Identification of established arrhythmogenic right ventricular cardiomyopathy mutation in a patient with the contrasting phenotype of hypertrophic cardiomyopathy

Matthew Neil Bainbridge, Lili Li, Yanli Tan, Benjamin Y. Cheong, Ali J. Marian

Advances in the nucleic acid sequencing technologies have ushered in the era of genetic-based "precision medicine". Applications of the genetic discoveries to practice of medicine, however, are hindered by phenotypic variability of the genetic variants. The report illustrates extreme pleiotropic phenotypes associated with an established causal mutation for hereditary cardiomyopathy. We report a 61-year old white female who presented with syncope and echocardiographic and cardiac magnetic resonance (CMR) imaging findings consistent with the diagnosis of hypertrophic cardiomyopathy (HCM). The electrocardiogram, however, showed a QRS pattern resembling an Epsilon wave, a feature of arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole exome sequencing (mean depth of coverage of exons 178X) analysis did not identify a pathogenic variant in the known HCM genes but identified an established causal mutation for ARVC. The mutation involves a canonical splice accepter site (c.2146-1G > C) in the PKP2 gene, which encodes plakophillin 2. Sanger sequencing confirmed the mutation. PKP2 is the most common causal gene for ARVC but has not been implicated in HCM. Findings on echocardiography and CMR during the course of 4-year follow up showed septal hypertrophy and a hyperdynamic left ventricle, consistent with the diagnosis of HCM. However, neither baseline nor follow up echocardiography and CMR studies showed evidence of ARVC. The right ventricle was normal in size, thickness, and function and there was no evidence of fibro-fatty infiltration in the myocardium. The patient carries an established pathogenic mutation for ARVC and a subtle finding of ARVC but exhibits the classic phenotype of HCM, a contrasting phenotype to ARVC. The case illustrates the need for detailed phenotypic characterization for patients with hereditary cardiomyopathies as well as the challenges physicians face in applying the genetic discoveries in practicing genetic-based "precision medicine".