Plakophilin-2 (PKP2) is the most frequently mutated desmosomal gene in arrhythmogenic cardiomyopathy (ACM), a disease characterized by structural and electrical alterations predominantly affecting the right ventricular myocardium. Notably, ACM cases without overt structural alterations are frequently reported, mainly in the early phases of the disease. Recently, the PKP2 p.S183N mutation was found in a patient affected by Brugada syndrome (BS), an inherited arrhythmic channelopathy most commonly caused by sodium channel gene mutations. We here describe a case of a patient carrier of the same BS-related PKP2 p.S183N mutation but with a clear diagnosis of ACM. Specifically, we report how clinical and molecular investigations can be integrated for diagnostic purposes, distinguishing between ACM and BS, which are increasingly recognized as syndromes with clinical and genetic overlaps. This observation is fundamentally relevant in redefining the role of genetics in the approach to the arrhythmic patient, progressing beyond the concept of “one mutation, one disease”, and raising concerns about the most appropriate approach to patients affected by structural/electrical cardiomyopathy. The merging of genetics, electroanatomical mapping, and tissue and cell characterization summarized in our patient seems to be the most complete diagnostic algorithm, favoring a reliable diagnosis.

中文翻译：

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临床和分子数据定义了 Brugada 综合征相关 PKP2 突变携带者的致心律失常性心肌病的诊断

Plakophilin-2 (PKP2) 是致心律失常性心肌病 (ACM) 中最常见的桥粒基因突变，ACM 是一种以结构和电学改变为特征的疾病，主要影响右心室心肌。值得注意的是，没有明显结构改变的 ACM 病例经常被报道，主要是在疾病的早期阶段。最近，在一名受 Brugada 综合征 (BS) 影响的患者中发现了 PKP2 p.S183N 突变，这是一种最常由钠通道基因突变引起的遗传性心律失常性离子通道病。我们在这里描述了一个具有相同 BS 相关 PKP2 p.S183N 突变但明确诊断为 ACM 的患者携带者病例。具体来说，我们报告了如何将临床和分子研究整合到诊断目的，区分 ACM 和 BS，越来越多地被认为是临床和遗传重叠的综合征。这一观察结果与重新定义遗传学在治疗心律失常患者的方法中的作用有着根本的相关性，超越了“一种突变，一种疾病”的概念，并引发了对最适合受结构性/电心肌病影响的患者的方法的担忧。在我们的患者中总结的遗传学、电解剖图以及组织和细胞特征的合并似乎是最完整的诊断算法，有利于可靠的诊断。并提出对受结构性/电性心肌病影响的患者的最合适方法的担忧。在我们的患者中总结的遗传学、电解剖图以及组织和细胞特征的合并似乎是最完整的诊断算法，有利于可靠的诊断。并提出对受结构性/电性心肌病影响的患者的最合适方法的担忧。在我们的患者中总结的遗传学、电解剖图以及组织和细胞特征的合并似乎是最完整的诊断算法，有利于可靠的诊断。