| Title: | Disease Penetrance and Phenotypic Spectrum of Desmoplakin Variant Carriers in the Population |
| Journal: | Heart Rhythm |
| Published: | 21 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41130550/ |
| DOI: | https://doi.org/10.1016/j.hrthm.2025.10.043 |
Publication 16689
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Abstract
BACKGROUND: Desmoplakin (DSP) variants cause arrhythmogenic cardiomyopathy, a disorder characterized by myocardial fibrosis, arrhythmias, and sudden cardiac death. DSP-mediated arrhythmogenic cardiomyopathy often involves left ventricular dysfunction and myocardial inflammation, yet existing diagnostic criteria may underdetect disease, underscoring the need for population-based penetrance estimates.</p>
OBJECTIVE: This study aimed to assess the prevalence and phenotypic penetrance of DSP variants in a genotyped population.</p>
METHODS: Among 200,580 UK Biobank participants with exome sequencing, DSP variants were classified as predicted deleterious (pDel), predicted loss of function (pLOF), or ClinVar 2∗ pathogenic/likely pathogenic (P/LP). A subset of pDel carriers underwent electrocardiographic (ECG) and cardiac magnetic resonance testing, matched to genotype-negative controls. Phenotypic penetrance was assessed using the International Classification of Diseases, Tenth Revision, diagnoses, ECG, and cardiac magnetic resonance imaging. Variant clustering within functional DSP domains was also evaluated.</p>
RESULTS: Of 200,580 participants, 1407 (0.7%) carried a pDel, 168 (0.08%) a pLOF, and 44 (0.02%) a ClinVar 2∗ P/LP DSP variant. Myocarditis occurred in 0.28% of pDel, 1.8% of pLOF, and 4.5% of ClinVar P/LP carriers vs 0.07% of controls (P < .05). Cardiomyopathy prevalence increased from 1.4% (pDel) to 5.4% (pLOF) and 6.8% (P/LP) vs 0.6% in controls (P < .01). DSP carriers had more frequent lateral T-wave inversions and abnormal left ventricular strain. Missense variants clustered within 2 functional DSP domains.</p>
CONCLUSION: DSP pDel variants are common but show low penetrance for myocarditis and cardiomyopathy, with risk increasing with more stringent classification. ECG and strain abnormalities may aid early detection, supporting genotype-first approaches for DSP interpretation.</p>
12 Authors
- Manasa Gurumoorthi
- Ghaith Sharaf Dabbagh
- Rachel Wolfe
- Kerrick Hesse
- Ravi Shah
- Leonie Kurzlechner
- Kanishk Yadav
- Brittany Balint
- Babken Asatryan
- Farah Sheikh
- C Anwar A Chahal
- Andrew P Landstrom
1 Application
| Application ID | Title |
|---|---|
| 48286 | Do persons with epilepsy (PWE) have known pathogenic mutations in ion channel or other known sudden cardiac arrest-related genes at a greater frequency than non-epileptics? |
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