Hereditary sick sinus syndrome – phenotypic spectrum, genetic basis, cellular dysfunction and implications for therapy

窦病综合征（SSS）是一种常见的临床疾病，发病率和死亡率都很高，是电子起搏器植入的主要指征。然而，SSS的发病机制尚不完全清楚。此外，目前对SSS患者的评估和治疗决策主要基于临床症状，而没有考虑基于机制的方面。我们和其他人证明，SSS至少部分源于不同的遗传缺陷和/或易感的遗传星座，但迄今为止还没有对遗传性SSS的机制进行全面评估。鉴于家族性SSS的广泛表型谱，包括重叠心律失常综合征和结构性心脏异常，我们假设特定的遗传缺陷是不同临床特征的关键。我们建立了一个临床定义明确的原发性SSS患者的大队列。在预备候选基因方法中，我们已经确定了起搏器基因HCN4的新突变，将基于我们最近开发的特异性生成人类ipsc衍生起搏器细胞的方法，使用体外SSS疾病模型对其进行深入的功能表征。下一步，我们将进行RNA测序，以描绘与ipsc衍生的起搏器细胞分化有关的重要途径，以揭示新的，但未知的起搏器相关靶点和SSS的潜在机制。与携带已鉴定的致病性HCN4突变的起搏器细胞进行比较转录组分析将为HCN4相关转录网络提供新的见解。为了在我们的患者登记中识别潜在的新型SSS突变和疾病基因，我们将应用下一代和全外显子组测序。确定的突变将在分子和电生理水平上表征。我们的目标是建立一个全面的分类遗传性SSS为未来，个性化的临床评估基于机制特异性疾病概况。

Sick sinus syndrome (SSS) is a frequent clinical entity with significant morbidity and mortality, which is a major indication for the implantation of electronic pacemakers. However, the pathogenetic mechanisms underlying SSS are incompletely understood. Furthermore, current assessment and therapeutic decision making of SSS patients is largely based on clinical symptoms and does not consider mechanism-based aspects. We and others demonstrated that SSS at least in parts originates from distinct genetic defects and/or predisposing genetic constellations, but a comprehensive assessment of mechanisms underlying hereditary SSS is not available to date. Given the broad phenotypic spectrum of familial SSS including overlapping arrhythmia syndromes and structural cardiac abnormalities, we hypothesize that specified genetic defects are key to distinct clinical profiles. We have established a large cohort of clinically well-defined patients with primary SSS. In a preparatory candidate gene approach we have identified novel mutations in the pacemaker gene HCN4, which will be subjected to in-depth functional characterization using an in vitro SSS disease model on the basis of our recently developed approach to specifically generate human iPSC-derived pacemaker cells. In a next step we will perform RNA sequencing to delineate pathways importantly implicated in the cellular differentiation of iPSC-derived pacemaker cells to unveil novel, yet unknown pacemaker relevant targets and potential mechanisms for SSS. Comparative transcriptome analysis with pacemaker cells carrying the identified pathogenic HCN4 mutations will provide novel insight into HCN4-related transcriptional networks. To identify potentially novel SSS mutations and disease genes within our patient registry we will apply next-generation and whole exome sequencing. Identified mutations will be characterized at molecular and electrophysiological levels. Our goal is to establish a comprehensive classification of hereditary SSS for future, individualized clinical assessment based on mechanism-specific disease profiles.