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PKP2 and DSG2 genetic variations in Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy registry patients.

ABSTRACT: OBJECTIVE:The Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD-C) registry was established to determine the genetic background of ARVD-C for analyzing discovered genetic variation frequencies in the European and Latvian populations. METHODS:In total, 38 patients with suspected ARVD-C were selected. The clinical parameters were defined according to the ARVD-C guidelines, PKP2 and DSG2 gene analysis was performed using the Sanger sequencing. Additionally, large deletions/duplications were analyzed using the multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS:Twenty symptomatic patients were enrolled in the study. Typical ARVD abnormalities were found in electrocardiography for 10 (50%) patients, in Holter monitoring for 19 (95%), in transthoracic echocardiography for 20 (100%), and in cardiac magnetic resonance for 6 (30%). Different benign genetic variations were found. Three novel, unregistered, possibly benign variations were found in the PKP2 gene: c.2489+131G>A, c.2489+72delA, and c.1035-5T>C and three in the DSG2 gene: c.404G>A, c.1107G>A, and c.379-15A>G. Two genetic variations in the PKP2 gene: c.1592T>G, c.2489+1G>A are possibly pathogenic. For the first time, variation c.1592T>G, has been discovered in the homozygote form. Using the MLPA analysis, large deletions or duplications were not found. CONCLUSION:The prevalence of the majority of non-pathological genetic variations is similar in the Latvian ARVD-C patients and the European population. Possibly, pathogenic variations were found only in 10% of our registry patients, which could mean that PKP2 and DSG2 are not the most commonly affected genes in the Latvian population.

SUBMITTER: Bidina L

PROVIDER: S-EPMC6280287 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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PKP2 and DSG2 genetic variations in Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy registry patients.

Bidina Luize L Kupics Kaspars K Sokolova Emma E Pavlovics Mihails M Dobele Zane Z Caunite Laima L Kalejs Oskars O Gailite Linda L

Anatolian journal of cardiology 20181101 5

<h4>Objective</h4>The Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD-C) registry was established to determine the genetic background of ARVD-C for analyzing discovered genetic variation frequencies in the European and Latvian populations.<h4>Methods</h4>In total, 38 patients with suspected ARVD-C were selected. The clinical parameters were defined according to the ARVD-C guidelines, PKP2 and DSG2 gene analysis was performed using the Sanger sequencing. Additionally, larg ...[more]

PMID: 30391969

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Project description: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 < 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 < 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.

Project description:Purpose To determine the incidence of ventricular fatty replacement and late gadolinium enhancement (LGE) at cardiac magnetic resonance (MR) imaging in patients with arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) and the relationship of these findings to disease severity. Materials and Methods This was a retrospective institutional review board-approved HIPAA-compliant study. All subjects provided written informed consent. Seventy-six patients with ARVD/C were enrolled from 2002 to 2012. Quantitative and qualitative cardiac MR imaging analyses of the RV and the left ventricle (LV) were performed to determine cardiac MR imaging-specific Task Force Criteria (TFC) and non-TFC features (ARVD/C-type pattern of fatty infiltration and/or nonischemic pattern LGE). Patients were separated into four groups on the basis of cardiac MR imaging TFC: (a) patients with major cardiac MR imaging criteria, (b) patients with minor criteria, (c) patients with partial criteria, and (d) patients with no criterion. Continuous variables were compared by using the independent Student t test and analysis of variance. Categoric variables were compared by using the Fisher exact test. Results Of 76 patients (mean age, 34.2 years ± 14 [standard deviation]; 51.3% men), 42 met major cardiac MR imaging criteria, seven met minor criteria, seven met partial criteria, and 20 met no criterion. Most probands (36 [80.0%] of 45) met major or minor cardiac MR imaging criteria. Only 13 (41.9%) of 31 family members met any cardiac MR imaging criterion. The most common non-TFC MR imaging features were RV fatty infiltration (28.9%) and LV LGE (35.5%). Non-TFC cardiac MR imaging features were seen in 88.1% of subjects with major criteria, in 28.6% of those with minor criteria, in 71.4% of those with partial criteria, and in 10.0% of those with no criteria. Conclusion In this large cohort of patients with ARVD/C, non-TFC findings of ventricular fatty infiltration and LGE were frequent and were most often found in those who met major cardiac MR imaging criteria and in probands. (©) RSNA, 2016 Online supplemental material is available for this article.

Project description:Background Despite growing use of the subcutaneous implantable cardioverter-defibrillator (S- ICD ), its clinical role in arrhythmogenic right ventricular cardiomyopathy/dysplasia ( ARVC /D) patients remains undefined. We aim to elucidate the cardiac phenotype, implant characteristics, and long-term efficacy regarding appropriate therapy and complications in ARVC /D patients with an S- ICD implant. Methods and Results A transatlantic cohort of ARVC /D patients who underwent S- ICD implantation was analyzed for clinical characteristics, S- ICD therapy, and long-term outcome including device-related complications. The cohort included 29 patients (52% male, 76% probands, 59% with ARVC /D-associated mutation, 59% primary prevention [no prior sustained ventricular arrhythmias], and 45% first-generation S- ICD devices). At implant, all inducible patients (27/29) had conversion of induced ventricular fibrillation. Two patients (7%) had superficial infections of the incision site that were treated conservatively. Over a median follow-up of 3.16 years (interquartile range: 2.21-4.51 years), all episodes (6 patients, 4% per year) of sustained ventricular arrhythmias were appropriately detected and treated. Six patients (21%) experienced 39 inappropriate shocks, with 3 requiring device explantation. Oversensing of noncardiac signal (n=4; especially myopotentials) and cardiac signal (n=4) was the most frequent etiology. No lead or device dislodgement, infection, skin erosion, or explantation related to need for antitachycardia pacing was noted. Conclusions S- ICD can effectively treat both induced and spontaneous ventricular arrhythmias in patients with ARVC /D. The rate of inappropriate shocks, although considerable, is comparable to that in ARVC /D patients treated with transvenous ICD s. When they occurred, inappropriate shocks were primarily due to cardiac and, uniquely, noncardiac oversensing. We suggest potential strategies for minimizing inappropriate therapy.

Dataset Information

PKP2 and DSG2 genetic variations in Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy registry patients.

Publications

PKP2 and DSG2 genetic variations in Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy registry patients.

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