Open AccessUnique genetic background and outcome of non‐Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy
Author(s) -
Wada Yuko,
Ohno Seiko,
Aiba Takeshi,
Horie Minoru
Publication year - 2017
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.311
Subject(s) - missense mutation , medicine , proband , arrhythmogenic right ventricular dysplasia , cardiomyopathy , cardiology , mutation , gastroenterology , genetics , heart failure , biology , gene
Background Arrhythmogenic right ventricular dysplasia/cardiomyopathy ( ARVD /C) is an inherited cardiomyopathy mainly caused by desmosomal gene mutation. More than half of Caucasian probands have desmosomal mutations, which lead to earlier onset of ventricular arrhythmias. Among non‐Caucasians, the genetic background of ARVD /C probands and its prognostic impact remain unclear. Methods and Results We genotyped 99 unrelated Japanese ARVD /C probands for plakophilin 2 ( PKP 2 ), desmoglein 2 ( DSG 2 ), desmoplakin ( DSP ), and desmocollin 2 ( DSC 2 ) between 2005 and 2014. Seventy‐five probands who fulfilled “definite” category according to the 2010 Task Force Criteria ( TFC ) were enrolled and followed up for 6.4 years. Sixty‐four percent of probands had desmosomal mutations; DSG 2 was predominant (48% of mutations) followed by PKP 2 (38%). DSG 2 mutations were almost missense, whereas over 90% of PKP 2 mutations were truncating mutations. Lethal ventricular arrhythmias ( VA s, sustained ventricular tachycardia/fibrillation) occurred in 57% of probands as the first manifestation and 71% at the end of follow‐up. Five died during follow‐up. Truncating mutation carriers exhibited earlier lethal VA s onset compared to missense mutation carriers or mutation negatives (age at onset 35 ± 12, 49 ± 16, and 50 ± 19 years, respectively, P < 0.05 in each). Cox proportional hazard analysis revealed for the first time that, compared to mutation negatives, truncating mutation carriers had higher risk for lethal VA s, and especially for onset by their 40s, in an age‐dependent manner ( RR = 4.6, P < 0.01 by their 40s; RR = 2.9, P = 0.01 by their 50s). Conclusion The genetic background of Japanese ARVD /C probands is distinct from that of Caucasian probands, leading to distinct prognosis. The most affected gene mutations in Japanese probands were missense mutations in DSG 2 leading to modest outcome, whereas PKP 2 truncating mutations were the second most and might be a strong marker for lethal VA s in non‐Caucasian Japanese ARVD /C probands.