Whole genome and exome sequencing is being widely used to identify disease-causing variants in patients with hereditary and rare diseases. Discovering the true disease-causing variants often requires testing different modes of inheritance (de novo, compound heterozygote, recessive, or dominant). Indeed, selecting the most promising ones that best explain a patient’s entire phenotype, can be very time-consuming. In this presentation, we will present our new one-step trio workflow, which automatically checks for all modes of inheritance using optimized parameter settings for the complete data analysis, filtering, and interpretation workflow. We will illustrate this by reporting data from cases with undiagnosed genetic disorders. In combination with our new patient phenotype-driven sorting algorithm, which ranks variants using phenotype-disease associations, this simplifies and accelerates the identification of disease-causing variants.