Diagnostic Yield of Cardiomyopathy and Arrhythmia Genetic Testing

Quick Takes

  • In a cohort of patients with any suspicion (low, moderate, or high) for genetic cardiomyopathy or arrhythmia, disease-causing variants were found in 19.9% of patients, with 66.0% of these positive cases having genetic variants that could alter clinical management.
  • Combined genetic testing for cardiomyopathy and arrhythmia compared to disease-specific testing yielded more positive results (14.4% of positive results on combined testing would have been missed with disease-specific testing).

Study Questions:

What is the diagnostic value and impact on management of combined cardiomyopathy and arrhythmia genetic testing for suspected cases of either genetic cardiomyopathy or arrhythmia?


This was a retrospective cohort study of patients with suspected genetic cardiomyopathy or arrhythmia (based on personal or family history) referred for genetic testing from July 2019–July 2020. DNA sequencing for genes associated with cardiomyopathy and arrhythmia was performed. Rates of positive genetic testing with the combined cardiomyopathy and arrhythmia testing were compared to disease-specific gene testing (hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, noncompaction cardiomyopathy, long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome). Patients with specific genetic variants/mutations associated with adverse clinical outcomes, increased arrhythmogenic risk, or targeted therapies were identified as having positive testing that had clinical management implications.


A total of 4,782 patients with suspected genetic cardiomyopathy or arrhythmia were included in this study. Key demographics included: mean (standard deviation) age, 40.5 (21.3) years; aged ≥60 years, 21.5%; male, 53.3%; Ashkenazi Jewish, 0.8%; Asian, 2.4%; Black or African American, 11.9%; Hispanic, 7.8%; White, 59.9%; multiple races and/or ethnicities, 5.0%; other races and/or ethnicities, 2.9%; unknown race and/or ethnicity, 9.2%. In terms of indications for genetic testing, personal history of suspected or known genetic cardiomyopathy or arrhythmia was noted in 89.3% of patients and concerning family history in 49.3%.

Positive genetic testing for disease-causing variants was noted in 954 of 4,782 patients (19.9%). Positivity rates varied based on age and disease-specific indication. Of the positive cases, 630 patients (66.0% of positive cases, 13.2% of all tested patients) had genetic variants with potential clinical management implications. If testing were restricted to only those identified by clinicians as high index of suspicion of genetic cardiomyopathy or arrhythmia, 137 of 954 positive results (14.4%) would have been undetected. If testing were restricted to disease-specific gene panels based on the clinical history, 75 of 689 positive tests (10.9%) would have been missed. For patients with positive genetic testing, cascade testing led to positive tests in family members in 402 of 958 cases (42.0%).


Combined cardiomyopathy and arrhythmia genetic testing compared to disease-specific testing identified additional disease-causing variants. This has potential implications on clinical management and family screening.


Genetic testing to determine etiologies for cardiomyopathies and arrhythmias remains an important tool. For patients and clinicians, much goes into the decision to send for testing, which includes but is not limited to cost of testing, level of suspicion for genetic etiologies, and implications of positive or uncertain results on personal and clinical matters. While there are limitations to this study (lack of clinical data and outcomes), it provides many important findings that will influence practice. First, even in a broad population that includes patients with low and moderate clinician-suspicion for genetic causes for disease, 19.9% of patients had positive genetic testing, with 66.0% of these having genetic variants that could alter clinical management. Second, combined comprehensive testing for cardiomyopathy and arrhythmia genes compared to disease-specific gene panel testing helped to identify more disease-causing variants (14.4% of positive results), possibly due to overlapping phenotypes and imprecise phenotype definitions. Third, there were a high number of variants of uncertain significance (VUS) noted, which is a trade-off to broader testing. This can be problematic to both clinicians and patients given the uncertainty in the findings. This latter point highlights the need for appropriate genetic counseling prior to testing and strategies for addressing VUS findings. Overall, the results of this study are meaningful and add to our understanding of genetic testing strategies.

Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Heart Failure and Cardiomyopathies, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, Acute Heart Failure

Keywords: Arrhythmias, Cardiac, Brugada Syndrome, Cardiomyopathies, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Genetic Testing, Heart Failure, Long QT Syndrome, Mutation, Phenotype, Sequence Analysis, DNA, Tachycardia, Ventricular

< Back to Listings