Exome sequencing as a first-tier test for copy number variant detection : retrospective evaluation and prospective screening in 2418 cases

Purpose Despite exome (ES) or genome sequencing (GS) availability, chromosomal microarray (CMA) remains the first-line diagnostic tests in most rare disorders diagnostic work-up, looking for Copy-number variations (CNV), with a diagnostic yield of 10-20%. The question of the equivalence of CMA and ES in CNV calling is an organisational and economic question, especially when ordering a GS after a negative CMA and/or ES. Methods This work measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNV on a retrospective cohort of 615 unrelated individuals. A prospective detection of ES 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 was accurately detected (64/64 events). In the prospective cohort, 32 diagnostics were performed among the 2418 individuals with CNVs ranging from 704bp 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. Conclusions Combining 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 GS after a negative ES, a careful reanalysis with updated CNV calling and SNV annotation should be considered.