Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics

Abstract

BACKGROUND: Inherited primary arrhythmia syndromes and arrhythmogenic cardiomyopathies can lead to sudden cardiac arrest in otherwise healthy individuals. The burden and expression of these diseases in a real-world, well-phenotyped cardiovascular population is not well understood. METHODS: Whole exome sequencing was performed on 8574 individuals from the CATHGEN cohort. Variants in 55 arrhythmia-related genes (associated with 8 disorders) were identified and assessed for pathogenicity based on American College of Genetics and Genomics/Association for Molecular Pathology criteria. Individuals carrying pathogenic/likely pathogenic (P/LP) variants were grouped by arrhythmogenic disorder and matched 1:5 to noncarrier controls based on age, sex, and genetic ancestry. Long-term phenotypic data were annotated through deep electronic health record review. RESULTS: Fifty-eight P/LP variants were found in 79 individuals in 12 genes associated with 5 arrhythmogenic disorders (arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, hypertrophic cardiomyopathy, LMNA -related cardiomyopathy, and long QT syndrome). The penetrance of these P/LP variants in this cardiovascular cohort was 33%, 0%, 28%, 83%, and 4%, respectively. Carriers of P/LP variants associated with arrhythmogenic disorders showed significant differences in ECG, imaging, and clinical phenotypes compared with noncarriers, but displayed no difference in survival. Carriers of novel truncating variants in FLNC, MYBPC3, and MYH7 also developed relevant arrhythmogenic cardiomyopathy phenotypes. CONCLUSIONS: In a real-world cardiovascular cohort, P/LP variants in arrhythmia-related genes were relatively common (1:108 prevalence) and most penetrant in LMNA . While hypertrophic cardiomyopathy P/LP variant carriers showed significant differences in clinical outcomes compared with noncarriers, carriers of P/LP variants associated with other arrhythmogenic disorders displayed only ECG differences.

Reduction of Filamin C Results in Altered Proteostasis, Cardiomyopathy, and Arrhythmias

“…Biobank participants with FLNC truncation variants had significantly increased odds of DCM, LV dysfunction, supraventricular tachycardia, and arrhythmia. 45 Because of findings like these and other reports, 46 the American College of Medical Genetics and Genomics recently recommended reporting pathogenic FLNC variants incidentally identified through genome sequencing citing the high penetrance and elevated risk for cardiomyopathy and sudden death. In these studies, the penetrance of FLNC variants was relatively low, supporting the idea that additional stressors or second “hits” likely contribute to disease manifestation.…”

Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases

“…The etiology of CVD is complex and includes behavioral, environmental, and genetic risk factors (1,2). Collectively, inherited cardiovascular conditions are relatively common and encompass a range of phenotypes such as cardiomyopathies, arrhythmias, dyslipidemias, aortopathies, and some clinical presentations of transthyretin amyloidosis; heritable cardiovascular phenotypes also occur within a constellation of vascular, metabolic and neuromuscular disorders (3)(4)(5)(6)(7).…”

Genetic Testing for Inherited Heart Disease in the Era of Next-Generation Sequencing: Now, Next, and Beyond

“…In this edition of Circulation: Genomics and Precision and Medicine , Nafissi and colleagues report on the prevalence, phenotypic expression, and mortality outcomes associated with variants in genes implicated in arrhythmia predisposition identified in a cardiovascular cohort composed of patients referred for cardiac catheterization. 5 Fifty-eight likely pathogenic/pathogenic variants were identified in 79 individuals, representing a clinically meaningful prevalence of ~1%. These variants were in 12 of the 55 genes analyzed, including genes implicated in primary arrhythmia syndromes, as well as inherited arrhythmogenic and hypertrophic cardiomyopathies.…”