VarPPUD: Variant post prioritization developed for undiagnosed genetic disorders.

Patients with chronic, undiagnosed and underdiagnosed genetic conditions often endure expensive and excruciating years-long diagnostic odysseys without clear results. In many instances, clinical genome sequencing of patients and their family members fails to reveal known disease-causing variants, although compelling variants of uncertain significance are frequently encountered. Existing computational tools struggle to reliably differentiate truly disease-causing variants from other plausible candidate variants within these prioritized sets. Consequently, the confirmation of disease-causing variants often necessitates extensive experimental follow-up, including studies in model organisms and identification of other similarly presenting genotype-matched individuals, a process that can extend for several years. Here, we present VarPPUD, a tool trained specifically to distinguish likely from unlikely to be confirmed pathogenic variants that were prioritized across cases in the Undiagnosed Diseases Network. By evaluating the importance and impact of different input feature values on prediction, we gain deeper insights into the distinctive attributes of difficult-to-identify diagnostic variants. For patients who remain undiagnosed following comprehensive whole genome sequencing, our new method VarPPUD may reveal pathogenic variants amid a pool of candidate variants, thereby advancing diagnostic efforts where progress has otherwise stalled.