Assessment of the Diagnostic Yield of Combined Cardiomyopathy and Arrhythmia Genetic Testing

Abstract

Importance: Genetic testing can guide management of both cardiomyopathies and arrhythmias, but cost, yield, and uncertain results can be barriers to its use. It is unknown whether combined disease testing can improve diagnostic yield and clinical utility for patients with a suspected genetic cardiomyopathy or arrhythmia.

Objective: To evaluate the diagnostic yield and clinical management implications of combined cardiomyopathy and arrhythmia genetic testing through a no-charge, sponsored program for patients with a suspected genetic cardiomyopathy or arrhythmia.

Design, setting, and participants: This cohort study involved a retrospective review of DNA sequencing results for cardiomyopathy- and arrhythmia-associated genes. The study included 4782 patients with a suspected genetic cardiomyopathy or arrhythmia who were referred for genetic testing by 1203 clinicians; all patients participated in a no-charge, sponsored genetic testing program for cases of suspected genetic cardiomyopathy and arrhythmia at a single testing site from July 12, 2019, through July 9, 2020.

Main outcomes and measures: Positive gene findings from combined cardiomyopathy and arrhythmia testing were compared with findings from smaller subtype-specific gene panels and clinician-provided diagnoses.

Results: Among 4782 patients (mean [SD] age, 40.5 [21.3] years; 2551 male [53.3%]) who received genetic testing, 39 patients (0.8%) were Ashkenazi Jewish, 113 (2.4%) were Asian, 571 (11.9%) were Black or African American, 375 (7.8%) were Hispanic, 2866 (59.9%) were White, 240 (5.0%) were of multiple races and/or ethnicities, 138 (2.9%) were of other races and/or ethnicities, and 440 (9.2%) were of unknown race and/or ethnicity. A positive result (molecular diagnosis) was confirmed in 954 of 4782 patients (19.9%). Of those, 630 patients with positive results (66.0%) had the potential to inform clinical management associated with adverse clinical outcomes, increased arrhythmia risk, or targeted therapies. Combined cardiomyopathy and arrhythmia gene panel testing identified clinically relevant variants for 1 in 5 patients suspected of having a genetic cardiomyopathy or arrhythmia. If only patients with a high suspicion of genetic cardiomyopathy or arrhythmia had been tested, at least 137 positive results (14.4%) would have been missed. If testing had been restricted to panels associated with the clinician-provided diagnostic indications, 75 of 689 positive results (10.9%) would have been missed; 27 of 75 findings (36.0%) gained through combined testing involved a cardiomyopathy indication with an arrhythmia genetic finding or vice versa. Cascade testing of family members yielded 402 of 958 positive results (42.0%). Overall, 2446 of 4782 patients (51.2%) had only variants of uncertain significance. Patients referred for arrhythmogenic cardiomyopathy had the lowest rate of variants of uncertain significance (81 of 176 patients [46.0%]), and patients referred for catecholaminergic polymorphic ventricular tachycardia had the highest rate (48 of 76 patients [63.2%]).

Conclusions and relevance: In this study, comprehensive genetic testing for cardiomyopathies and arrhythmias revealed diagnoses that would have been missed by disease-specific testing. In addition, comprehensive testing provided diagnostic and prognostic information that could have potentially changed management and monitoring strategies for patients and their family members. These results suggest that this improved diagnostic yield may outweigh the burden of uncertain results.

Figure 1.. Clinician-Provided Reasons for Referring Patients

There were 4782 total patients. The family history category includes patients meeting 1 or more inclusion criterion for a family history of a primary cardiomyopathy or arrhythmia and/or a family history of sudden cardiac death. The multiple cardiomyopathy (CM) and arrhythmia (AR) category includes patients with a combination of suspected or known cardiomyopathies and arrhythmias. ARVC indicates arrhythmogenic right ventricular cardiomyopathy; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction cardiomyopathy; LQTS, long QT syndrome; and PM, post mortem.

Figure 2.. Flowchart of Testing Results for Original Cohort and Family Members

Family-specific follow-up testing could include up to 150 genes associated with cardiomyopathies and arrhythmias or be limited to a specific gene or variant.

Figure 3.. Test Results Stratified by Diagnostic Indication

Negative or carrier category indicates results in which no molecular diagnosis was identified, including observation of only benign or likely benign variant(s), pseudodeficiency allele(s), or a pathogenic or likely pathogenic variant in an autosomal recessive gene or an X-linked recessive gene in female patients. AR indicates arrhythmia; ARVC, arrhythmogenic right ventricular cardiomyopathy; BrS, Brugada syndrome; CM, cardiomyopathy; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; and LVNC, left ventricular noncompaction cardiomyopathy.