Skip to main content
Search
Search
Quick Search anywhere
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Skip main navigation
JACC Journals › JACC › Archives › Vol. 85 No. 10
Previous
Next

Clinical Effect of Genetic Testing in Inherited Cardiovascular Diseases: A 14-Year Retrospective StudyGET ACCESS

Original Research

JACC. 2025 Mar, 85 (10) 988–999
Topic(s):
Editorial Comment: Genetic Testing for Cardiovascular Disease: Evidence Grows But Challenges Remain
Sections

Central Illustration

Abstract

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.

References

  • 1. Schwartz P.J., Ackerman M.J., Antzelevitch C., et al. "Inherited cardiac arrhythmias". Nat Rev Dis Primers . 2020;6:58.

    CrossrefMedlineGoogle Scholar

  • 2. Wilde A.A.M., Semsarian C., Márquez M.F., et al. "European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases". Heart Rhythm . 2022;19:e1-e60.

    CrossrefMedlineGoogle Scholar

  • 3. Hathaway J., Heliö K., Saarinen I., et al. "Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients". BMC Cardiovasc Disord . 2021;21:126.

    CrossrefMedlineGoogle Scholar

  • 4. Laberge A.M., Michaud J., Richter A., et al. "Population history and its impact on medical genetics in Quebec". Clin Genet . 2005;68:287-301.

    CrossrefMedlineGoogle Scholar

  • 5. Anderson-Trocmé L., Nelson D., Zabad S., et al. "On the genes, genealogies, and geographies of Quebec". Science . 2023;380:849-855.

    CrossrefMedlineGoogle Scholar

  • 6. Karczewski K.J., Francioli L.C., Tiao G., et al. "The mutational constraint spectrum quantified from variation in 141,456 humans". Nature . 2020;581:434-443.

    CrossrefMedlineGoogle Scholar

  • 7. Grondin S., Davies B., Cadrin-Tourigny J., et al. "Importance of genetic testing in unexplained cardiac arrest". Eur Heart J . 2022;43:3071-3081.

    CrossrefMedlineGoogle Scholar

  • 8. Corrado D., Perazzolo Marra M., et al. "Diagnosis of arrhythmogenic cardiomyopathy: the Padua criteria". Int J Cardiol . 2020;319:106-114.

    CrossrefMedlineGoogle Scholar

  • 9. Roberts A.E., Allanson J.E., Tartaglia M., Gelb B.D. "Noonan syndrome". Lancet . 2013;381:333-342.

    CrossrefMedlineGoogle Scholar

  • 10. Friedman D. "Sudden unexpected death in epilepsy". Curr Opin Neurol . 2022;35:181-188.

    CrossrefMedlineGoogle Scholar

  • 11. Wang K., Li M., Hakonarson H. "ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data". Nucleic Acids Res . 2010;38:e164.

    CrossrefMedlineGoogle Scholar

  • 12. McLaren W., Gil L., Hunt S.E., et al. "The Ensembl Variant Effect Predictor". Genome Biol . 2016;17:122.

    CrossrefMedlineGoogle Scholar

  • 13. Richards S., Aziz N., Bale S., et al. "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology". Genet Med . 2015;17:405-424.

    CrossrefMedlineGoogle Scholar

  • 14. Giudicessi J.R., Roden D.M., Wilde A.A.M., Ackerman M.J. "Classification and reporting of potentially proarrhythmic common genetic variation in long QT syndrome genetic testing". Circulation . 2018;137:619-630.

    CrossrefMedlineGoogle Scholar

  • 15. Chen S., Francioli L.C., Goodrich J.K., et al. "A genomic mutational constraint map using variation in 76,156 human genomes". Nature . 2024;625:92-100.

    CrossrefMedlineGoogle Scholar

  • 16. Awadalla P., Boileau C., Payette Y., et al. "Cohort profile of the CARTaGENE study: Quebec’s population-based biobank for public health and personalized genomics". Int J Epidemiol . 2013;42:1285-1299.

    CrossrefMedlineGoogle Scholar

  • 17. Tadros R., Francis C., Xu X., et al. "Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect". Nat Genet . 2021;53:128-134.

    CrossrefMedlineGoogle Scholar

  • 18. Devalla H.D., Gélinas R., Aburawi E.H., et al. "TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT". EMBO Mol Med . 2016;8:1390-1408.

    CrossrefMedlineGoogle Scholar

  • 19. Sun B., Yao J., Ni M., et al. "Cardiac ryanodine receptor calcium release deficiency syndrome". Sci Transl Med . 2021;13:579: eaba7287.

    CrossrefGoogle Scholar

  • 20. Dellefave-Castillo L.M., Cirino A.L., Callis T.E., et al. "Assessment of the diagnostic yield of combined cardiomyopathy and arrhythmia genetic testing". JAMA Cardiol . 2022;7:966-974.

    CrossrefMedlineGoogle Scholar

  • 21. Verdonschot J.A.J., Hazebroek M.R., Krapels I.P.C., et al. "Implications of genetic testing in dilated cardiomyopathy". Circ Genom Precis Med . 2020;13:476-487.

    CrossrefMedlineGoogle Scholar

  • 22. Butters A., Bagnall R.D., Ingles J. "Revisiting the diagnostic yield of hypertrophic cardiomyopathy genetic testing". Circ Genom Precis Med . 2020;13:e002930.

    CrossrefMedlineGoogle Scholar

  • 23. Lahrouchi N., Tadros R., Crotti L., et al. "Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome". Circulation . 2020;142:324-338.

    CrossrefMedlineGoogle Scholar

  • 24. Winbo A., Earle N., Marcondes L., et al. "Genetic testing in Polynesian long QT syndrome probands reveals a lower diagnostic yield and an increased prevalence of rare variants". Heart Rhythm . 2020;17:1304-1311.

    CrossrefMedlineGoogle Scholar

  • 25. Murphy J., Kirk C.W., Lambert D.M., et al. "Diagnostic yield from cardiac gene testing for inherited cardiac conditions and re-evaluation of pre-ACMG variants of uncertain significance". Ir J Med Sci . 2024;193:1775-1785.

    CrossrefMedlineGoogle Scholar

  • 26. Nauffal V., Morrill V.N., Jurgens S.J., et al. "Monogenic and polygenic contributions to QTc prolongation in the population". Circulation . 2022;145:1524-1533.

    CrossrefMedlineGoogle Scholar

  • 27. Makarawate P., Glinge C., Khongphatthanayothin A., et al. "Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand". Heart Rhythm . 2020;17:2145-2153.

    CrossrefMedlineGoogle Scholar

  • 28. Stafford F., Krishnan N., Richardson E., et al. "The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic". Genome Med . 2022;14:145.

    CrossrefMedlineGoogle Scholar

  • 29. Ingles J., MacArthur D.G. "The moral and practical urgency of increasing diversity in genomics". Eur Heart J . 2023;44:5157-5159.

    CrossrefMedlineGoogle Scholar

  • 30. Landrum M.J., Lee J.M., Benson M., et al. "ClinVar: improving access to variant interpretations and supporting evidence". Nucleic Acids Res . 2018;46:D1062-D1067.

    CrossrefMedlineGoogle Scholar

  • 31. Watkins H., McKenna W.J., Thierfelder L., et al. "Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy". N Engl J Med . 1995;332:1058-1064.

    CrossrefMedlineGoogle Scholar

  • 32. Allouba M., Walsh R., Afify A., et al. "Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy". Eur Heart J . 2023;44:5146-5158.

    CrossrefMedlineGoogle Scholar

  • 33. Coppini R., Ho C.Y., Ashley E., et al. "Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations". J Am Coll Cardiol . 2014;64:2589-2600.

    View ArticleGoogle Scholar

  • 34. Theopistou A., Anastasakis A., Miliou A., Rigopoulos A., Toutouzas P., Stefanadis C. "Clinical features of hypertrophic cardiomyopathy caused by an Arg278Cys missense mutation in the cardiac troponin T gene". Am J Cardiol . 2004;94:246-249.

    CrossrefMedlineGoogle Scholar

  • 35. Schuldt M., Johnston J.R., He H., et al. "Mutation location of HCM-causing troponin T mutations defines the degree of myofilament dysfunction in human cardiomyocytes". J Mol Cell Cardiol . 2021;150:77-90.

    CrossrefMedlineGoogle Scholar

  • 36. Szczesna D., Zhang R., Zhao J., Jones M., Guzman G., Potter J.D. "Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy". J Biol Chem . 2000;275:624-630.

    CrossrefMedlineGoogle Scholar

  • 37. Hernandez O.M., Szczesna-Cordary D., Knollmann B.C., et al. "F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers". J Biol Chem . 2005;280:37183-37194.

    CrossrefMedlineGoogle Scholar

  • 38. Escobar-Lopez L., Ochoa J.P., Royuela A., et al. "Clinical risk score to predict pathogenic genotypes in patients with dilated cardiomyopathy". J Am Coll Cardiol . 2022;80:1115-1126.

    View ArticleGoogle Scholar

  • 39. Gigli M., Merlo M., Graw S.L., et al. "Genetic risk of arrhythmic phenotypes in patients with dilated cardiomyopathy". J Am Coll Cardiol . 2019;74:1480-1490.

    View ArticleGoogle Scholar

  • 40. Heliö K., Cicerchia M., Hathaway J., et al. "Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients". Front Cardiovasc Med . 2023;10:1254272.

    CrossrefGoogle Scholar

  • 41. Gudmundsson S., Singer-Berk M., Watts N.A., et al. "Variant interpretation using population databases: lessons from gnomAD". Hum Mutat . 2022;43:1012-1030.

    CrossrefMedlineGoogle Scholar