Table_2_Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing.XLS

BackgroundAtrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia. Growing evidence suggests that family aggregation and genetic factors are involved in AVNRT. However, in families with a history of AVNRT, disease-causing genes have not been reported.
ObjectiveTo investigate the genetic contribution of familial AVNRT using a whole-exome sequencing (WES) approach.
MethodsBlood samples were collected from 20 patients from nine families with a history of AVNRT and 100 control participants, and we systematically analyzed mutation profiles using WES. Gene-based burden analysis, integration of previous sporadic AVNRT data, pedigree-based co-segregation, protein-protein interaction network analysis, single-cell RNA sequencing, and confirmation of animal phenotype were performed.
ResultsAmong 95 related reference genes, seven candidate pathogenic genes have been identified both in sporadic and familial AVNRT, including CASQ2, AGXT, ANK2, SYNE2, ZFHX3, GJD3, and SCN4A. Among the 37 reference genes from sporadic AVNRT, five candidate pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, ryanodine receptor 2 (RYR2), COL4A3, NOS1, and ATP2C2. To identify the common pathogenic mechanisms in all AVNRT cases, five pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, RYR2, COL4A3, NOS1, and ATP2C2. Considering the unique internal candidate pathogenic gene within pedigrees, three genes, TRDN, CASQ2, and WNK1, were likely to be the pathogenic genes in familial AVNRT. Notably, the core calcium-signaling pathway may be closely associated with the occurrence of AVNRT, including CASQ2, RYR2, TRDN, NOS1, ANK2, and ATP2C2.
ConclusionOur pedigree-based studies demonstrate that RYR2 and related calcium signaling pathway play a critical role in the pathogenesis of familial AVNRT using the WES approach.

背景：房室结折返性心动过速（Atrioventricular nodal reentrant tachycardia, AVNRT）是一种常见的心律失常。越来越多的证据表明，家族聚集性与遗传因素参与了房室结折返性心动过速的发病过程。然而，在存在房室结折返性心动过速家族史的家系中，尚未见致病基因的相关报道。
目的：采用全外显子组测序（Whole-exome sequencing, WES）技术探究家族性房室结折返性心动过速的遗传贡献度。
方法：本研究采集了9个存在房室结折返性心动过速家族史的家系中的20例患者以及100名对照受试者的血液样本，通过全外显子组测序系统分析其突变谱。随后开展了基于基因的负担分析、整合既往散发性房室结折返性心动过速数据集、基于家系的共分离分析、蛋白质相互作用网络分析、单细胞RNA测序，并对动物表型进行了验证。
结果：在95个相关参考基因中，共鉴定出7个在散发性与家族性房室结折返性心动过速中均存在的候选致病基因，分别为CASQ2、AGXT、ANK2、SYNE2、ZFHX3、GJD3及SCN4A。在源自散发性房室结折返性心动过速的37个参考基因中，有5个候选致病基因在家族性与散发性房室结折返性心动过速患者中均被检出，即LAMC1、兰尼碱受体2（Ryanodine receptor 2, RYR2）、COL4A3、NOS1及ATP2C2。为明确所有房室结折返性心动过速病例共有的致病机制，本研究鉴定出5个在家族性与散发性房室结折返性心动过速患者中均存在的致病基因，即LAMC1、RYR2、COL4A3、NOS1及ATP2C2。结合家系内特有的内部候选致病基因，TRDN、CASQ2及WNK1这3个基因可能为家族性房室结折返性心动过速的致病基因。值得注意的是，核心钙信号通路可能与房室结折返性心动过速的发生密切相关，涉及CASQ2、RYR2、TRDN、NOS1、ANK2及ATP2C2。
结论：本研究基于家系的全外显子组测序分析证实，RYR2及其相关的钙信号通路在家族性房室结折返性心动过速的发病机制中发挥关键作用。