RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP 1234
OP 1240
DO 10.1136/jmg-2022-108439
VO 59
IS 12
A1 Quentin Testard
A1 Xavier Vanhoye
A1 Kevin Yauy
A1 Marie-Emmanuelle Naud
A1 Gaelle Vieville
A1 Francis Rousseau
A1 Benjamin Dauriat
A1 Valentine Marquet
A1 Sylvie Bourthoumieu
A1 David Geneviève
A1 Vincent Gatinois
A1 Constance Wells
A1 Marjolaine Willems
A1 Christine Coubes
A1 Lucile Pinson
A1 Rodolphe Dard
A1 Aude Tessier
A1 Bérénice Hervé
A1 François Vialard
A1 Ines Harzallah
A1 Renaud Touraine
A1 Benjamin Cogné
A1 Wallid Deb
A1 Thomas Besnard
A1 Olivier Pichon
A1 Béatrice Laudier
A1 Laurent Mesnard
A1 Alice Doreille
A1 Tiffany Busa
A1 Chantal Missirian
A1 Véronique Satre
A1 Charles Coutton
A1 Tristan Celse
A1 Radu Harbuz
A1 Laure Raymond
A1 Jean-François Taly
A1 Julien Thevenon
YR 2022
UL http://jmg.bmj.com/content/59/12/1234.abstract
AB 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.