Technical Performance of a 430-Gene Preventative Genomics Assay to Identify Multiple Variant Types Associated with Adult-Onset Monogenic Conditions, Susceptibility Loci, and Pharmacogenetic Insights

Abstract

DNA-based screening in individuals without known risk factors potentially identifies those who may benefit from genetic counseling, early medical interventions, and/or avoidance of late or missed diagnoses. While not currently in widespread usage, technological advances in genetic analysis overcome barriers to access by enabling less labor-intensive and more cost-efficient means to discover variants of clinical importance. This study describes the technical validation of a 430-gene next-generation sequencing based assay, GeneCompass™, indicated for the screening of healthy individuals in the areas of actionable health risks, pharmaceutical drug response, and wellness traits. The test includes genes associated with Mendelian disorders and genetic susceptibility loci, encom-passing 14 clinical areas and pharmacogenetic variants. The custom-designed target enrichment capture and bioinformatics pipelines interrogate multiple variant types, including single nucleotide variants, insertions/deletions (indels), copy number variants, and functional haplotypes (star alleles), including tandem alleles and structural variants. Validation was performed against reference DNA from three sources: 1000 Genomes Project (n = 3), Coriell biobank (n = 105), and previously molec-ularly characterized biological specimens: blood (n = 15) and saliva (n = 11). Analytical sensitivity and specificity for single nucleotide variants (SNVs) were 97.57% and 99.99%, respectively, and for indels were 74.57% and 97.34%, respectively. This study demonstrates the validity of an NGS assay for genetic screening and the broadening of access to preventative genomics.