Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes

Abstract

Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System. In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes. This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.

Identification of potential candidate genes and pathways in atrioventricular nodal reentry tachycardia by whole‐exome sequencing

“…Because the disease information of UK Biobank was not specific enough, we chose the only known AVNRT genetic sequencing study to further validate our candidate pathogenic genes. The study, published in 2018, was carried out in Denmark, and 67 known arrhythmia target genes were detected in AVNRT cases by next‐generation sequencing 13 . Among our candidate genes, SCN1A, RYR2 , and PRKAG2 , there were 11 rare variants in SCN1A and three rare variants in RYR2 detected in AVNRT patients in the Danish study, especially, a rare variant in RYR2 (c.4652A > G, p.Asn1551Ser, rs185237690) in our present study was also found in one Danish AVNRT case, which supports SCN1A and RYR2 gene as candidate pathogenic genes in our study.…”

“…However, little is known about the hereditary role in AVNRT compared with that for Wolff‐Parkinson‐White syndrome 8,9 . A recent study involving the sequencing of 67 selected genes associated with arrhythmia in 298 AVNRT patients found the greatest number of variants in sodium and calcium channels, indicating that AVNRT might be an arrhythmic disease with abnormal sodium and calcium handling 13 . Among the reference genes from the present study, many rare variants were detected in KCNJ12, RYR3, RYR2, ZFHX3, ANK2, AKAP9, GNB3, SYNE2, CACNA1D, CACNA1I, GNB3, MYH6, SCN5A, SCN1A, SCN3A, HCN4 , and KCNH2 .…”

“…A total of 95 reference AVNRT genes were selected to detect rare variants in AVNRT cases and controls. The genes were elected based on the following criteria according to another pioneering study on gene rare variants in AVNRT 13 : (1) genes involved in PR interval in electrocardiogram identified by genome‐wide association studies, 14 (2) genes selected based on expression levels in human atrioventricular conduction axis, 15 (3) plausible genes based on protein function, and association with other cardiac diseases, especially arrhythmic diseases 13,16‐18 . Selected genes are listed in Supplementary Table S1.…”

Novel SCN5A Frameshift Mutation in Brugada Syndrome Associated With Complex Arrhythmic Phenotype

“…While it is certain that SCN5A mutations can cause BrS, it is less clear whether the SCN5A mutation described herein could be responsible for the other phenotypes. Variants in genes not tested for in our patients have been associated with AVNRT (Andreasen et al, 2018). Thus, we cannot rule out the existence of AVNRT-causing variants that were not detected in this study.…”

Clinical report of 8 families with atrioventricular nodal reentrant tachycardia from China

“…However, there is no report on the pathogenic gene of AVNRT. It was proposed that this disease with abnormal sodium and calcium handling by next-generation sequencing in 298 AVNRT patients [8]. Most recently, we first revealed potential candidate genes and pathways associated with the neuronal system or ion channels in AVNRT using whole-exome sequencing [9].…”