Next Generation Variant Exon Screening: Moving Forward in Routine Genetic Disease Investigations

PurposePatients with genetic diseases often seek testing to reach a firm diagnosis. Based on clinical phenotypes, exome sequencing (ES) for small nucleotide variations or array-based methods for copy number variations (CNVs) are commonly offered to identify the underlying causative genetic variants. In this study, we investigated whether data from a standard ES test could be used to additionally identify pathogenic CNVs and increase diagnostic yield.MethodsProspectively, 134 patients presenting with a skin condition suspected of being genetic in origin were offered the next generation variant exon screening (ngVES) test. Sequencing data was analyzed for both SNVs and CNVs using established algorithms.ResultsThe positive detection rate for skin diseases using ngVES was 66% (88/134) with the most common diagnoses being neurofibromatosis type1 (n=48) and tuberous sclerosis type2 (n=12). The diagnostic increased yield from 58% to 66% was the result of additional detection of pathogenic CNVs. Each of the 9 CNVs were verified by independent genetic tests.ConclusionsThe advances in the ngVES bioinformatics pipeline is a proof of concept which improved identification of genetic variants associated with skin disease. Simultaneous SNV/INDEL and CNV detection by this approach demonstrates ngVES potential as a first-tier screen for any suspected genetic disease.