Abstract 4127919: Disease-associated variants in DSP -encoded desmoplakin are common, yet low penetrant alleles associated with development of myocarditis and cardiomyopathy at a population level

encoded desmoplakin is implicated in a distinct form of arrhythmic cardiomyopathy (ACM), often involving the LV and characterized by myocardial inflammation. Conventional ACM diagnostic criteria has poor sensitivity for -associated ACM, thus highlighting the need to identify the full spectrum of phenotypic risk associated with disease-associated variants. To analyze the genotypic and phenotypic spectrum of -mediated disease at a large population level. UK Biobank participants with exome sequencing (ES) were included. Variants were filtered by gene evidence category, yielding 3 groups: predicted deleterious (pDel); subset with predicted loss of function (LOF); and ultra-filtered subset by ClinVar 2* pathogenic/likely pathogenic (P/LP). Phenotypic penetrance was analyzed with -neg individuals as control. Variant location analysis assessed LOFs by susceptibility to nonsense mediated decay region and missenses by amino acid sequence to identify mutational hotspots where P/LPs localize. Out of 200,580 with ES, 1407 carriers had pDel, 168 with LOF, and 44 with ClinVar 2* P/LP. carriers had higher burden of myocarditis, cardiomyopathy (CM), and heart failure. A progressive enrichment in myocarditis and CM was observed by more stringent variant filtering in carriers compared to control. A higher proportion of carriers had myocarditis – 0.28% (4) of the pDels, 1.8% (3) of LOFs, and 4.5% (2) compared to control 0.07% (p<0.05). A parallel trend noted the proportion of carriers with CM growing from 1.4% (19) to 5.4% (9) and 6.8% (3) in the pDel, LOF, and ClinVar 2* P/LPs respectively compared to 0.6% in the control group (p<0.01). Location analysis of missense variants revealed that P/LPs localized in higher proportions (74%) to key domains compared to non-P/LPs (50%; p<0.001), highlighting prognostic value of predicting pathogenicity of missense variants by mutation hotspots. While variants are relatively common in the population, variant presence is associated with low penetrance. Enhancing clinical penetrance with increasingly stringent filtering of variants emphasizes the importance of variant evaluation in clinical risk assessment. This first-in-kind population study of provides insights into novel risk prediction factors, allowing us to predict pathogenicity by type and location of mutation and using variant filtering strategy to better assess phenotypic penetrance.

Duke Scholars

Author Andrew Paul Landstrom Pediatrics, Cardiology