Disease penetrance and phenotypic spectrum of desmoplakin variant carriers in the population.

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. OBJECTIVE: This study aimed to assess the prevalence and phenotypic penetrance of DSP variants in a genotyped population. 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. 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. 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.

Duke Scholars

Author Andrew Paul Landstrom Pediatrics, Cardiology