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Keywords: Copy number/structural variation; Clinical testing; Genetic testing

J. Schleit 1; I. Saarinen 2; K. Gall 1; J. Hathaway 1; E. Salminen 2; J. Koskenvuo 2; T.-P. Alastalo 1

1) Blueprint Genetics, San Francisco; 2) Blueprint Genetics, Helsinki Finland

Copy number variants (CNVs) are an important cause of hereditary disease. The prevalence of CNVs across various disease categories is only beginning to be understood as next generation sequencing (NGS) technologies have become more sensitive at detecting these. However, an NGS assay’s ability to detect various sized CNVs is highly dependent upon the testing platform and bioinformatics pipeline.
We describe the frequency and characteristics of diagnostic CNVs identified on a whole exome sequencing platform across 15 medical specialities in patients referred for clinical genetic testing. We report on the proportion of diagnostic CNVs that contribute to the overall diagnostic yield in each disease category.
Methods: Next-generation sequencing (NGS) was performed using the IDT xGEN Exome Research Panel with added custom probes and the Illumina NovaSeq 6000 platform.We performed a retrospective review of all genetic tests run on this platform from April 2018 to April 2019. The type of CNV (deletion or duplication), size (in bp), genomic coordinates, impacted gene(s), classification and the presence of other variants (reported as primary findings) was extracted from our internal database.
Overall, CNVs made up 9.8% of all diagnostic variants (401/4093) and were the primary diagnostic variant in 3.7% of all tests. The majority (91.5%) of diagnostic CNVs were deletions. The median size of all deletions was 10.7kb (range 122bp-154Mb), and 25.9% of deletions were ≤ 500bp. The median size of all duplications was 1.2Mb (range 374bp-72Mb) and 5.9% of duplications were ≤ 500bp. Diagnostic CNVs made up the highest proportion of all diagnostic findings in whole exome tests (45.3%), pulmonology tests (33.3%) and ear-nose-throat tests (20.1%). Diagnostic CNVs made up the smallest proportion of all diagnostic findings in ophthalmology, endocrinology and cardiology (6.9%, 6.9% and 6.0% respectively).
Diagnostic CNVs are identified in approximately 10% of all tests performed on this whole exome sequencing platform. CNVs ranging from one exon deletions/duplications to multiple gene deletions/duplications were identified in multiple genes across almost all medical specialties. Importantly, 24.2% of CNVs were less than or equal to two exons in size. These results highlight the importance of a comprehensive genetic testing approach with high sensitivity to detect CNVs less than 2 exons in size across all medical specialities.