie, a CNV with at least one exon not in a dark zone) was accurately called (64/64 events). In the prospective cohort, 32 diagnoses were performed among the 2418 individuals with CNVs ranging from 704 bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure.

Conclusion Combining single-nucleotide variant (SNV) and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare Mendelian disorders. Before considering the prescription of a WGS after a negative WES, a careful reanalysis with updated CNV calling and SNV annotation should be considered.

  • genetic variation
  • high-throughput nucleotide sequencing
  • molecular diagnostic techniques
  • congenital, hereditary, and neonatal diseases and abnormalities

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • QT and XV are joint first authors.

  • QT and XV contributed equally.

  • Contributors QT and XV wrote the manuscript. JT, LR and J-FT designed the study and revised the manuscript. KY, M-EN, GV, FR, BD, VM, SB, DG, VG, CW, MW, CC, LP, RD, AT, BH, FV, IH, RT, BC, WD, TB, OP, BL, LM, AD, TB, CM, VS, CC, TC and RH contributed to patient ascertainment and medical data management. All authors have read and approved the final manuscript. JT and J-FT are guarantors.

  • Funding This study was partially subsidised by ANRT (CIFRE grant) and by MIAI@Grenoble Alpes (ANR-19-P3IA-0003).

  • Competing interests QT, XV, LR and J-FT are employed by Eurofins Biomnis, a private medical biology laboratory. KY is employed by Seqone Genomics a private bioinformatics software provider.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.