Clinical utility of Whole Exome Sequencing for rare Mendelian disorders: phenotypic-driven strategy for a high diagnostic yield and identification of 48 novel variants

About 6,000 to 7,000 different rare disorders with suspected genetic etiologies have been described and in almost 4,500 of them the causative gene(s) have been identified. The advent of Next-Generation Sequencing (NGS) technologies has revolutionized genomic research and diagnostics, representing a major advance in identification of pathogenic genetic variations. WES facilitates a faster and more cost-effective route for definite diagnosis of rare genetic disorders, minimizing previous “diagnostic odysseys” for the patients. Due to the limitation that WES is not reimbursed in Greece, we aimed to minimize cost per patient/family through applying WES in the proband, followed by targeted family segregation studies when necessary. Furthermore, for variant filtration and interpretation we applied a phenotypic-driven strategy in close collaboration with clinical geneticists or referring clinicians. In this study we report the clinical application of WES in the diagnosis of 162 cases referred to investigate patients with undiagnosed genetic disorders. The overall molecular diagnostic yield reached 52.5%. Our experience as an academic diagnostic laboratory using WES, although limited to the last two years, allowed characterization of 94 pathogenic variants in 85 positive cases, 48 of which were novel, contributing information to the community of disease and variant databases.