Hypertrophic Cardiomyopathy Polygenic Risk Score Correlates with Genotype but Not Clinical Severity.

: Hypertrophic cardiomyopathy (HCM) is associated with ventricular arrhythmias and an increased risk of sudden death. Although more than 25 genes have been associated with HCM, more than half of HCM patients lack an identifiable monogenic cause for their disease. An HCM polygenic risk score (HCM-PRS) derived from an HCM genome wide association study data appears to correlate with both the risk of developing HCM and adverse outcomes. To determine whether the HCM-PRS correlates with genotype or disease severity in a large single center cohort of patients with HCM. The cohort consisted of 664 patients (40% female) previously enrolled and consented for research genetic testing with an average age at diagnosis of 44±19 years old. Of these, there were 247 (37%) genotype-positive (likely pathogenic/pathogenic/VUS) and 417 (63%) genotype-negative for variants in definitive/strong HCM-susceptibility genes. A custom SNP panel was produced from Agena Biosciences encompassing the 20 previously published SNPs. To calculate the HCM-PRS, the SNPs were added using published β scores. The average HCM-PRS score for the cohort was 1.367±0.2817. Importantly, the average HCM-PRS score was higher for patients classified as genotype-negative compared to the genotype-positive patients (1.385±0.2800 vs. 1.337±0.2825; p=0.04). Furthermore, when looking at the correlation of the HCM-PRS to the Mayo Clinic Genotype Risk Predictor Score (which correlates with clinical phenotype), a linear test for trend showed a decreasing Genotype Predictor Score from 5 to 4 (strong HCM phenotype; 1.334±0.2784) vs. 3 to 2 (1.344±0.2833) vs. 1 to -1 (1.390±0.2803) correlated with an increase of the PRS-HCM (p-value=0.03). There was no linear correlation between HCM-PRS score and maximum left ventricular wall thickness (R-squared= 0.0002974; p=0.7). Finally, there was no association in PRS between those that had a myectomy, arrhythmic event, or a New York Heart Association Class (NYHA) III/IV at presentation. : HCM patients with an elevated HCM-PRS are more likely to be genotype-negative as compared to those that have a variant in an HCM gene suggesting that the PRS may be contributing to HCM in these individuals. While there was no direct correlation with HCM phenotypic characteristics, an inverse association with the Mayo Clinic Genotype Predictor score, which is strongly associated with clinical phenotype, was observed. [ABSTRACT FROM AUTHOR]