Harshvir S Bal, Akhil Pampana, Amrita Nayak, Mokshad Gaonkar, Sahaj Patel, Krishin Yerabolu, Nehal Vekariya, Nirav Patel, Rajat Kalra, Peng Li, Garima Arora, Pankaj Arora
Diagnostic uncertainty in prenatal genomics is a persistent clinical reality rather than a transient evidence gap. Longitudinal variant reinterpretation combined with transparent shared decision-making is vital to safely navigate borderline classifications and optimize reproductive trajectories.
Hypertrophic cardiomyopathy (HCM) has traditionally been considered a Mendelian disease driven by pathogenic or likely pathogenic variants in sarcomere-encoding genes (SARC-HCM-P/LP). However, these variants explain only one-third of cases, and variable penetrance suggests additional polygenic contributions. Existing HCM polygenic risk scores (PRSs), largely derived from European-ancestry cohorts, have limited generalizability. Here we develop a multiancestry PRS using summary statistics from the BioBank Japan, Million Veteran Program and a meta-analysis of seven European-ancestry cohorts and evaluate its association with HCM in a USA-based multiancestry population. Individuals with the highest PRS quintile had a 2.11-fold increased risk of HCM in the overall population and nearly 70-fold higher risk among SARC-HCM-P/LP carriers. The PRS improved risk stratification and showed trends toward improved ancestry-specific prediction. Among individuals with HCM, a higher PRS was also associated with adverse cardiovascular outcomes. These findings support the integration of multiancestry PRSs into HCM risk assessment and prognostication.