TY - JOUR T1 - Exome sequencing as a first-tier test for copy number variant detection: retrospective evaluation and prospective screening in 2418 cases JF - Journal of Medical Genetics JO - J Med Genet SP - 1234 LP - 1240 DO - 10.1136/jmg-2022-108439 VL - 59 IS - 12 AU - Quentin Testard AU - Xavier Vanhoye AU - Kevin Yauy AU - Marie-Emmanuelle Naud AU - Gaelle Vieville AU - Francis Rousseau AU - Benjamin Dauriat AU - Valentine Marquet AU - Sylvie Bourthoumieu AU - David Geneviève AU - Vincent Gatinois AU - Constance Wells AU - Marjolaine Willems AU - Christine Coubes AU - Lucile Pinson AU - Rodolphe Dard AU - Aude Tessier AU - Bérénice Hervé AU - François Vialard AU - Ines Harzallah AU - Renaud Touraine AU - Benjamin Cogné AU - Wallid Deb AU - Thomas Besnard AU - Olivier Pichon AU - Béatrice Laudier AU - Laurent Mesnard AU - Alice Doreille AU - Tiffany Busa AU - Chantal Missirian AU - Véronique Satre AU - Charles Coutton AU - Tristan Celse AU - Radu Harbuz AU - Laure Raymond AU - Jean-François Taly AU - Julien Thevenon Y1 - 2022/12/01 UR - http://jmg.bmj.com/content/59/12/1234.abstract N2 - 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.All data relevant to the study are included in the article or uploaded as supplementary information. ER -