A retrospective study highlighted the challenges of genetic testing interpretation for less-represented groups in public databases of genetic variation.
The study covered French-Canadians at a large, dedicated, regional center with extensive infrastructure and multidisciplinary expertise in hereditary arrhythmia and cardiomyopathy.
Family history had been crucial for successful genetic testing at the center, and the interpretation of variant pathogenicity had to take into account certain rare genetic variants being especially enriched in French-Canadians.
Genetic testing for hereditary arrhythmia and cardiomyopathy in an area with known founder effects on local genetic variants had a high yield in identification of pathogenic variants by taking into account the local population and family history, researchers reported.
Out of 2,062 consecutive probands evaluated for suspicion of these conditions at a Montreal center, contemporary state-of-the-art genetic testing had a 24% yield in identifying a pathogenic or likely pathogenic (P/LP) variant causing the disease.
Genetic testing resulted in diagnostic refinement with a potential change in clinical management in 8% of probands, according to Rafik Tadros, MD, PhD, of Montreal Heart Institute, and colleagues.
Importantly, family history had been crucial for the high yield of genetic testing at the center, and the interpretation of variant pathogenicity rested on allele frequency data from a local reference cohort, as certain rare genetic variants are especially enriched in a cohort of predominantly French-Canadian descent, the investigators detailed in the Journal of the American College of Cardiology.
Nine variants had their classification changed by the researchers due to case-control enrichment in the local population-based cohort.
The present findings "emphasize the importance of increasing diversity in genomics research and clinical databases," study authors concluded.
The French-Canadian population, Tadros and colleagues explained, "exemplifies the practical challenges of genetic testing interpretation for groups that are less represented in public databases of genetic variation such as the Genome Aggregation Database (gnomAD)." French-Canadians descend from around 8,500 French colonists, and that period of restriction on genomic variety in the population left known founder effects.
Quinn Wells, MD, MSCI, and two colleagues of Vanderbilt University Medical Center in Nashville, agreed that the interpretation of variant pathogenicity remains challenging. "This is particularly true for underrepresented populations in which inaccurate assessments of variant enrichment can arise from discrepant estimates of allele frequencies in reference databases as compared with population-specific data," they wrote in an accompanying editorial.
The Montreal study could be considered a report from a system that works relatively well. Patients had no financial barriers to genetic testing, as the institution is part of a public healthcare system.
"The laudable approach described in the current report was successful because the investigators have an extensive infrastructure and multidisciplinary expertise at a large, dedicated, regional center with experience in the diagnosis and management of inherited cardiomyopathies and channelopathies, availability of imaging expertise for these phenotypes, and knowledge of gene and variant interpretation," commented Wells and colleagues.
Most other settings, they said, would struggle to implement genetic testing for cardiovascular diseases.
"Part of the long-term solution, no doubt, includes continued expansion of multidisciplinary cardiovascular genetics centers of excellence into underserved regions to connect expertise with need," the editorialists suggested. "This will require expansion of a trained workforce through advanced genetics education for cardiologists and fellows, development of formal training pathways for cardiovascular genetics specialists, and growth of genetic counselor programs."
Tadros and colleagues performed a retrospective study of patients at the Montreal Heart Institute Cardiovascular Genetics Centre who had suspected heritable cardiomyopathies or arrhythmias and for whom both clinical data and genetic testing results were available. The authors did not include family members who were referred for screening.
Patients with hereditary arrhythmia and cardiomyopathy averaged 47 years old when they got their diagnosis and 51 at genetic testing. The group was 63% men, and 71% had at least one parent of French-Canadian descent. Leading diagnoses were hypertrophic cardiomyopathy (42%) and dilated cardiomyopathy (19%).
Study authors acknowledged that "genetic variant classification is inherently dynamic, and it is possible that the classification of variants reported in this study may change over time as new data become available."
Additionally, there may have been temporal changes in the yield of genetic testing introduced by changing gene panels and greater adoption of the practice over time, according to Tadros' group.
Wells and colleagues also pointed out that most of the Montreal cohort still ultimately had negative or inconclusive results.
"This underscores the need for more research to define genotype-phenotype associations and to elucidate the genetic architecture of heritable cardiovascular disease through gene discovery, more research of variants of uncertain significance, and the further elucidation of oligogenic and polygenic risk," they stressed.
"Beyond gene-disease association and variant interpretation, increasing the clinical impact of genetic testing requires system-wide improvements to identify who should be referred for testing, who in the cardiology community has domain-specific expertise, and how resources should be allocated to promote equitable accessibility," the trio added.
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Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow
Disclosures
The study was supported institutionally through the Philippa and Marvin Carsley Chair.
Tadros reported support from the Canada Research Chairs program.
The editorialists disclosed no conflicts of interest.
Primary Source
Journal of the American College of Cardiology
Source Reference: Grondin S, et al "Clinical effect of genetic testing in inherited cardiovascular diseases: a 14-year retrospective study" J Am Coll Cardiol 2025; DOI: 10.1016/j.jacc.2024.11.025.
Secondary Source
Journal of the American College of Cardiology
Source Reference: Laws JL, et al "Genetic testing for cardiovascular disease: evidence grows but challenges remain" J Am Coll Cardiol 2025; DOI: 10.1016/j.jacc.2025.01.007.