Cardiac arrhythmias and genetics – current stage

Authors, Journal, Affiliations, Type, DOI

• Sven Dittmann, Janis Kerkering, Eric Schulze-Bahr
• medizinische genetik 2025; 37(2): 125–136
• Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Germany; ERN Reference Centre Guard-Heart
• Narrative review article
• DOI: https://doi.org/10.1515/medgen-2025-2006

Overview

A current-state review of inherited cardiac arrhythmias from a cardiogenetics perspective, authored by the University of Münster IfGH group. The review covers the genetic basis, diagnostic yield, and clinical utility of genetic testing in LQTS, Brugada syndrome, CPVT, and SQTS, and summarises ClinGen-curated gene lists. It also addresses the emerging need for dedicated interdisciplinary cardiogenetic centres, variant reclassification, and future directions including polygenic risk scores and whole genome sequencing.

Keywords

Inherited cardiac arrhythmias; Cardiac ion channel disorders; Cardiogenetics; Long-QT syndrome; Sudden cardiac death; SCD

Key Takeaways

Epidemiology and Genetic Architecture

• Inherited cardiac arrhythmias are rare (prevalence <1:2,000), predominantly autosomal dominant "primary electrical heart disorders" diagnosed by ECG in the absence of structural heart disease.
• Most pathogenic variants are "private" (family-specific); allelic heterogeneity is extreme (>650 KCNQ1 variants, >300 KCNH2 variants).
• Variant detection rates (sensitivity of genetic testing) differ substantially across syndromes: LQTS 70–80%, CPVT 50–60%, BrS 20–30%, SQTS 25%, IVF/AF 10–20%.
• Phenotypic expressivity ranges from non-penetrance to high penetrance; environmental triggers (genotype-specific) modulate clinical risk.

Genetic Testing Methods

• NGS (multi-gene panels) has replaced Sanger sequencing; WGS is superior to WES for detecting structural variants (SVs, CNVs) and non-coding variants.
• Large panels/WES increase yield of variants of uncertain significance (ACMG class 3) and incidental findings — requiring expert bioinformatic interpretation.
• Genetic testing recommendations per EHRA/HRS/APHRS/LAHRS consensus: Class I for LQTS, BrS (type 1 ECG), CPVT, SQTS; Class IIa for adult-onset IVF, scTdP, MEPPC; Class IIb for BrS type 2/3 ECG, SIDS/SADS, familial SND, familial AF; Class III for early repolarisation syndrome.

Long-QT Syndrome (LQTS)

• QTc >450 ms (males) or >460 ms (females) is indicative; overlap with normal population exists.
• Schwartz Score (≥3.5 = diagnostic) incorporates ECG, clinical and family history criteria; indicative genetic result now accepted as diagnostic in recent ESC guidelines.
• In a cohort of 1,710 LQTS cases: mean QTc 471±45 ms, but a large portion had QTc <460 ms (47% LQT1, 36% LQT2, 35% LQT3).
• Asymptomatic family members with normal QTc (< 440–460 ms) who carry a pathogenic variant have a tenfold increased cardiac event risk vs. non-carriers.
• ClinGen 2020 (Adler et al.) confirmed only 3 definitive isolated LQTS genes: KCNQ1 (~35%), KCNH2 (~30%), SCN5A (~10–15%). CACNA1C definitive for Timothy syndrome, CALM1/2/3 definitive for neonatal/calmodulinopathy LQTS.
• Drug-induced QTc prolongation is genetic in only 10–15% of cases ("unmasked hidden LQTS").

Brugada Syndrome (BrS)

• Diagnosed when spontaneous type 1 ECG (J-point ≥2 mm, descending ST, negative T in V1/V3) is present, OR inducible type 1 + cardiac arrest/VF (ESC Class I).
• Shanghai Diagnostic Score: ≥3.5 = definitive BrS; 2–3 = possible/suspected. Incorporates clinical features beyond the type 1 ECG to address phenocopies.
• SCN5A is the only core gene (AD); implicated in 20–30% of BrS. A 2019 study (Campuzano et al.) also identified SLMAP, SEMA3A, SCNN1A, and SCN2B as additional BrS-related genes.
• SCN5A variant finding and polygenic risk scores (PRS from GWAS) may play prognostic role in future — clinical evaluation ongoing.
• Prevalent ~1:2,000; higher in Asian countries; symptomatic patients typically male in 3rd–4th decade.

CPVT and Ca²⁺ Release Deficiency Syndrome (CRDS)

• Bidirectional or polymorphic VT during physical/emotional stress; baseline ECG normal. Mortality 30–50% by age 35 if untreated; onset typically before age 10.
• RYR2 gain-of-function (autosomal dominant): ~50–60% of cases (CPVT1). CASQ2 loss-of-function (autosomal recessive): ~5%, more severe and beta-blocker resistant.
• ClinGen definitive CPVT genes: RYR2, CASQ2, TECRL, TRDN. Moderate evidence: CALM1/2/3, TRDN. Disputed: KCNJ2, PKP2, SCN5A.
• Ca²⁺ Release Deficiency Syndrome (CRDS): A newly established RYR2 loss-of-function phenotypic spectrum — distinct from CPVT. Associated with short-coupled ventricular torsade-de-pointes arrhythmias (not exercise-induced); some with LVNC overlap (RYR2 exon 3 deletion). CRDS patients do not show typical exercise-induced arrhythmias.
• Beta-blockers primary prevention; flecainide add-on; LCSD for refractory cases; ICD as last resort.

Short-QT Syndrome (SQTS)

• Very rare (<1:10,000); can present with syncope, paroxysmal AF, VF, or SCD; ~30% of patients have SCA/SCD as first manifestation.
• Diagnostic criteria vary: HRS/EHRA/APHRS: QTc ≤330 ms, or 330–360 ms + ≥1 additional feature; ESC SCD: QTc ≤340 ms (Class I); ESC VA/SCD: QTc ≤320 ms or 320–360 ms + gene/family/SCA.
• ClinGen: four core genes — KCNH2 (definitive), KCNQ1 (moderate), KCNJ2 (moderate), SLC4A3 (moderate). SLC4A3 loss-of-function disrupts membrane anion exchange → intracellular alkalinisation → shortened AP duration.
• Phenocopies to exclude: carnitine deficiency, hyperparathyroidism, Klinefelter syndrome, digitalis intoxication, hyperthermia, certain drugs (rufinamide, levcromakalim).
• ICD is first-line; quinidine is the pharmacological option.

Cardiogenetic Services and Variant Reclassification

• Interdisciplinary cardiogenetic centres integrate cardiac electrophysiology, imaging, genetics, and genetic counselling under one roof with an accredited genetic laboratory.
• Variant reclassification rate >36% over time (cardiomyopathies 28%, channelopathies 38%), driven by additional case information, functional data, population databases. Primarily results in downgrading of pathogenicity (per ACMG criteria).
• Clinical geneticists are responsible for communicating reclassification to variant carriers and healthcare professionals.
• Polygenic risk scores (PRS) remain under evaluation for arrhythmia syndromes; a UK Biobank study (>26,000 participants) showed PRS contributed to 21% of individuals with QTc >480 ms alongside monogenic variants.

Limitations of the Document

• Narrative review without systematic literature search; selection of cited studies reflects author expertise.
• German healthcare context influences some access and reimbursement discussion (not directly generalizable).
• Phenotypic data rely on cited cohort studies of varying size; some variant detection rates have wide confidence intervals.
• Variant reclassification rates cited from single studies and may not represent all patient populations.

Key Concepts Mentioned

• concepts/Cascade-Family-Screening — arrhythmia-specific cascade genetic screening, role in cardiogenetic centres
• concepts/Cardiogenetic-Centers — interdisciplinary care model introduced
• concepts/Variant-Reclassification — >36% reclassification rate across channelopathies
• concepts/Schwartz-Score — diagnostic scoring in LQTS and SQTS
• concepts/Shanghai-Score-System — diagnostic scoring in BrS
• concepts/Sudden-Cardiac-Death — cross-syndrome risk context
• concepts/iPSC-Derived-Cardiomyocytes — mentioned as disease model platform

Key Entities Mentioned

• entities/Long-QT-Syndrome — detailed genetics, ClinGen gene curation, asymptomatic carrier risk
• entities/Brugada-Syndrome — SCN5A, Shanghai score, polygenic risk scores
• entities/CPVT — RYR2/CASQ2, CRDS introduced, ClinGen curation
• entities/Short-QT-Syndrome — SLC4A3 as core gene, phenocopies
• entities/SCN5A — BrS, LQT3, CCD, AF, DCM phenotypes summarised
• entities/RYR2 — CPVT1 and CRDS (new loss-of-function spectrum)
• entities/KCNQ1 — LQT1 (LOF), SQTS2 (GOF), Jervell-Lange-Nielsen syndrome
• entities/KCNH2 — LQT2 (LOF), SQTS1 (GOF)
• entities/KCNJ2 — ATS/LQT7 (LOF), SQTS3 (GOF)

Wiki Pages Updated

• wiki/sources/arrhythmia-genetics-mgenetik-2025.md (created)
• wiki/concepts/Cardiogenetic-Centers.md (created)
• wiki/concepts/Variant-Reclassification.md (created)
• wiki/entities/Long-QT-Syndrome.md (updated)
• wiki/entities/Brugada-Syndrome.md (updated)
• wiki/entities/CPVT.md (updated)
• wiki/entities/Short-QT-Syndrome.md (updated)
• wiki/entities/RYR2.md (updated)
• wiki/entities/SCN5A.md (updated)
• wiki/concepts/Cascade-Family-Screening.md (updated)
• wiki/wikiindex.md (updated)
• log.md (updated)