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Updated: May 16, 2025

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

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Prevalence of deleterious cardiomyopathy variants in early-onset atrial fibrillation

Quim Bech Vilaseca, Oliver Bundgaard Vad, Christian Paludan-Müller

    Medrxiv : the Preprint Server for Health Sciences
    |March 31, 2025
    PubMed

    Insights

    Genetic variants in cardiomyopathy genes are common in early-onset atrial fibrillation (AF). This finding supports genetic testing and cardiomyopathy screening for individuals diagnosed with AF at a young age.

    Area of Science:

    • Cardiovascular Genetics
    • Cardiac Arrhythmias
    • Genetic Cardiology

    Background:

    • Atrial fibrillation (AF) is a prevalent arrhythmia linked to significant health risks, including stroke and heart failure.
    • Emerging evidence suggests early-onset AF may indicate a higher risk for heart failure and dilated cardiomyopathy.
    • Identifying genetic predispositions in early-onset AF is crucial for understanding disease mechanisms and risk stratification.

    Purpose of the Study:

    • To investigate the prevalence of genetic variants in cardiomyopathy-associated genes within a cohort of early-onset atrial fibrillation patients.
    • To analyze the relationship between age of AF onset and the presence of rare, potentially deleterious genetic variants.

    Main Methods:

    • Targeted sequencing of 29 cardiomyopathy genes in 478 early-onset AF patients from a Danish cohort.
    • Whole exome sequencing analysis of 374,289 individuals from the UK Biobank, including 29,108 with AF.
    • Focus on rare, loss-of-function truncating variants and deleterious missense variants, stratified by age of AF onset.

    Main Results:

    • A significant proportion (8.8%) of early-onset AF patients in the Danish cohort carried truncating variants in cardiomyopathy genes.
    • The UK Biobank analysis revealed a decreasing prevalence of truncating variants with increasing age of AF onset (3.8% for onset <45 years vs. 1.4% in controls).
    • A similar pattern was observed for the prevalence of rare missense variants.

    Conclusions:

    • Deleterious genetic variants in cardiomyopathy-associated genes are highly prevalent in individuals with early-onset AF.
    • These findings support current guidelines recommending genetic evaluation for early-onset AF.
    • Genetic testing and cardiomyopathy surveillance are warranted for selected patients diagnosed with AF at a young age.
    Abstract

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