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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.

Background: Atrioventricular 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., Objective: To investigate the genetic contribution of familial AVNRT using a whole-exome sequencing (WES) approach., Methods: Blood 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., Results: Among 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 ., Conclusion: Our 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Luo, Zheng, Cao, Zhu, He, Liu, Yang, Wu and Li.)

We report a three-generation family coming from southeastern region of Poland (Podkarpackie voivodship) with 6 women having normal hearts and presenting with a history of paroxysmal tachycardia with onset of symptoms in the adulthood. Recordings of clinical SVT, dual AVN electrophysiology, induction of typical AVNRT and results of RFCA are available. The history of this family shows the significance of a careful and detailed collection of medical history, and point towards the importance of family screening in AVNRT patients.