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Updated: Jun 30, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

Prevalence and Clinical Impact of Pathogenic Variants in Cardiomyopathy Genes Among Individuals with Cardiac

Temidayo A Abe, Favour E Markson, Quinn S Wells

    Medrxiv : the Preprint Server for Health Sciences
    |June 29, 2026
    PubMed

    Insights

    Individuals with primary cardiac conduction disorders have a higher prevalence of pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy genes. Genetic testing may be beneficial for these patients, especially younger ones with heart failure.

    Area of Science:

    • Cardiology
    • Genetics
    • Genomics

    Background:

    • Cardiac conduction disorders are often secondary to structural heart disease, but isolated cases may precede heart failure (HF).
    • Shared genetic mechanisms may link conduction disorders and HF, prompting investigation into rare variants in cardiomyopathy genes.

    Purpose of the Study:

    • To determine the prevalence of pathogenic/likely pathogenic (P/LP) rare variants in cardiomyopathy genes within individuals exhibiting conduction disorders.
    • To assess the clinical significance and cardiovascular outcomes associated with P/LP variant carrier status in this population.

    Main Methods:

    • Analysis of whole genome sequence data from two large biobanks: Vanderbilt's BioVU (192,834 participants) and the All of Us Research Program (353,092 participants).
    • Identification of participants with primary conduction disorders (LBBB, RBBB, high-grade AVB), excluding secondary causes.
    • Evaluation of P/LP variant carrier status, incident HF, and composite outcomes of ventricular arrhythmias/sudden cardiac death/mortality.

    Main Results:

    • A significant association was found between conduction disorders and P/LP carrier status (2.6% in BioVU, 1.5% in AoU).
    • Carrier probability increased with earlier age of conduction disorder onset and presence of HF, reaching up to 20.2% in young LBBB patients with HF.
    • P/LP carrier status in individuals with conduction disorders was linked to a higher risk of incident HF and adverse cardiovascular events (VA/SCD/mortality).

    Conclusions:

    • Adults with primary conduction disorders exhibit a higher prevalence of P/LP variants in cardiomyopathy genes, particularly when diagnosed at younger ages.
    • An interaction between P/LP carrier status and conduction disorders increases the risk of HF and other cardiovascular outcomes.
    • Genetic evaluation in patients with primary conduction disorders, especially younger individuals and those with HF, may help predict long-term outcomes.
    Abstract

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