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: 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]

Hypertrophic cardiomyopathy (HCM) affects an estimated 1:500 individuals and is largely considered to be a disease of the sarcomere. However, disease-causative genetic variants in PLN -encoded phospholamban and JPH2 -encoded junctophilin-2 cause HCM via perturbations in intracellular calcium handling (ICH). Given recent case reports describing asymmetric left ventricular hypertrophy (LVH) in patients with arrhythmogenic cardiomyopathy (ACM)-predisposing genetic variants in PKP2 -encoded plakophilin-2, a gene known to play a role in ICH, we sought to examine the prevalence and clinical impact of an HCM phenotype in PKP2-ACM patients. In this retrospective study, review of 771 genotype-positive ACM patients evaluated between 01/2015 and 04/2024 was used to identify those with a pathogenic/likely pathogenic (P/LP) variant in PKP2. Pertinent demographic, electrocardiographic, imaging and outcome data was extracted from the electronic medical record. HCM was defined by the presence of maximal end-diastolic wall thickness of >15 mm anywhere in the left ventricle. Advanced heart failure (HF) and major VA outcomes [sudden cardiac arrest (SCA), sustained VT, and appropriate implantable cardioverter-defibrillator (ICD) shocks] were analyzed. Collectively, an HCM phenotype was observed in 9 (7.8%) of the 115 P/LP variant-positive patients (mean age 38±36; 51 (44%) male, and 57 with a ACM phenotype). Of note sigmoid subtype HCM was noted in 8/9 (89%) and left ventricular outflow tract obstruction present in 7/9 (78%; mean gradient of 57±48 mmHg). In comparison to PKP2-ACM patients without HCM, PKP2-HCM patients with HCM were older and less likely to have a family history of any cardiomyopathy (Table). Interestingly, in the patients with a positive phenotype, non-sustained VT and major VA outcomes were less prevalent in the HCM patients (Table). Nearly 8% of individuals with a P/LP variant in PKP2 have a concomitant HCM phenotype. Whether this observation reflects abnormal calcium handling in the setting of PKP2 haploinsufficiency or selection bias in the setting of the combined prevalence of HCM (1:500) and PKP2 loss-of-function (1:695) requires further studies. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Women with HCM tend to have a later onset but more severe disease course. However, the underlying pathobiological mechanisms for these differences remain unknown., Methods: Myectomy samples from 97 patients (53 males/44 females) with symptomatic obstructive HCM and 23 control cardiac tissues were included in this study. RNA-sequencing was performed on all samples. Mass spectrometry-based proteomics and phosphoproteomics was performed on a representative subset of samples., Results: The transcriptome, proteome, and phosphoproteome was similar between sexes and did not separate on PCA plotting. Overall, there were 482 differentially expressed genes (DEGs) between control females and control males while there were only 53 DEGs between HCM females and HCM males. There were 1983 DEGs between HCM females and control females compared to 1064 DEGs between HCM males and control males. Additionally, there was increased transcriptional downregulation of hypertrophy pathways in HCM females and in HCM males. HCM females had 119 differentially expressed proteins compared to control females while HCM males only had 27 compared to control males. Finally, the phosphoproteome showed females had 341 differentially phosphorylated proteins (DPPs) compared to controls while males only had 184. Interestingly, there was hypophosphorylation and inactivation of hypertrophy pathways in females but hyperphosphorylation and activation in males., Conclusion: There are subtle, but biologically relevant differences in the multi-omics profile of HCM. This study provides the most comprehensive atlas of sex-specific differences in the transcriptome, proteome, and phosphoproteome present at the time of surgical myectomy for obstructive HCM., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-causative genes compared with the gold-standard patch clamp., Methods: A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2 , and 50 SCN5A ) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, ESM1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp., Results: Considering variants in all 3 genes, the ESM1b model had a receiver operator curve-area under the curve of 0.75 ( P =0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operator curve-area under the curve of 0.85 ( P <0.0001), sensitivity of 80%, and specificity of 76%., Conclusions: Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis.