Unique genetic background and outcome of non-Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy
Authors: Seiko Ohno
Takeshi Aiba
Minoru Horie
Yuko Wada
Journal: Molecular genetics & genomic medicine (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Arrhythmogenic right ventricular dysplasia/cardiomyopathy; genetics; phenotype; prognosis; racial difference.
Affiliations: Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan., Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

Abstract:  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 (PKP2), desmoglein 2 (DSG2), desmoplakin (DSP), and desmocollin 2 (DSC2) 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; DSG2 was predominant (48% of mutations) followed by PKP2 (38%). DSG2 mutations were almost missense, whereas over 90% of PKP2 mutations were truncating mutations. Lethal ventricular arrhythmias (VAs, 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 VAs onset compared to missense mutation carriers or mutation negatives (age at onset 35 ± 12, 49 ± 16, and 50 ± 19 years, respectively, P &lt; 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 VAs, and especially for onset by their 40s, in an age-dependent manner (RR = 4.6, P &lt; 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 DSG2 leading to modest outcome, whereas PKP2 truncating mutations were the second most and might be a strong marker for lethal VAs in non-Caucasian Japanese ARVD/C probands. 

Retracted: No

PubPeer comments:
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 There are several concerns about the data in Figures 3A and 4B. The red line (Truncating group) in Fig. 3A is very similar to the yellow line (Single missense group) in Fig. 4B, which may actually indicate Truncating group. Even if that is the case, these lines are not perfectly fit to each other. In Fig. 4B, the sample size of (probably) Single missense group (N=14) is estimated as Nu226516 from the purple line. The missense mutation carriers shown in Fig. 3A (blue line, Non-truncating) were separated into two groups; Single missense (probably purple) and Multiple missense (probably red) in Fig. 4B. However, the blue line in Fig. 3A is not in agreement with the data combining purple and red lines in Fig. 4B. ![file] , 
 The authors applicate careful and detailed inquiries about our paper. We apologize for the lateness of the response. As all authors looked through the original data, we found several errors as the inquiry. During correction, we also found other small numerical errors as well. Currently we are processing to re-submit an erratum to the u201cMolecular Genetics and Genomic Medicineu201d regarding all the comments we have had here. Numbers in Table1 have some errors. Some of them had occurred during revision by demoting one founder mutation (DSG2 D494A) into non-pathogenic mutation. Also authors would like to state statistics employed in the amended tables as below: u201cFor continuous variables, Wilcoxon rank sum test between two groups or Kruskal-Wallis test among three groups were employed as appropriate. Steel-Dwass test was added after Kruskal-Wallis test as a post-hoc analysis. For categorical variables, Chi-squared test or Fisheru2019s exact test was employed as appropriate. Among three groups, logistic regression analysis was added after Chi-squared test.u201d In some variables, several cases had lacked the electrocardiogram to test u201cMajor repolarization anomalyu201d or u201cMajor repolarization anomalyu201d and also the cardio-imaging to test u201cMajor structural anomalyu201d. In those variables in Table1 and Table3, authors clarified parameters and appropriate ratio in the same cell. The lack of clinical testing in these cases did not interfere with patientsu2019 diagnosis. Regarding the number differences between patient numbers and first manifestations in total and mutation negative columns, we did not include the asymptomatic patient in the first manifestation. In the amended Table1, authors added a new variable u201cAsymptomaticu201d. After the correction, there are no new critical differences found in terms of the main point of the paper. ![file] ![file] , 
 #2 Numbers in Table3 have some errors as well, for the same reason as those in Table1. The authors have corrected Table3 as the attached. After the correction, there are no new critical differences found in terms of the main point of the paper. ![file] ![file] , 
 #3 Please see the reply to the comments #1-2. ![file] , 
 #4 Kaplan-Meier curves of truncating mutation carriers (red line in original Figure3A and yellow line in original Figure4B) were originally identical. However, for the same reason as above mentioned change, the Figure 3A and Figure4B should have been corrected as the attached. ![file] ,