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Genetic testing in monogenic early-onset atrial fibrillation

European Journal of Human Genetics volume 31, pages 769–775 (2023)Cite this article

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Abstract

A substantial proportion of atrial fibrillation (AF) cases cannot be explained by acquired AF risk factors. Limited guidelines exist that support routine genetic testing. We aim to determine the prevalence of likely pathogenic and pathogenic variants from AF genes with robust evidence in a well phenotyped early-onset AF population. We performed whole exome sequencing on 200 early-onset AF patients. Variants from exome sequencing in affected individuals were filtered in a multi-step process, prior to undergoing clinical classification using current ACMG/AMP guidelines. 200 AF individuals were recruited from St. Paul’s Hospital and London Health Sciences Centre who were ≤ 60 years of age and without any acquired AF risk factors at the time of AF diagnosis. 94 of these AF individuals had very early-onset AF ( ≤ 45). Mean age of AF onset was 43.6 ± 9.4 years, 167 (83.5%) were male and 58 (29.0%) had a confirmed family history. There was a 3.0% diagnostic yield for identifying a likely pathogenic or pathogenic variant across AF genes with robust gene-to-disease association evidence. This study demonstrates the current diagnostic yield for identifying a monogenic cause for AF in a well-phenotyped early-onset AF cohort. Our findings suggest a potential clinical utility for offering different screening and treatment regimens in AF patients with an underlying monogenic defect. However, further work is needed to dissect the additional monogenic and polygenic determinants for patients without a genetic explanation for their AF despite the presence of specific genetic indicators such as young age of onset and/or positive family history.

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Fig. 1: Categorizing atrial fibrillation genes based on the ClinGen framework for gene to disease association.
Fig. 2: Flow diagram used to identify variants across atrial fibrillation genes with robust evidence.
Fig. 3: Specific criteria used to clinically evaluate variants across atrial fibrillation genes that met our filtering criteria.

Data availability

Data will be made available upon request.

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Funding

This work was supported by the Canadian Cardiovascular Society, University of British Columbia Cardiology Academic Practice Plan; Charles Kerr Scholarship in Cardiovascular Genetics.

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Author notes

  1. These authors contributed equally: Anna Lehman, Zachary Laksman.

Authors and Affiliations

  1. Department of Medical Genetics, University of British Columbia, Vancouver, Canada

    Brandon Chalazan, Arezoo Mohajeri & Anna Lehman

  2. Department of Medicine, University of British Columbia, Vancouver, Canada

    Emma Freeth, Krishnan Ramanathan, Matthew Bennett, Jagdeep Walia, Laura Halperin & Thomas Roston

  3. Department of Medicine and Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Canada

    Julieta Lazarte & Robert A. Hegele

  4. Department of Medicine and The School of Biomedical Engineering, University of British Columbia and the Centre for Heart Lung Innovation, Vancouver, Canada

    Zachary Laksman

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  1. Brandon Chalazan
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Contributions

Conceptualization: BC, AL, ZL; Data curation: BC, AL; Formal analysis: BC, AM; Investigation: BC; Resources: AL, ZL; Software: AL; Visualization: BC; Writing-original draft: BC; Writing-review & editing: BC, EL, AL, KR, MB, JW, LH, TR, JL, RH, AL, ZL.

Corresponding author

Correspondence to Zachary Laksman.

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We attest that the research included in this report was conducted in a manner consistent with the principles of research ethics, such as those described in the Declaration of Helsinki and/or the Belmont Report. In particular, this research was conducted with the voluntary, informed consent of any research participants, free of coercion or coercive circumstances, and received Research Ethics Board (REB) approval from the University of British Columbia that is consistent with the principles of research ethics and the legal requirements of the lead authors’ jurisdiction(s). Written informed consent was obtained from all participants under a protocol approved by the University of British Columbia Research Ethics Board (H16-02531).

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Chalazan, B., Freeth, E., Mohajeri, A. et al. Genetic testing in monogenic early-onset atrial fibrillation. Eur J Hum Genet 31, 769–775 (2023). https://doi.org/10.1038/s41431-023-01383-z

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