Prevalence and Electronic Health Record-Based Phenotype of Loss-of-Function Genetic Variants in Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes

Abstract

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with variants in desmosome genes. Secondary findings of pathogenic/likely pathogenic variants, primarily loss-of-function (LOF) variants, are recommended for clinical reporting; however, their prevalence and associated phenotype in a general clinical population are not fully characterized.

Methods: From whole-exome sequencing of 61 019 individuals in the DiscovEHR cohort, we screened for putative loss-of-function variants in PKP2, DSC2, DSG2, and DSP. We evaluated measures from prior clinical ECG and echocardiograms, manually over-read to evaluate ARVC diagnostic criteria, and performed a PheWAS (phenome-wide association study). Finally, we estimated expected penetrance using Bayesian inference.

Results: One hundred forty individuals (0.23%; 59±18 years old at last encounter; 33% male) had an ARVC variant (G⁺). None had an existing diagnosis of ARVC in the electronic health record, nor significant differences in prior ECG or echocardiogram findings compared with matched controls without variants. Several G⁺ individuals satisfied major repolarization (n=4) and ventricular function (n=5) criteria, but this prevalence matched controls. PheWAS showed no significant associations of other heart disease diagnoses. Combining our best genetic and disease prevalence estimates yields an estimated penetrance of 6.0%.

Conclusions: The prevalence of ARVC loss-of-function variants is ≈1:435 in a general clinical population of predominantly European descent, but with limited electronic health record-based evidence of phenotypic association in our population, consistent with a low penetrance estimate. Prospective deep phenotyping and longitudinal follow-up of a large sequenced cohort is needed to determine the true clinical relevance of an incidentally identified ARVC loss-of-function variant.

Keywords: desmosomes; echocardiography; electronic health records; genomics; whole exome sequencing.

Figure 1.

A) Phenome-wide Association (PheWAS) analysis comparing unrelated individuals in DiscovEHR 60k cohort carrying ARVC LOF variants and remaining cohort without ARVC LOF variants. No significant associations were found for any phenotypes with ARVC variant status. B) PheWAS analysis comparing subset of individuals with LOF variants in PKP2 gene against remaining cohort without ARVC LOF variants; again no significant associations with cardiovascular disease were observed. ARVC: Arrhythmogenic right ventricular cardiomyopathy; LOF: loss of function.