부산대학교 도서관

Introduction: Arrhythmogenic cardiomyopathy (ACM) is associated with genetic variants in desmosome genes. Incidental findings of pathogenic/likely pathogenic (P/LP) variants in these genes, primarily loss-of-function (LOF) variants, are recommended for clinical return; however, their prevalence and associated phenotype in a general clinical population are not well characterized. Hypothesis: Individuals with LOF variants in ACM genes have a distinct electronic health record (EHR) phenotype. Methods: From whole exome sequencing of 61,019 individuals in the Geisinger MyCode project, we identified LOF (frameshift, stop gain, splice site) variants in PKP2 , DSC2 , DSG2 , DSP , and JUP. Missense variants in these genes (plus TMEM43) with a two-star P/LP rating in Clinvar were also retained. These individuals were age- and sex-matched to controls lacking such variants. Encounter diagnoses in the EHR were compared between groups by Phenome-wide Association (PheWAS). The most recent resting 12-lead electrocardiograms (ECG) and Holter monitor reports were manually reviewed (blinded to group) to evaluate ACM diagnostic criteria. Finally, we estimated expected penetrance using Bayesian inference. Results: 152 individuals (58 ± 18 years; 33% male) were identified with an ACM variant. None of these individuals had an existing diagnosis of ACM in the EHR. PheWAS showed no significant associations of any other EHR diagnoses with ACM variants. Over 80% of individuals had a previous ECG, and four individuals with an ACM variant satisfied a major criterion for repolarization abnormalities; however, this prevalence matched controls (Table). Findings of other ECG/Holter criteria were also no different and did not coincide with repolarization criteria for ACM variant cases. Combining our observed genetic prevalence (0.25% of the MyCode population) with disease prevalence estimates (1 in 5000; 58% with genetic variant), yields a penetrance estimate of 4.7%. Conclusions: The prevalence of ACM LOF variants is approximately 1:400 in a general clinical population, but there is no evidence of phenotypic association in the EHR, consistent with a low penetrance estimate. Prospective clinical evaluation is therefore needed. [ABSTRACT FROM AUTHOR]