Copy number variant detection by exome/genome sequencing versus chromosomal microarray: A comparative study of over 9000 clinical cases

Copy number variants (CNVs) are implicated in many health conditions. Chromosomal microarray (CMA) has traditionally been the first-tier test for CNV detection. However, exome and genome sequencing (ES/GS) can identify CNVs alongside other variant types. This study compares CNV detection using CMA versus ES/GS in a large clinical cohort.

CNV calls from CMA and ES/GS were analyzed in a diverse cohort of over 9000 individuals tested in a high-throughput clinical laboratory. Concordance between platforms was evaluated, with discordant findings reviewed to determine their nature and causes.

ES/GS showed >99% concordance with CMA. CMA results not detected by ES/GS were typically CNVs <3 exons, CNVs outside regions of interest, or low-level mosaicism. Interestingly, 0.68% of cases had a CNV reported by ES/GS only, usually CNVs below the CMA detection limit. The additional CNV detection by CMA after ES/GS was ≤1%. When considering non-CNV findings, the added yield of ES/GS was >41%.

ES/GS matched or exceeded CMA performance for CNV detection and identified additional variant types. These findings support the adoption of ES/GS as first-tier tests for CNV detection, streamlining diagnostic workflows and improving the diagnostic rate by capturing both small and large structural variants with high accuracy.