Abstract

Utility of Whole Exome Sequencing (WES) in clinical diagnostics has been limited by the non-uniform sequencing coverage across exons, leaving a substantial proportion of the regions with shallow coverage that prevents accurate variant detection. We evaluated a WES assay that is specifically designed for clinical use, enables uniform sequencing coverage resembling high-coverage gene-panel based assays, and provides high sensitivity in variant detection.

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We performed WES capture experiments using an assay with boosted clinical content, namely IDT xGen Exome Research Panel assay that was spiked-in with custom designed clinical content including baits for >1,400 clinically relevant noncoding variants. Sequencing was performed at Blueprint Genetics using an Illumina NovaSeq sequencing system and data was downsampled to 100M reads. Performance of the assay was assessed by using reference samples with highquality sequence variant calls, or samples with known clinically relevant del/dups.

Blueprint Genetics’ WES has a high diagnostic yield with diagnoses involving non-coding variants, small del/dups, and likely diagnostic candidate variants in novel disease genes.

Blueprint Genetics’ WES results in a likely diagnosis in known disease genes for 41% of cases, supplemented by strong candidate variant findings in 4%.

Keywords: whole exome sequencing, boosted clinical content, deletion/duplication, variant detection, noncoding variant, diagnostic yield

Authors: Mikko Muona, Miko Valori, Ville Kytölä, Pertteli Salmenperä, Matias Rantanen, Massimiliano Gentile, Samuel Myllykangas