Idetification of CACNA1B (p.K567R) mutation responsible for familiar AVNRT

Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of paroxysmal supraventricular tachycardia (PSVT). The exact cause of AVNRT has not yet been found. However, an increasing number of reports suggest that AVNRT is hereditary, but no precise pathogenic gene has been found so far. In our study, we found that a point mutation of CACNA1B (p.K567R) which encoded the α1 subunit of N-type calcium channel (Cav 2.2), was cosegregated with AVNRT in one family. Previous research showed that overexpression and point mutations of human CACNA1B in zebrafish embryos may be related to abnormal heart rate. Telemetric ECG recordings showed that rats with a CACNA1B point mutation displayed sporadic supraventricular tachycardia and altered QRS complex morphology. In addition, the CACNA1B (p.K567R) rats presented a double path phenomenon and AVNRT induction by intracardiac electrophysiological examination. Indexes of heart rate variance in CACNA1B mutation rats showed an in cardiac sympathetic activity and an imbalance of cardiac sympathetic and parasympathetic activity. Single-cell RNA sequencing indicated that the number of neurons in the superior cervical ganglion (SCG) of mutant rats was higher than in wild-type (WT) rats, accompanied by an increased expression of CACNA1B . Functional enrichment in SCG proteomics suggests that point mutant rats have abnormalities in synaptic function and ion transport, which could lead to the release of neurotransmitters. This could affect the cardiac autonomic neural activity and lead to an imbalance in sympathetic and parasympathetic activity and the subsequent occurrence of AVNRT. Our findings indicate that CACNA1B (p.K567R) is the pathogenic gene of AVNRT in familial AVNRT and confirm that CACNA1B is the first definitive AVNRT pathogenic gene that has been discovered. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from the Chinese National Natural Science Foundation (No. 81770379, 32171182, 81470521, and 81670290). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committee of the Sichuan Academy of Medical Sciences and the Sichuan Provincial People Hospital gave ethical approval for this work（No.2021-239）. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript.