Technical Performance of a 455-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 455-gene assay that is comprehensive both in its scope of medical conditions and variant detection capabilities. The GeneCompass test analyzes genes associated with Mendelian inheritance, susceptibilities, and pharmaceutical drug response to conditions in 12 clinical areas (e.g., cardiovascular disease, oncology, psychiatry, neurology). The custom-designed next-generation sequencing (NGS) capture and bioinformatics pipelines discover multiple variant types, including single nucleotide variants, insertion/deletion (indel), larger copy number variants, and functional haplotypes (star alleles). Validation was performed against reference DNA from three sources: 1000 Genomes Project (n=3), Coriell biobank (n=15), and internal leftover blood (n=21) and saliva (n=12) specimens from a previously validated assay. Overall analytical sensitivity and specificity for single nucleotide variants were 97.57% and 99.99%, respectively, and for indels were 74.57% and 97.35%, respectively. This study demonstrates validity of a NGS assay that is technically capable for screening purposes and potentially broadens access to preventative genomics usage.