Abstract 12832: Prediction of Pathogenicity of Plakophilin-2 Missense Mutations in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Introduction: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is considered a hereditary disease. Genetic screening identifies pathogenic mutations in the majority of ARVD/C patients. However, whilst pathogenicity of truncating or splice site mutations has been widely accepted, pathogenicity of missense variants remains controversial.
Aim: Assessment of pathogenicity of ARVD/C related missense variants and associated phenotypic characteristics.
Methods: Pathogenic mutations were identified in 571 patients (239 families, age 43±18 years) from US/Dutch ARVD/C cohorts by screening of desmosomal (PKP2, DSC2, DSG2, DSP, JUP)and/or nondesmosomal (PLN, TMEM43) genes. Patients with >1 mutation or variant were excluded. Missense variants were considered pathogenic when 1) both algorithms SIFT and PolyPhen-2 predicted pathogenicity (SIFT: tolerance index score ≤0.05, PolyPhen-2: pathogenicity score >0.90) and 2) minor allele frequency in 1000 genomes was <0.014. Survival and arrhythmic outcome was compared between missense and pathogenic non-missense (truncating and splice site) mutation carriers.
Results: A pathogenic missense mutation was identified in 86/571 patients (15%). Frequently occurring mutations were PKP2 c.2386T>C (p.Cys796Arg; 34/86) and DSG2 c.137G>A (p.Arg46Gln; 9/86). Survival curves (p=0.065), and more importantly, sustained arrhythmia (ventricular tachycardia/fibrillation or appropriate ICD therapy) free survival curves (p=0.810) of patients with a missense mutation were similar to those with pathogenic non-missense (330/571 truncating, 129/571 splice site) mutations (Fig 1).
Conclusion: ARVD/C related missense mutations have a similar pathogenic character as non-missense mutations regarding survival and substantial arrhythmic burden. Pathogenicity of missense mutations can be correctly predicted by the combined criteria from SIFT, PolyPhen-2, and 1000 genomes.
- © 2012 by American Heart Association, Inc.