Key result
Genetic testing identifies disease-causing variants in 24% of suspected heritable cardiomyopathy or arrhythmia cases.
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Why the study?
The clinical impact of genetic testing in a contemporary real-life cohort of heritable cardiomyopathies or arrhythmias was not well defined, and the genetic spectrum in the French-Canadian population was unknown.
Cohort (n=2,062)
No
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“This study of >2,000 probands represents an important addition to the literature supporting the use of clinical genetic testing for cardiomyopathies and arrhythmia syndromes and highlights opportunities to improve clinical relevance of a genetic evaluation. The authors demonstrate a significant yield of genetic testing in appropriately selected patients, with a causal variant identified in nearly one-quarter of patients. Importantly, the detection of a P/LP variant in 1 in 5 apparently sporadic cases underscores the value of routine genetic testing in cardiomyopathy and arrhythmia phenotypes even in the absence of a positive family history.”
Supports genetic testing consideration in inherited CVD; leaves open prospective validation of local references for outcomes.
BACKGROUND The clinical impact of genetic testing in a contemporary real-life cohort of patients with heritable cardiomyopathies or arrhythmias is not well defined. Additionally, the genetic spectrum of these conditions in the French-Canadian population is unknown, and interpretation of genetic variants can be challenging because of a known founder effect. OBJECTIVES This study sought to evaluate the clinical utility of arrhythmia and cardiomyopathy genetic testing and assess the utility of allele frequency data from a local reference population. METHODS The study included consecutive probands seen at the Montreal Heart Institute Cardiovascular Genetics Centre (Montreal, Quebec, Canada) for suspected heritable cardiomyopathies or arrhythmias for which both clinical data and genetic testing results were available. The study analyzed the enrichment of recurrent rare genetic variants by comparing their prevalence in the case cohort with that of a local population cohort. RESULTS A total of 2,062 probands (mean age at diagnosis 47 ± 17 years) were included. Overall, genetic testing identified a pathogenic/likely pathogenic (P/LP) variant in 496 (24%) probands. A total of 9 variants had their classification changed after comparing their prevalence (case control enrichment) using a local population-based cohort. Genetic testing resulted in diagnostic refinement with a potential impact on clinical management in 168 (8%) probands. CONCLUSIONS Genetic testing in a clinical context identified a disease-causing variant in 24% of probands, thus highlighting the high yield of rare variant genetic testing. Beyond the impact on family screening, the genetic testing result affected clinical management. Access to allele frequency data from a local population refines variant interpretation and classification.
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Grondin et al. (2025) conducted a cohort in Suspected heritable cardiomyopathies or arrhythmias (n=2,062). Genetic testing vs. Local population cohort (for variant enrichment analysis) was evaluated on Identification of a pathogenic/likely pathogenic (P/LP) variant. Genetic testing in probands with suspected heritable cardiomyopathies or arrhythmias identified a disease-causing variant in 24% of cases and affected clinical management in 8%.
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