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Diagnostic yield from cardiac gene testing for inherited cardiac conditions and re-evaluation of pre-ACMG variants of uncertain significance

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Abstract

Background

Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives.

Aims

We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020.

Results

Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively.

Conclusion

Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families.

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Data availability

The data generated and analysed during this study can be found within the published article and its supplementary files.

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Acknowledgements

The authors would like to thank the patients and healthcare providers from the various clinical services who facilitated this study. We acknowledge the scientists of the Next Generation Sequencing Laboratory of the Mater Misericordiae University Hospital, Dublin, for technical assistance provided during the study, with particular thanks to Sarada Gandhi Kolli for assistance with genetic variant interpretation.

Funding

Jane Murphy, Claire Kirk, Deborah Lambert, and Sally Ann Lynch were funded by grants from the National Children’s Research Centre, Crumlin, Ireland (Grant No. C/18/14), and the Higher Education Authority COVID-19 Extensions Programme. Terri McVeigh was supported at the time of the research by a HRB/HSE National Academic Specialist Registrar Fellowship award (HSE/HRB NSAFP 2014/1). We are also grateful to the European Joint Programme for Rare Diseases (EJP-RD) who funded Jane Murphy for a training fellowship with the groups of Prof Connie Bezzina and Dr Saskia Van der Crabben of University of Amsterdam Academic Medical Centre, Netherlands.

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Authors and Affiliations

  1. School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland

    Jane Murphy, Claire W. Kirk & Deborah M. Lambert

  2. Family Heart Screening Clinic, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland

    Catherine McGorrian & Joseph Galvin

  3. Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands

    Roddy Walsh

  4. Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, United Kingdom

    Terri P. McVeigh

  5. Department of Cardiology, Children’s Health Ireland at Crumlin, Crumlin, Dublin 12, Ireland

    Terence Prendiville

  6. Centre for Cardiac Risk in the Young Persons, Tallaght University Hospital, Dublin 24, Ireland

    Deirdre Ward

  7. Department of Clinical Genetics, Children’s Health Ireland at Crumlin, Crumlin, Dublin 12, Ireland

    Sally Ann Lynch

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  1. Jane Murphy
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Contributions

Conceived and designed the study: JM and SAL. Generated the study data: JM, CK, CMcG, TP, JG, DW, SAL. Performed the analyses: JM. Wrote the paper: JM. Assisted in drafting the manuscript: SAL, RW, TPMcV, DML. Critically revised the final manuscripts: JM, CK, DML, CMcG, RW, TPMcV, LJK, TP, DW, JG, SAL.

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Correspondence to Jane Murphy.

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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). https://doi.org/10.1007/s11845-024-03650-4

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