Disease Penetrance and Phenotypic Spectrum of Desmoplakin Variant Carriers in the Population.

Abstract

Background: Desmoplakin (DSP) variants cause arrhythmogenic cardiomyopathy (ACM), a disorder characterized by myocardial fibrosis, arrhythmias, and sudden cardiac death. DSP-mediated ACM often involves left ventricular (LV) dysfunction and myocardial inflammation, yet existing diagnostic criteria may underdetect disease, underscoring the need for population-based penetrance estimates.

Objective: 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-star pathogenic/likely pathogenic (P/LP). A subset of pDel carriers underwent ECG and CMR testing, matched to genotype-negative controls. Phenotypic penetrance was assessed using ICD-10 diagnoses, ECG, and CMR. 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 versus 0.07% of controls (p<0.05). Cardiomyopathy prevalence increased from 1.4% (pDel) to 5.4% (pLOF) and 6.8% (P/LP) versus 0.6% in controls (p<0.01). DSP carriers had more frequent lateral T-wave inversions and abnormal LV strain. Missense variants clustered within two functional DSP domains.

Conclusions: DSP pDel variants are common but show low penetrance for myocarditis and cardiomyopathy, with risk increasing with more stringent classification. Electrocardiographic and strain abnormalities may aid early detection, supporting genotype-first approaches for DSP interpretation.