Bhuiyan Zahurul A, Jongbloed Jan D H, van der Smagt Jasper, Lombardi Paola M, Wiesfeld Ans C P, Nelen Marcel, Schouten Meyke, Jongbloed Roselie, Cox Moniek G P J, van Wolferen Marleen, Rodriguez Luz M, van Gelder Isabelle C, Bikker Hennie, Suurmeijer Albert J H, van den Berg Maarten P, Mannens Marcel M A M, Hauer Richard N W, Wilde Arthur A M, van Tintelen J Peter
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Circ Cardiovasc Genet. 2009 Oct;2(5):418-27. doi: 10.1161/CIRCGENETICS.108.839829. Epub 2009 Aug 1.
This study aimed to evaluate the prevalence and type of mutations in the major desmosomal genes, Plakophilin-2 (PKP2), Desmoglein-2 (DSG2), and Desmocollin-2 (DSC2), in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We also aimed to distinguish relevant clinical and ECG parameters.
Clinical evaluation was performed according to the Task Force Criteria (TFC). We analyzed the genes in (a) 57 patients who fulfilled the ARVD/C TFC (TFC+), (b) 28 patients with probable ARVD/C (1 major and 1 minor, or 3 minor criteria), and (c) 31 patients with 2 minor or 1 major criteria. In the TFC+ ARVD/C group, 23 patients (40%) had PKP2 mutations, 4 (7%) had DSG2 mutations, and 1 patient (2%) carried a mutation in DSC2, whereas 1 patient (2%) had a mutation in both DSG2 and DSC2. Among the DSG2 and DSC2 mutation-positive TFC+ ARVD/C probands, 2 carried compound heterozygous mutations and 1 had digenic mutations. In probable ARVD/C patients and those with 2 minor or 1 major criteria for ARVD/C, mutations were less frequent and they were all heterozygous. Negative T waves in the precordial leads were observed more (P<0.002) among mutation carriers than noncarriers and in particular in PKP2 mutation carriers.
Mutations in DSG2 and DSC2 are together less prevalent (10%) than PKP2 mutations (40%) in Dutch TFC+ ARVD/C patients. Interestingly, biallelic or digenic DSC2 and/or DSG2 mutations are frequently identified in TFC+ ARVD/C patients, suggesting that a single mutation is less likely to cause a full-blown ARVD/C phenotype. Negative T waves on ECG were prevalent among mutation carriers (P<0.002).
本研究旨在评估致心律失常性右室发育不良/心肌病（ARVD/C）患者主要桥粒基因盘状球蛋白2（PKP2）、桥粒芯糖蛋白2（DSG2）和桥粒胶蛋白2（DSC2）的突变率及突变类型。我们还旨在鉴别相关的临床和心电图参数。
根据工作组标准（TFC）进行临床评估。我们分析了以下三组患者的基因：（a）57例符合ARVD/C TFC的患者（TFC+），（b）28例可能患有ARVD/C的患者（1项主要标准和1项次要标准，或3项次要标准），以及（c）31例有2项次要标准或1项主要标准的患者。在TFC+ ARVD/C组中，23例患者（40%）有PKP2突变，4例（7%）有DSG2突变，1例患者（2%）携带DSC2突变，而1例患者（2%）同时有DSG2和DSC2突变。在DSG2和DSC2突变阳性的TFC+ ARVD/C先证者中，2例携带复合杂合突变，1例有双基因座突变。在可能患有ARVD/C的患者以及有2项次要标准或1项ARVD/C主要标准的患者中，突变频率较低，且均为杂合突变。与非携带者相比，尤其是PKP2突变携带者，突变携带者胸前导联出现负向T波的情况更多（P<0.002）。
在荷兰TFC+ ARVD/C患者中，DSG2和DSC2共同突变的发生率（10%）低于PKP2突变（40%）。有趣的是，在TFC+ ARVD/C患者中经常发现双等位基因或双基因座DSC2和/或DSG2突变，这表明单个突变不太可能导致典型的ARVD/C表型。心电图上的负向T波在突变携带者中很常见（P<0.002）。
