Managing Secondary Genomic Findings Associated With Arrhythmogenic Right Ventricular Cardiomyopathy: Case Studies and Proposal for Clinical Surveillance

DNA variants that are expected to confer risk for arrhythmogenic right ventricular cardiomyopathy (ARVC) are recommended as returnable secondary findings from clinical genomic sequencing. However, ARVC presents several distinct challenges for the care and management of patients ascertained through this genome-first approach. We discuss these challenges and present recent cases that exemplify their impact in a clinical setting. We also propose a standard approach to management of genome-first ARVC evaluations and surveillance and finally discuss potential diagnostic innovations that may provide substantial benefits to patients in this setting, particularly given the acceleration of precision health. The increasing use of wide-scale sequencing in both clinical medicine and research is creating scenarios in which genetic risk for cardiovascular diseases are identified unexpectedly, often before symptoms manifest. The cardiovascular genetic community has developed recommendations for detection and management of genotype-positive, phenotype-negative patients in the context of directed familial cascade screening. However, approaches to managing secondary findings identified through diagnostic sequencing for other conditions or as part of large-scale exome or genome sequencing research efforts remain uncertain.1 These scenarios pose novel challenges to medical care by necessitating clinical decisions about what constitutes an actionable genetic finding and what particular action should be taken. As a starting point, the American College of Medical Genetics and Genomics has published recommendations for the reporting of secondary findings from clinical sequencing.2,3 These recommendations currently include a minimum list of 59 genes representing 27 conditions, which were selected based on the availability of confirmatory diagnostic testing and the existence of potential preventive or treatment measures. Research studies often use this list as a starting place to design their return of results protocols. One of these conditions is ARVC, also known as arrhythmogenic right ventricular dysplasia. Although the identification of a pathogenic DNA variant associated with …