The Genetics and Epigenetics of Ventricular Arrhythmias in Patients Without Structural Heart Disease

Authors, Journal, Affiliations, Type, DOI

• Mengru Wang and Xin Tu
• Frontiers in Cardiovascular Medicine, Vol 9, Article 891399, June 2022
• Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
• Narrative review; PubMed database search to 2021 using terms "idiopathic ventricular arrhythmias", "genetics", "epigenetics", "DNA methylation"
• DOI: https://doi.org/10.3389/fcvm.2022.891399

Overview

A comprehensive 2022 narrative review covering the monogenic, polygenic, and epigenetic basis of ventricular arrhythmias in structurally normal hearts, encompassing LQTS, BrS, SQTS, CPVT, IVF, and idiopathic RVOT-VT. The genetics section provides a 30+ gene reference table (Table 2) cataloguing all major arrhythmia genes by ion current type, functional effect, phenotype, and frequency. The epigenetics section is the most distinctive contribution of the paper, systematically reviewing five regulatory mechanisms: non-coding RNA (miR-19b, circulating miRNAs, U1 snRNA/KCNH2 splicing), DNA methylation (SCN5A H558R, KCNQ1OT1 imprinting), histone modifications (KChIP2/H3K4me3, HEY2 regulation), genomic imprinting (KCNQ1OT1-KCNQ1 axis), and 3D genome architecture (SCN10A enhancer-SCN5A promoter loop, CTCF loops). This is a medium-quality review — useful for its structured synthesis and gene table, but limited by its 2021 search date, minimal critical appraisal, and reliance on largely preclinical findings.

Keywords

gene, pathogenesis, non-structural ventricular arrhythmias with genome, ventricular arrhythmias, non-structural heart disease

Key Takeaways

Genetic Factors — Monogenic

Sodium Ion Channel Genes

• SCN5A (Nav1.5): GOF mutations → LQTS (5–10%); LOF mutations → BrS (20–25%). SCN5A is the most commonly mutated gene in non-structural VA. Additional roles: LQTS, isolated conduction defect, AF, DCM, multifocal ectopic Purkinje-related complexes.
• SCN1B/SCN2B/SCN3B (β-subunits 1–3): LOF → reduced Nav1.5 cell surface expression → BrS (all rare).
• SCN4B (β-subunit 4, LQT10): GOF → late INa increase → LQTS (rare). L179F mutation identified.
• GPD1L (A280V mutation): reduces SCN5A membrane expression → reduced INa → BrS (rare).
• RANGRF/MOG1 (Nav1.5 co-factor): dominant-negative mutations → impaired Nav1.5 trafficking → BrS (rare). MOG1 is also the target of AAV9 gene therapy for BrS.
• SCN10A (Nav1.8): co-expression with SCN5A increases INa; R14L/R1268Q mutations → LOF of Nav1.5 → BrS (~10%). Most SCN10A variants are common population variants, limiting pathogenicity assignment.

Potassium Ion Channel Genes

• HCN4: If↓ → idiopathic ventricular tachycardia (IVT) — rare.
• Ito channels (BrS): Three genes encode subunits of the Ito channel complex:
  • KCND3 (Kv4.3, α-subunit): GOF → Ito↑ → BrS. Arg431His mutation increases membrane protein expression of Kv4.3 without affecting mRNA level. Rare.
  • KCNE3 (MiRP2, β-subunit): GOF Arg99His (R99H) → when co-expressed with KCND3, significantly increases Ito compared to WT KCNE3+KCND3 → BrS. Rare.
  • KCNE5 (MiRP4, β-subunit): X-linked; when co-expressed with KCND3, BrS-associated mutations upregulate Ito vs wild type → BrS and IVF. Rare.
• IKs channels (LQTS/SQTS): KCNQ1 (LQTS 30–35%; SQTS rare — GOF); KCNE1 (LQTS rare — LOF). KCNQ1 A341V + AKAP9 variant interaction → enhanced QTc prolongation (genetic modifier concept).
• IKr channels (LQTS/SQTS): KCNH2 (LQTS 25–30% — LOF; SQTS rare — GOF); KCNE2 (LQTS rare — LOF).
• Kir channels: KCNJ2 (SQTS — GOF/IK1↑; LQTS rare — LOF; Andersen-Tawil syndrome — LOF); KCNJ5 (LQTS rare — IKACh↓); KCNJ8 (BrS rare — IKATP↑); ABCC9 (BrS rare — IKATP↑; ClinGen-disputed).

Calcium Channel and Handling Genes

• CACNA1C (Cav1.2, LQT8): GOF exon 8 → Timothy syndrome (severe LQTS + multiorgan dysfunction); other exon GOF → LQTS without TS (1–2%); LOF → BrS (1–2%).
• CACNB2: LOF → ICaL↓ → BrS (1–2%; ClinGen-disputed).
• CACNA2D1: LOF → BrS/SQTS susceptibility (rare).
• RYR2 (ryanodine receptor): GOF → CPVT (55–60%); LOF variants → Ca²⁺ release deficiency and IVF (rare) — and unusually a LOF D3291V mutation causes a CPVT phenotype by reducing luminal Ca²⁺ sensitivity. GOF/LOF phenotype correlation still being defined.
• CASQ2 (calsequestrin-2): buffers SR Ca²⁺ and inhibits RYR2 via triadin/junctin signalling; LOF → CPVT (<5%).
• TRDN (triadin): anchors CASQ2 to junctional SR; deficiency → reduced RYR2/CASQ2/junctin protein → defective EC coupling → CPVT and LQTS (1–2%).
• CALM1–3 (calmodulin 1–3): Ca²⁺ sensor binding to both LTCC and RYR2; LOF of Ca²⁺-binding → eliminates Ca²⁺-dependent LTCC inactivation → LQTS; dysregulation of RYR2 Ca²⁺ release → CPVT (both rare).

Other Related Genes

• SNTA1 (α-1 syntrophin, LQT12): GOF → INa↑ → LQTS (rare).
• SLMAP: Nav1.5 intracellular transport regulator; LOF → reduced INa → BrS (rare).
• PKP2 (plakophilin-2): desmosomal protein; PKP2 deletion → decreased INa → BrS association (rare; ClinGen-disputed in BrS; definitive in ARVC).
• ANK2 (ankyrin-2/ankyrin-B, LQT4): LOF (E1425G) → impaired coordination of multiple ion channels → LQTS (rare).
• CAV3 (caveolin-3): scaffold protein in cardiomyocyte caveolae; GOF → INa↑, ICaL↑, IK↓, Ito↓ → LQTS (rare).
• TECRL (TERL): ER-localized oxidoreductase; AR disease; homozygous pathogenic variants → reduced RYR2 and CASQ2 protein levels → reduced SR calcium storage and aberrant calcium handling → mixed phenotype of CPVT and LQTS (rare). ClinGen Definitive for AR CPVT3.
• SLC4A3 (AE3 anion exchanger): Cl⁻/HCO₃⁻ exchange; mutations → increased intracellular pH → QT shortening in zebrafish → SQTS (rare).
• TRPM4 (non-selective Ca²⁺-activated cation channel): both GOF and LOF variants reported in BrS and LQTS — paradoxical bidirectional mutation-phenotype relationship. ClinGen-refuting for BrS (12/2025).

IVF-Specific Genes

• DPP6: promotes surface expression of KCND2 (Kv4.2 — Ito channel); DPP6 haplotype and mutation → disturbed K⁺ efflux → IVF (unknown frequency).
• IRX3 (Iroquois homeodomain transcription factor, His-bundle specific): mutations → downregulation of SCN5A and connexin-40 mRNA → IVF (unknown frequency).

Somatic Mutations (RVOT-VT)

• GNAI2 (F200L): found in biopsy from RVOT-VT origin but not remote myocardium → increases intracellular cAMP → inhibits adenosine-mediated cAMP suppression → adenosine-insensitive RVOT-VT (rare).
• ADORA1 (R296C): somatic mutation at VT origin → RVOT-VT; exact mechanism unclear (rare).
• GNAS (W234R, Gs-alpha): somatic mutation at VT origin only → impairs GTP hydrolysis → elevated basal cAMP → increased ICaL → DADs and triggered activity → RVOT-VT (rare). In silico modelling confirmed triggered activity mechanism.

Genetic Factors — Polygenic

• Single SCN5A mutation in a Dutch family caused both LQTS and BrS — same gene, opposite phenotypes, illustrating functional pleiotropy.
• KCND3+SCN5A interaction: Nav1.5 and Kv4.3 regulate each other through trafficking and gating — compound heterozygosity can amplify severity.
• Digenic LQTS (SCN5A R800L + SNTA1 A261V): family members carrying both mutations had the strongest clinical phenotype.
• BrS polygenic architecture: GWAS identified SCN5A-SCN10A locus (rs10428132), HEY2 (rs9388451), and SCN5A (rs11708996) as independently associated with BrS susceptibility; cumulative effect confirmed. Barc 2022 GWAS confirmed that mutation accumulation effects correlate with BrS clinical traits — polygenic risk validated.
• AKAP9 (scaffolding protein) variants alter QTc and cardiac event risk in KCNQ1 A341V carriers — genetic modifier concept.
• NOS1AP rs12143842 T allele significantly associated with reduced risk of IVT in Northern Chinese cohort.

Epigenetic Factors

Non-coding RNA

miR-19b — Multi-channel Regulator and LQTS Candidate

• miR-19b deficiency in zebrafish: significantly prolonged action potential duration, severe bradycardia, arrhythmia susceptibility, cardiomyopathy — phenocopying LQTS.
• Targets multiple ion channel-related genes simultaneously:
  • SCN1B (Na channel β1 subunit): directly regulated by miR-19b; upregulated upon miR-19b loss → increased late INa → prolonged APD.
  • KCNE4 and KCNE1: upregulated upon miR-19b reduction → impaired cardiac repolarization by inhibiting KCNQ1 → reduced IKs → prolonged AP and bradycardia.
  • KCNA4 and KCND3: downregulated indirectly → reduced Ito → increased stage 1 AP potential.
  • CACNA1C and SCN12B: also indirectly downregulated by miR-19b reduction.
• miR-19b reduction can rescue SQTS phenotype in heterozygous zebrafish — bidirectional relevance (LQTS and SQTS).

Circulating miRNAs — Disease Markers

• miR-133: elevated in plasma of pediatric patients with VT (without organic heart disease) vs healthy controls — potential paediatric VT biomarker.
• miR-320: significantly higher in IVT patients vs ACM patients — may distinguish idiopathic VT from arrhythmogenic cardiomyopathy using a simple plasma marker.
• Mutation detection has been reported in the UTR regions of SCN5A and SCN1B — miRNA binding sites within arrhythmia gene UTRs may modulate expression.

U1 snRNA and KCNH2 Splicing Regulation

• KCNH2 intron 9 is inefficiently spliced in human heart: only 1/3 of precursor mRNA → functional Kv11.1a; 2/3 → non-functional C-terminal truncated Kv11.1a-USO isoform.
• U1 snRNA (the RNA component of U1 small nuclear ribonucleoprotein) recognises the 5' splice site of intron 9 — the degree of U1 snRNA–splice site complementarity determines splicing efficiency.
• KCNH2 IVS9-2delA mutation found in a large LQTS family: switches all functional Kv11.1a isoform production to non-functional Kv11.1a-USO.
• Therapeutic concept: modifying U1 snRNA sequence to improve complementarity to the KCNH2 intron 9 5' splice site → significantly improved splicing efficiency → increased functional Kv11.1a expression → increased IKr current. A potential RNA-based therapy for IVS9-2delA LQTS.

DNA Methylation

SCN5A H558R — Epigenetic-Genetic Modifier of BrS

• SCN5A H558R (rs1805124) is a common polymorphism functioning as a genetic modifier of BrS: it improves abnormal channel gating kinetics and membrane trafficking in pathogenic SCN5A mutation carriers, reducing phenotypic severity.
• Mechanistically, H558R reduces methylation of the SCN5A promoter → increases SCN5A expression in cardiac tissue → prevents VF. This is an epigenetic (methylation-mediated) mechanism in addition to direct protein-protein functional rescue.
• The G allele of H558R is associated with QTc prolongation in population studies — reflecting its pleiotropic effects on sodium channel function.

KCNQ1OT1/KCNQ1 — Imprinting and QT Interval

• KvDMR1 is a differentially methylated region within the KCNQ1 locus that regulates KCNQ1, long non-coding RNA KCNQ1OT1, and CDKN1C (Table 1).
• KCNQ1OT1 only expresses the paternal allele (promoter located within KvDMR1 — maternally methylated/silenced). KCNQ1OT1 coordinates chromatin conformation changes and histone modifications to regulate KCNQ1 spatiotemporal expression.
• KCNQ1 is biallelic in adult heart and fetal heart (unlike other tissues where it shows maternal imprinting) — KCNQ1OT1-mediated regulation explains why KCNQ1-LQTS appears largely autosomal dominant rather than maternally transmitted.
• KCNQ1OT1 rs11023840 AA genotype increases KCNQ1OT1 promoter methylation → prolonged QTc interval in symptomatic patients — direct methylation-phenotype link.
• ATO-induced LQTS: Arsenic trioxide (ATO — used for acute promyelocytic leukaemia) decreases KCNQ1OT1 transcription → KCNQ1OT1 silencing inhibits KCNQ1 expression → prolonged AP duration in vitro and LQTS in vivo. ATO also induces miR-133 and miR-1 dysregulation: miR-133 inhibits ERG protein (KCNH2 product) → reduced IKr; miR-1 downregulates Kir2.1 (KCNJ2 product) → reduced IK1 → QT prolongation.

Histone Modifications

KChIP2 and H3K4me3

• H3K4me3 (active trimethylation of histone H3 at lysine 4) plays a pivotal role in maintaining KChIP2 gene expression in differentiated cardiomyocytes.
• Decreased H3K4me3 → reduced KChIP2 expression → attenuated Ito and INa → prolonged APD → increased ICaL and enhanced cardiac contractile function.
• KChIP2 is heterogeneously expressed in human and mouse ventricular walls, contributing to the transmural Ito gradient (epicardium > endocardium). KChIP2 deficiency in mice eliminates fast Ito entirely and confers susceptibility to VT.
• No KChIP2 coding mutations have been associated with human cardiac disease — but epigenetic regulation of KChIP2 expression via H3K4me3 may influence arrhythmia susceptibility.

HEY2 and H3K4me3/H3K27ac

• HEY2 is a BrS susceptibility gene (GWAS-validated) that regulates SCN5A expression and cardiac conduction system formation, as well as expression of transmural potassium channels (Kcnip2, KCND2) — affecting transmural Ito and INa electrophysiological gradients.
• H3K4me3 and H3K27ac (active histone marks) bind to the HEY2 promoter or enhancer, regulating HEY2 transcription and thus ventricular myocyte depolarization and repolarization.

Genomic Imprinting

• KCNQ1 and KCNQ1OT1 are imprinted genes within the same locus; KCNQ1OT1 uses differential methylation/chromatin conformation to modulate KCNQ1 spatiotemporal expression.
• Despite KCNQ1OT1 regulation making LQTS appear autosomal dominant, clinical reports still document some female predominance and maternal transmission distortion in KCNQ1-LQTS patients — likely reflecting residual genomic imprinting effects or incomplete tissue-specific switching.
• Methylation state of KCNQ1OT1 (rs11023840 AA genotype) independently associated with prolonged QTc — imprinting methylation variation as a continuous clinical risk modifier.

Three-Dimensional Genome Architecture

SCN10A Enhancer–SCN5A Promoter Loop

• The SCN10A intronic enhancer (ENHA) physically interacts with the SCN5A promoter in 3D chromatin space — necessary for normal SCN5A in vivo expression.
• The major allele G of common SNP rs6801957 (within ENHA) establishes a conserved T-box transcription factor binding site that promotes enhancer activity.
• The risk allele significantly reduces SCN5A expression — providing a mechanistic explanation for the GWAS association of SCN10A variants with both QRS prolongation and BrS susceptibility.

CTCF/Cohesin Chromatin Loops

• CTCF and cohesin assemble 3D chromatin loops and maintain topological domain boundaries that restrict interactions between functional genomic elements.
• CTCF knockout → dysregulated expression of RYR2, KCND2, KCNQ1, SCN5A, CACNB1 in the ventricle → heart failure, suggesting a potential broader arrhythmia susceptibility mechanism.
• CTCF binding site variants in arrhythmia-relevant genes have not been reported in non-structural VA but represent a plausible mechanism.

KCNH2 Locus Enhancer

• A conserved cardiac cis-acting element in the KCNH2 locus acts as an enhancer and regulates KCNH2 expression through physical proximity to the KCNH2 promoter.
• Common LQTS-associated variants at the KCNH2 locus (identified by GWAS) may disrupt this enhancer, providing a functional mechanism for polygenic QT regulation.

Limitations of the document

• Narrative review; no PRISMA methodology or study quality assessment; heavily descriptive.
• PubMed search only (to 2021); some epigenetic findings are based on single studies with limited sample sizes.
• Most epigenetic findings from zebrafish or murine models — human translation unconfirmed.
• Somatic mutation data (RVOT-VT) based on single small studies.
• Gene table (Table 2) includes genes with disputed ClinGen validity (ABCC9, SCN4B, PKP2, TRPM4) without flagging this; frequency data may be outdated.
• ATO-induced LQTS findings from guinea pig models; direct relevance to clinical LQTS mechanism uncertain.

Key Concepts Mentioned

• concepts/Epigenetics-Cardiac-Arrhythmia — entire epigenetics section: miR-19b, U1 snRNA/KCNH2 splicing, H558R methylation, KCNQ1OT1 imprinting, KChIP2/H3K4me3, HEY2 regulation, SCN10A 3D enhancer loop
• concepts/Ion-Channel-Mutations — comprehensive Table 2 gene reference across all ion channel classes
• concepts/GWAS-Cardiac-Genetics — BrS polygenic GWAS (SCN5A-SCN10A/HEY2); NOS1AP-IVT association; KCNH2 locus GWAS enhancer

Key Entities Mentioned

• entities/Brugada-Syndrome — KCND3/KCNE3/KCNE5 Ito GOF channels; somatic GNAI2/ADORA1/GNAS in RVOT-VT; H558R as BrS genetic-epigenetic modifier; SCN10A enhancer-SCN5A loop; polygenic BrS GWAS loci
• entities/Long-QT-Syndrome — KCNQ1/KCNH2/SCN5A genotypes and frequencies; miR-19b LQTS mechanism; U1 snRNA/KCNH2 splicing; KCNQ1OT1 imprinting and ATO-LQTS; H558R as QTc modifier
• entities/CPVT — RYR2/CASQ2/TRDN/CALM1-3 gene summary; TECRL mixed CPVT/LQTS phenotype (homozygous variants reduce RYR2/CASQ2 protein levels); RYR2 LOF associated with Ca²⁺ release deficiency/IVF
• entities/RYR2 — CTCF knockout dysregulates RYR2 expression; RYR2 GOF (CPVT 55–60%); RYR2 LOF (IVF, rare; D3291V unique LOF-CPVT phenotype)
• entities/SCN5A — SCN5A H558R promoter methylation modifier; SCN10A ENHA-SCN5A promoter physical interaction

Wiki Pages Updated

• wiki/sources/genetics-va-fcvm-2022.md (created)
• wiki/concepts/Epigenetics-Cardiac-Arrhythmia.md (created — new)
• wiki/entities/CPVT.md (updated — TECRL mixed CPVT/LQTS phenotype and mechanism)
• wiki/entities/Brugada-Syndrome.md (updated — KCNE3, KCNE5 Ito channels; SCN5A H558R methylation modifier)
• wiki/sourceindex.md (updated)
• wiki/wikiindex.md (updated — new Epigenetics-Cardiac-Arrhythmia row)