Abstract 12675: Comprehensive Analysis of Cardiomyopathy and Arrhythmia Genes Yields Unanticipated Molecular Diagnoses

Abstract

Introduction: Professional societies recommend genetic testing to improve diagnosis and inform management of inherited cardiovascular disease, yet genetic testing is not widely utilized in cardiovascular practice. To reduce barriers to genetic testing and facilitate following of existing guidelines, we initiated a program of sponsored genetic testing with genetic counseling at no cost to patients suspected of having a genetic arrhythmia or cardiomyopathy. Here, we describe unanticipated molecular diagnoses provided by a comprehensive analysis of cardiomyopathy and arrhythmia genes. Methods: With IRB approval, de-identified genetic and clinical data provided by ordering clinicians were reviewed from 1,606 individuals referred for testing through the sponsored, no-charge Detect Cardiomyopathy and Arrhythmia genetic testing program between July 2019 and January 2020. Testing consisted of a cardiomyopathy and arrhythmia panel of up to 150 genes detecting single nucleotide, small indel, and exon-level deletion and duplication variants. Results: Overall, 20.5% (329/1606) of patients had a pathogenic or likely pathogenic (P/LP) variant identified. The most common reasons for referral were hypertrophic cardiomyopathy (40%), dilated cardiomyopathy (24%), and long QT syndrome (13%). The diagnostic yield was 25% (130/527) among patients whose healthcare provider reported a high or moderate index of clinical suspicion for a genetic cardiomyopathy, of whom 2% (2/130) had P/LP variants only in the arrhythmia gene KCNQ1 . Conversely, among patients with a high or moderate index of clinical suspicion for a genetic arrhythmia, the diagnostic yield was 20% (28/137), of which 18% (5/28) had P/LP variants only in the cardiomyopathy-associated genes MYBPC3 (2) and TTR (3). Conclusions: These data demonstrate that comprehensive genetic testing, without cost as a barrier, identifies clinically-relevant variants in 1 in 5 suspected cardiomyopathy or arrhythmia patients. Notably, genetic testing with a multi-condition panel yielded unanticipated molecular findings likely to change clinical management in up to 18% of genetically-positive patients. These unanticipated findings would have likely been missed by targeted, disease-specific panels.