부산대학교 도서관

Background:Monogenic disorders are relatively common in aggregate, affecting 1/40 individuals, but are underdiagnosed. Electronic health records (EHR) integrated with population-based genetic sequencing provides an opportunity to study the prevalence and penetrance of these disorders. We integrated EHR records with genetic sequencing and identified clinical phenotypes in carriers of rare variants in arrhythmia-related genes.Methods:Whole exome sequencing was performed on 8,783 individuals from the CATHGEN cohort, a study of sequential individuals undergoing cardiac catheterization at Duke University. Variants in 47 arrhythmia-related genes were identified and assessed for pathogenicity using the ClinVar database. ACMG criteria were applied to define pathogenic/likely pathogenic (P/LP) variants. Individuals carrying a P/LP variant were grouped by electrophysiologic (EP) disorder and matched 1:5 to noncarriers based on age, sex, and race. Individuals with other P/LP cardiovascular disease variants or variants of unknown significance in arrhythmia-related genes were excluded. Phenotypic data were annotated through curated and manual EHR review.Results:Forty P/LP variants in 10 arrhythmia-related genes were identified in 51 individuals. In the arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), and long QT syndrome (LQTS) groups, P/LP variant carriers met diagnostic criteria in 33%, 0%, and 4% of carriers, respectively. In the LMNA-related dilated cardiomyopathy (LMNA) group, 83% of variant carriers were phenotype positive. ECG findings alone were significantly different in variant carriers compared with noncarriers in the ARVC, BrS, and LQTS groups, whereas clinical outcomes including heart transplantation and ventricular tachycardia were significantly different in the LMNA group. Interestingly, clinical features associated with EP disorders, such as syncope and ICD implantation, were not significantly different between variant carriers and noncarriers in any group.Conclusions:Based on EHR review, P/LP variants in arrhythmia-related genes among individuals referred for cardiac catheterization are associated with variable phenotypic expression in different EP disorders.