BACKGROUND Arrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown. METHODS A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed. Real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. RESULTS The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (c.832delG) in Desmoplakin (DSP) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant plasmids expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin (JUP) and downregulation of β-catenin, when compared with WT. CONCLUSION We infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/β-catenin signaling pathway.

中文翻译：

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下一代测序技术在心律失常性心肌病患者中鉴定了新型的去氨铂金移码变异体。

背景技术心律失常性心肌病（AC）是心脏性猝死（SCD）的主要原因之一。最近的研究已经确定心脏桥粒中的突变是AC发病机理中的关键因素。但是，个别家庭的具体病因仍然未知。方法招募有晕厥，致死性室性心律不齐和SCD的4代家庭。进行有针对性的下一代测序（NGS），并通过Sanger测序验证。构建了含有突变和野生型（WT）的质粒。进行实时PCR，蛋白质印迹和免疫荧光检测突变引起的功能变化。结果该先证者是一名56岁的女性，表现出复发性心和晕厥。由于她的SCD家族史/ SCD流产而植入了ICD。NGS在5个家族成员中的Desmoplakin（DSP）中发现了一个新的杂合移码变体（c.832delG）。该变体导致移码和过早终止，产生截短的蛋白质。携带相同变异的家庭成员的心脏磁共振（CMR）显示右心室心肌变薄和脂肪浸润，双心室晚期late增强和严重RV功能障碍，满足AC的诊断标准。与野生型相比，用突变质粒转染的HEK293T细胞表达了截短的DSP mRNA和蛋白，核连接斑蛋白（JUP）的上调和β-catenin的下调。结论我们推断，DSP中的新型c.832delG变体与该家族中的AC相关，可能是通过Wnt /β-catenin信号通路引起的。