en Medical Genetics Medical Genetics Original Research: Basic Science in Medicine Original Research: Basic Science in Medicine <strong>Background: </strong>Arrhythmogenic ventricular cardiomyopathy (AVC) is an inherited cardiac disorder affecting 1 in 1000 individuals worldwide. The mean diagnosed age of disease is 31 years. In this article, an Iranian family reported that they were affected by ARVC due to a novel PKP2 mutation.<br> &nbsp;&nbsp; <strong>Methods:</strong> Clinical evaluations, 12-lead ECG, CMR, and signal-averaged ECG were performed. After DNA extraction, genetic testing was done, and PCR-sequencing was applied to find causal mutations. Segregation analysis was also performed for the family.<br> <strong>&nbsp;&nbsp; Results</strong>: ARVC criteria were documented in the patients. Genetic testing revealed a novel chain termination mutation (p.Tyr168Ter) in PKP2 gene; this mutation was transmitted from the mother to her 23-year-old son, but only the son was affected with ARVC.<br> <strong>&nbsp;&nbsp; Conclusion</strong>: Modifier genes were indicated using interactome analysis of Plakophilin 2 protein (PKP2); they might have led to phenotypic variability through cellular mechanisms, such as nonsense-mediated mRNA decay. At least, 9 proteins were identified that might have affected Plakophilin 2 protein function, and consequently, rationalizing this intrafamilial phenotypic variability. This study highlighted the role of modifier genes involved in ARVC as well as the major role of PKP2 mutation in developing the disease in our population.<br> &nbsp; ARVC/D, PKP2 gene, Phenotypic variability 22 26 http://mjiri.iums.ac.ir/browse.php?a_code=A-10-3658-1&slc_lang=en&sid=1 Nejat Mahdieh nmahdieh@gmail.com 200319475328460036712 200319475328460036712 No Cardiogenetic Research Laboratory, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran & Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran. Sedigheh Saedi saedised@gmail.com 200319475328460036713 200319475328460036713 No Cardiogenetic Research Laboratory, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran & Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran. Mahdieh Soveizi MAHTA_SH2@GMAIL.COM 200319475328460036714 200319475328460036714 No Cardiogenetic Research Laboratory, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran. Bahareh Rabbani baharehrabbani@yahoo.com 200319475328460036715 200319475328460036715 No Cardiogenetic Research Laboratory, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran & Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran & Growth and development Research Center, Tehran University of Medical Sciences, Tehran, Iran. Nasim Najafi nasnajafi@gmail.com 200319475328460036716 200319475328460036716 No Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Scienc-es, Tehran, Iran. Majid Maleki mmcardiacrhc@gmail.com 200319475328460036717 200319475328460036717 Yes Cardiogenetic Research Laboratory, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran & Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.