Abstract
Polygenic risk scores (PRS) have emerged as a potential tool for predicting complex genetic traits and disorders, which may complement traditional rare variant testing. As genome-wide association studies (GWAS) expand, PRS predictive accuracy improves, yet its role in clinical genetics remains undefined. Here, we discuss four scenarios for PRS integration into diagnostic workflows: (1) PRS as a first-tier screen to stratify patients for rare variant testing; (2) parallel testing with whole-genome sequencing (WGS) to capture both rare and common variant contributions; (3) selection between PRS and rare variant testing guided by clinical characteristics; and (4) PRS application in rare variant-negative cases to identify likely polygenic etiologies. We highlight different trade-offs of each approach, which include costs, turnaround time, diagnostic efficiency, and risk of secondary findings. While PRS shows promise in conditions with both monogenic and polygenic contributions, challenges remain in defining risk thresholds, equal accuracy across (non-European) ancestries, and integrating PRS into clinical decision-making. Although not yet standard practice, we envision PRS is likely to play an increasing role in genetic diagnostics, necessitating collaboration between clinicians and laboratory geneticists to optimize its application.