Prevalence and Clinical Impact of Pathogenic Variants in Cardiomyopathy Genes Among Individuals with Cardiac Conduction Disorders
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Importance Cardiac conduction disorders have traditionally been regarded as a secondary manifestation of underlying structural heart diseases. However, isolated conduction disorders may precede the onset of heart failure (HF) suggesting shared mechanisms. Objective To evaluate the prevalence and clinical significance of pathogenic/likely pathogenic (P/LP) rare variants in cardiomyopathy genes among individuals with conduction disorders. Design, Setting, and Participants Biobank analysis of 192,834 participants with whole genome sequence data from Vanderbilt’s BioVU and 353,092 participants from the All of Us Research Program ( AoU ). Participants with primary conduction disorder (left bundle branch block [LBBB], right bundle branch block [RBBB], high-grade atrioventricular block [AVB]) were identified after excluding secondary causes. Exposures P/LP variants in cardiomyopathy genes. Main Outcomes and Measures Primary outcome was P/LP carrier status by age and HF status. Secondary outcomes included incident HF and composite ventricular arrhythmias/sudden cardiac death/mortality (VA/SCD/mortality). Results Among 16,959 participants with conduction disorders in BioVU and 13,442 in AoU , 432 (2.6%) and 206 (1.5%) were P/LP carriers, respectively. Conduction disorder was independently associated with carrier status (BioVU p<0.001; AoU p=0.005). Carrier probability varied by age at conduction disorder onset and HF status. Among participants with HF at age 30 years, predicted carrier probability for LBBB was 7.5% in BioVU and 20.2% in AoU ; for high-grade AVB, 7.7% and 8.5%, respectively, compared with 3.7% and 2.9% among those with HF without conduction disorder. P/LP carrier status among participants with conduction disorders was associated with increased risk of incident HF (BioVU p<0.001; AoU p<0.001) and ventricular arrhythmia/sudden death/mortality (BioVU p<0.001; AoU p<0.001). Carriers also demonstrated increased susceptibility to conduction disorder following HF diagnosis, including more than two-fold higher risk of third-degree AVB (BioVU aOR 2.48, 95% CI 1.85–3.32; AoU aOR 2.26, 95% CI 1.35–3.80). Conclusions Adults with primary conduction disorders have an increased prevalence of P/LP variants in cardiomyopathy genes, which is most pronounced with diagnoses at early ages of adulthood. Furthermore, there is evidence of an interaction between P/LP carrier status and conduction disorder to increase HF risk and composite cardiovascular outcomes, underscoring the potential role of genetic evaluation in patients with primary conduction disorders to inform long-term outcomes. Key Points Question What is the prevalence of pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy genes among individuals with cardiac conduction disorders, and are carriers at increased risk for adverse cardiovascular outcomes? Findings In this biobank study of 192,834 participants with whole genome sequence data from Vanderbilt’s BioVU and 353,092 participants from the All of Us Research Program, conduction disorder was independently associated with P/LP carrier status, with predicted carrier probability reaching up to 20% among young participants with concurrent heart failure. Carriers with conduction disorder had higher risk of incident heart failure and ventricular arrhythmias, sudden cardiac death, or mortality. Meaning These findings suggest that genetic testing may be warranted in patients with conduction disorder, particularly younger individuals, and those with heart failure.
Source: medRxiv
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Heart Association, Vanderbilt University, Vanderbilt University Medical Center, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1435936284, Pharmacogenomics of Arrhythmia Therapy, Illinois Precision Medicine Consortium , G1531600799, G1766209448, G1846282300, G2103760183, Understanding the genetic risk underlying racial disparities in uterine fibroids, G2615776415, G2683268942, G3272238124, Improving Prediction of Drug Action, G3395468139, G3619590958, G364208108, G3791753988, G3938985443, G4049315607, G4198746417, Automated Storage and Retrieval of Biological Systems, G4395870004, G4410787187, University of Arizona-Banner Health All of Us Research Program , G560889077, G5679716143, G5717004637, Genetic Epidemiology of Multiple Sclerosis, Clinical Outcomes for Genetic Subtypes of Early-onset Atrial Fibrillation Across Diverse Genetic Ancestries, G6173849340, All of Us Pennsylvania, G6589054092, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment, G7163342664, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Vanderbilt Genome Electronic Records Project, G8098630230, Epidemiologic Architecture for Genes Linked to Environment (EAGLE), G8332127685, Vanderbilt Institute for Clinical and Translational Research (VICTR)
OpenAlex ID: W7164820642