Abstract Body (Do not enter title and authors here): Background
Disease expressivity in hypertrophic cardiomyopathy (HCM) varies widely, ranging from unaffected genetically predisposed individuals to life-threatening complications. Polygenic scores (PGS) were shown to predict disease penetrance of HCM-causing rare genetic variants (HCMrv) and HCM-related outcomes in large biobanks. However, the utility of PGS in clinical cohorts remains unclear.

Research Questions
Can PGS predict disease penetrance in carriers of HCMrv in the clinical setting? Is PGS associated with disease severity and complications in individuals with HCM?

Methods
We studied a well-characterized clinical HCM cohort from Canada, Italy, the Netherlands and Spain, comprising 6,111 individuals affected by HCM and/or carrying a HCMrv. We used SBayesRC to derive a novel PGS for HCM from the largest published genome-wide association study. Standardized ancestry-adjusted PGS were calculated for all individuals and tested for association with HCM penetrance, maximal left ventricular wall thickness (MLVWT) and major adverse clinical events (MACE) using logistic, linear and Cox regression models, respectively, with adjustment for sex, rare variant status, site, and other covariates as relevant. MACE were defined as major ventricular arrhythmic or heart failure event, stroke, septal reduction therapy or all-cause mortality.

Results
PGS was tested for association with HCM in the subset of 1,667 relatives carrying a HCMrv (age at last follow-up 47 ± 19, 49% female), of which 57% meet diagnostic criteria for HCM. PGS was associated with a diagnosis of HCM (Odds ratio 1.6 per standard deviation [SD] increase in PGS; 95% CI: 1.4-1.8). Male sex and hypertension also independently increased penetrance by 3-fold and 2-fold, respectively. HCM-penetrance increased with increasing PGS, in the entire set as well as in carriers of MYH7 pathogenic variants, MYBPC3 truncating variants, or intermediate effect variants (Figure). In 4,949 affected individuals (age at diagnosis 48 ± 17, 33% female, 49% carrying HCMrv), PGS was associated with disease severity. Each SD increase in PGS was associated with a 0.5 mm increase in MLVWT (95% CI: 0.3-0.6), and a 12% increase in lifetime risk of MACE (Hazard ratio 1.12, 95% CI: 1.06-1.18).

Conclusions
PGS assessment may enhance risk stratification and personalize monitoring strategies—guiding the timing, frequency, and scope of clinical evaluations in both genetically predisposed individuals and patients with manifest HCM.