Distinguishing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia–Associated Mutations From Background Genetic Noise

Abstract

Objectives: We sought to determine the spectrum and prevalence of “background genetic noise” in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide interpretation of a positive test. Background: ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibro-fatty tissue replacement of the right ventricle. Genetic variation among the ARVC-susceptibility genes have not been systematically examined and little is known about the “background noise” associated with the ARVC genetic test. Methods: Using direct DNA sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from The Netherlands and 427 ostensibly healthy controls of various ethnicities. 82 additional ARVC cases were obtained from the literature and additional mutations were included from the ARVC Genetic Variants Database. Results: The overall yield of mutations among ARVC cases was 58% versus 16% in controls. 0.5% of control individuals versus 43% of ARVC cases hosted radical mutations, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2. Conclusions: This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC-susceptibility genes. Radical mutations are high probability ARVC-associated mutations whereas rare missense mutations should be interpreted in the context of race/ethnicity, mutation location, and sequence conservation.