#genetic-testing #channelopathies #inherited-arrhythmias #sudden-cardiac-death #cascade-family-screening

Genetic Testing in Inherited Arrhythmias

Definition

Genetic testing in inherited arrhythmias is sequence analysis — in practice a targeted multigene panel — applied to the primary electrical diseases: long QT, Brugada, short QT and early repolarisation syndromes, catecholaminergic polymorphic VT, and idiopathic ventricular fibrillation. It exists to do three things: supply a molecular cause when the ECG phenotype is borderline or concealed, convert a clinical suspicion into a diagnosis firm enough to justify lifelong therapy, and identify relatives who either need surveillance or can be discharged from it. Unlike testing in structural heart disease, there is often no phenotype for the genotype to explain — the resting ECG is normal in CPVT and can be normal in concealed Brugada syndrome — so genotype and phenotype are treated as independent lines of evidence rather than cause and consequence. (sources/arrhythmia-genetics-mgenetik-2025, rating: high; sources/channelopathies-jaha-2025, rating: high)

The boundary with cardiomyopathy testing is real but porous. HCM, DCM and ARVC are covered by concepts/Genetic-Testing-in-Cardiomyopathy; this page covers the structurally normal heart. The two overlap in both directions — desmosomal, LMNA, FLNC and PLN variants cause arrhythmia, SCN5A and RYR2 sit on cardiomyopathy panels, and combined panels find cross-disease diagnoses in roughly a third of the cases that disease-specific panels would have missed. (sources/genetic-yield-jama-card-2022, rating: high)

Key Concepts

Indications and Guideline Classes

Syndrome	Recommendation	Trigger	Genes tested
LQTS	Class I	Suspected or definite LQTS; AHA 2020 also tests idiopathic QT prolongation with QTc >480 ms prepubertal or >500 ms in adults, even if asymptomatic	KCNQ1, KCNH2, SCN5A; CALM1/2/3, TRDN for atypical; CACNA1C for Timothy syndrome
Brugada	Class I (proband with spontaneous type 1)	Confirmed type 1 pattern; not for isolated type 2/3	SCN5A only
CPVT	Class I	Clinical suspicion or exercise-induced bidirectional/polymorphic VT	RYR2, CASQ2, TECRL, TRDN, calmodulin genes
Short QT	Class I	QTc ≤360 ms with supporting features	KCNH2, KCNQ1, KCNJ2, SLC4A3
Early repolarisation	Class III	Any	None established
Idiopathic VF	Class IIa (adult-onset, short-coupled TdP, MEPPC) per EHRA; Class IIb per ESC 2022	After systematic exclusion	Channelopathy and cardiomyopathy panels
SIDS / SADS	Class IIb (molecular autopsy)	Unexplained death; retain tissue	Guided by autopsy and family phenotype
ARVC / ACM	Class I	Suspected or definite ARVC	See concepts/Genetic-Testing-in-Cardiomyopathy

ESC 2022 states genetic testing as Class I across the channelopathies and separately for Brugada probands, short QT and Andersen–Tawil (KCNJ2); the EHRA/HRS/APHRS/LAHRS consensus assigns the same syndrome-level classes and adds the borderline ones — IIa for adult-onset idiopathic VF, short-coupled TdP and MEPPC, IIb for Brugada type 2/3, SIDS/SADS, familial sinus node disease and familial AF, III for early repolarisation. (sources/VA-SCD-ESC-2022, rating: very high; sources/arrhythmia-genetics-mgenetik-2025)

Phenotype precedes genotype. Both AHA 2020 and ESC 2022 require rigorous disease-appropriate phenotyping and a three-generation family history before testing, and testing should start with the most clearly affected relative: a panel ordered to resolve a vague suspicion mostly returns a VUS. (sources/genetic-test-aha-2020, rating: high)
Cardiac arrest is not by itself an indication. AHA 2020 advises testing in out-of-hospital cardiac arrest survivors only when there is clinical suspicion of a specific cardiomyopathy or channelopathy, not as routine workup for every survivor. (sources/genetic-test-aha-2020)
Atrial fibrillation is the evolving exception. Routine AF testing is not recommended by AHA 2020 or HRS/EHRA 2011; early-onset AF with cardiomyopathy features is the case where yield justifies a panel — see concepts/Genetic-Testing-in-AF. (sources/genetic-test-aha-2020)

Panel Composition and Gene Curation

Syndrome	ClinGen definitive or strong	Disputed, refuted or unsupported
LQTS	KCNQ1, KCNH2, CALM1/2/3 (definitive); SCN5A (definitive for typical LQTS in the 2020 curation, now handled under the broad SCN5A-related rhythm-disorder designation); TRDN (strong)	SCN4B (disputed); the numbered subtypes LQT4–LQT13 include genes no longer supported for isolated LQTS
Brugada	SCN5A (via the broad "SCN5A-related cardiac rhythm disorder" curation)	KCNH2, CACNA1C, CACNB2, ABCC9, SCN10A, HCN4, SCN1B, SCN2B, PKP2 (disputed); TRPM4, SCN3B (refuted)
CPVT	RYR2, CASQ2, TECRL, TRDN	PKP2, KCNJ2 (disputed)
Short QT	KCNH2 (definitive); KCNQ1, KCNJ2, SLC4A3 (moderate)	CACNA1C, CACNB2, CACNA2D1 (limited evidence)

(sources/clingen-summary-2026-05-09, rating: high; sources/arrhythmia-genetics-mgenetik-2025)

Panel size is a clinical decision, not a laboratory default. Larger panels and exome sequencing raise the VUS and incidental-finding burden without a proportionate gain in actionable results; AHA 2020 prefers targeted panels aligned with ClinGen-curated lists. (sources/genetic-test-aha-2020)
A "positive" result in a disputed gene is not a diagnosis, and should not be used to make management decisions or to cascade-test relatives. (sources/clingen-summary-2026-05-09)
Copy-number analysis belongs on the panel. In a combined cardiomyopathy–arrhythmia cohort, 3.4% of pathogenic findings were CNVs and a sixth of those were single-exon events that standard sequencing and some panels miss. (sources/genetic-yield-jama-card-2022)

Diagnostic Yield

Syndrome	Detection rate in a tested proband	What limits the yield
LQTS	70–80%	Phenotype overlap with normal QTc; multiple variants add severity, not detection
CPVT	50–60% (60.1% in clinically robust cases)	RYR2 hotspot architecture; rare missense variants common in the healthy population
Brugada	20–30%	SCN5A is the only supported gene and penetrance is ~50%
Short QT	~20–25%	Very small families; acquired phenocopies
Idiopathic VF / early-onset AF	10–20%	VUS outnumber P/LP findings

(sources/arrhythmia-genetics-mgenetik-2025; sources/cpvt-exome-circep-2017, rating: high)

Signal-to-noise differs by syndrome but the ordering is consistent. Against background population variation, the case-to-control excess is roughly 10:1 for CPVT, 15:1 for LQTS and 12:1 for HCM — high enough to be useful in a well-phenotyped proband, far too low to interpret an incidental finding. (sources/cpvt-exome-circep-2017)
Real-world yields in a broad referral population are lower than the specialist-cohort figures above. In 4,782 patients tested on a combined cardiomyopathy–arrhythmia panel, P/LP was found in 26.1% with an LQTS indication, 14.9% with Brugada, 3.9% with CPVT and 19.9% overall; 51.2% had VUS only. Referral indication, not assay performance, drives most of the difference. (sources/genetic-yield-jama-card-2022)
Disease-specific panels miss diagnoses in both directions. 10.9% of positives in that cohort would have been missed by a disease-specific panel, and 36% of the gains were cross-disease — an arrhythmia indication returning a cardiomyopathy gene or the reverse. (sources/genetic-yield-jama-card-2022)

Variant Interpretation and the VUS Problem

The modal result is a VUS. 51.2% of tested patients had VUS only in the combined-panel cohort, and CPVT had the highest VUS rate (63.2%) alongside the lowest positive yield. (sources/genetic-yield-jama-card-2022)
Incidental CPVT-gene variants are usually benign variation. Among 6,517 unselected clinical exome referrals, 8.8% carried a rare RYR2 or CASQ2 variant versus 6.0% of population controls; 97.7% were VUS, they overlapped control residues 60.4% of the time but case residues only 7.9%, and almost none sat in a canonical RyR2 hotspot. No low-suspicion referral had clinical CPVT. (sources/cpvt-exome-circep-2017)
A rare RYR2 missense variant is present in about 3% of healthy people, so a compelling CPVT phenotype raises the odds that the variant is causal only to roughly 20:1 — which is why the exercise test, not the panel, remains the diagnostic arbiter. (sources/inherited-arrhythmias-nrdp-2020, rating: very high)
Reclassification is frequent and mostly downgrades. Channelopathy variants reclassify at 38%, higher than cardiomyopathy variants at 28%; most move from pathogenic toward VUS as population databases grow, and no standard system exists to notify carriers. See concepts/Variant-Reclassification. (sources/arrhythmia-genetics-mgenetik-2025)
A negative panel does not exclude the diagnosis, because no syndrome has a 100% detection rate and because phenocopies and polygenic architecture are real — most Brugada cases have no monogenic explanation at all. See entities/Brugada-Syndrome. (sources/channelopathies-jaha-2025; sources/brs-jaccep-2022, rating: high)

Genotype-Directed Management

The genotype changes treatment only at the margins, and the exceptions are specific. Mexiletine for LQT3 (Class I, ESC 2022), avoidance of sodium-channel blockade in Brugada, quinidine in short QT and early repolarisation, and flecainide plus denervation before devices in CPVT all follow from the direction of the underlying current. (sources/VA-SCD-ESC-2022; sources/channelopathies-jaha-2025)
In the channelopathies there is no equivalent of the LMNA/PLN/FLNC ICD threshold. Risk stratification remains phenotype-driven — QTc, syncope, documented arrhythmia — and a genotype alone does not lower the LVEF or other threshold. The contrast with cardiomyopathy genetics is a genuine difference in how the result is used. (sources/VA-SCD-ESC-2022)
A genotype changes the safety of the diagnostic workup. In Brugada, a known SCN5A P/LP variant makes sodium-channel-blocker provocation testing higher risk, and the 2025 EHRA consensus advises against testing such patients outside an expert centre — the genotype functions as a procedural contraindication rather than a therapy selector. (sources/pharmacological-provocation-europace-2025, rating: high)
Genotype selects the beta-blocker. Only nadolol and propranolol are established in LQTS; metoprolol should not be used. (sources/inherited-arrhythmias-nrdp-2020)
Variant direction is the actionable unit, not the syndrome label. Gain-of-function RYR2 causes CPVT; loss-of-function RYR2 causes calcium release deficiency syndrome, a different disease with short-coupled TdP at rest that behaves unlike CPVT. See entities/RYR2. (sources/arrhythmia-genetics-mgenetik-2025)

Family Cascade, Reproduction and Postmortem Testing

Cascade testing is the main clinical product of a positive result. Once a class 4/5 variant is identified, first-degree relatives are offered single-variant testing; carriers enter surveillance and non-carriers are exonerated, subject to the caveat that a relative with an atypical phenotype may still have disease. See concepts/Cascade-Family-Screening. (sources/arrhythmia-genetics-mgenetik-2025; sources/genetic-test-aha-2020)
The family multiplier is large. In the combined-panel cohort, 958 relatives were tested and 42.0% were positive; relatives of postmortem-positive decedents were positive in 40.9%. (sources/genetic-yield-jama-card-2022)
De novo disease still carries reproductive risk. In the calmodulinopathy registry, 93% of screened families had a de novo variant, but the remainder had germline mosaicism in a parent — which means recurrence risk and a reason to offer prenatal or preimplantation testing even with a "negative" parental panel. See concepts/Calmodulinopathy. (sources/inherited-arrhythmias-nrdp-2020)
Molecular autopsy is time-critical. Tissue must be retained at autopsy, before anyone has decided to request genetics; panels are then chosen from the autopsy findings and from the living relatives' phenotypes. About 10% of infants dying suddenly in the first year carry an LQTS-causing variant, and 40% of young sudden deaths have a structurally normal heart. (sources/genetic-test-aha-2020; sources/inherited-arrhythmias-nrdp-2020)
After a positive molecular autopsy, cascade uptake is higher than after testing of a living proband (61.1% versus 32.1%), which argues for funding the postmortem test even when the decedent's own result cannot change their care. (sources/genetic-yield-jama-card-2022)

Service Delivery

Pretest and post-test counselling are mandatory, not optional extras: the patient must understand the chance of a VUS, the implications for relatives, and the insurance limits before consenting. GINA protects health insurance and employment in the US but not life, disability or long-term care insurance. (sources/genetic-test-aha-2020)
Interpretation depends on cardiogenetic expertise. Disciplines must be integrated — electrophysiology, imaging, genetics, counselling — and variant reinterpretation is done best where the cardiac phenotype is available to the reviewer. See concepts/Cardiogenetic-Centers. (sources/arrhythmia-genetics-mgenetik-2025)
Class I recommendations have outrun the infrastructure to deliver them. Testing is concentrated in academic centres, with payer-dependent access and no universal pathway for recontact when a variant is reclassified. (sources/arrhythmia-genetics-mgenetik-2025)

Contradictions / Open Questions

A Class I test usually returns a negative in Brugada and short QT. SCN5A explains 20–30% of Brugada, penetrance is about 50%, and the phenotype is probably polygenic in most cases; short QT detection is ~20–25%. A strong recommendation resting on a mostly negative test leaves the clinician without the reassurance the class implies. (sources/channelopathies-jaha-2025; sources/brs-jaccep-2022; sources/arrhythmia-genetics-mgenetik-2025)
Guidelines disagree at the borderline indications. Brugada type 2/3 is Class IIb to EHRA but "not indicated" to AHA; early repolarisation is Class III to EHRA and unaddressed by ESC 2022; idiopathic VF is IIa to EHRA for adult-onset disease but IIb to ESC 2022. The same patient can be tested or not depending on which document is being followed. (sources/arrhythmia-genetics-mgenetik-2025; sources/VA-SCD-ESC-2022; sources/genetic-test-aha-2020)
Reported yield is not actionable yield. Panel composition determines whether a "positive" result means anything: a panel carrying SCN4B or other disputed genes will report variants that should not be classified as pathogenic, and the proportion of positives that establish a molecular diagnosis is not reported consistently. (sources/arrhythmia-genetics-mgenetik-2025; sources/clingen-summary-2026-05-09)
VUS is the modal result and cannot be acted on. Over half of tested patients receive VUS only; a VUS does not justify cascade testing, yet it also does not reassure, and 38% of channelopathy variants are eventually reclassified — mostly downward. The infrastructure to notify the families affected by that reversal does not exist. (sources/genetic-yield-jama-card-2022; sources/arrhythmia-genetics-mgenetik-2025; concepts/Variant-Reclassification)
A genetic result can now be diagnostic on its own, in people who may never have an event. ESC 2022 accepts a pathogenic variant as sufficient for LQTS diagnosis irrespective of QTc, and the 2013 consensus treats a CPVT1 variant as equivalent to a clinical diagnosis — while a rare RYR2 missense sits in ~3% of healthy people and many carriers never have arrhythmia. Prophylactic beta-blockade in asymptomatic carriers is consensus, not trial evidence. (sources/VA-SCD-ESC-2022; sources/inherited-arrhythmias-nrdp-2020)
Combined panels versus disease-specific panels is unresolved. Combined testing gained 10.9% of diagnoses and one cross-disease diagnosis per six, but it also raises VUS and incidental findings, and the supporting evidence comes from one industry-sponsored programme with no comparator arm. (sources/genetic-yield-jama-card-2022)
Molecular autopsy is unevenly practised for a time-critical test. Tissue retention is decided by pathologists before the question of genetics arises, 40% of young sudden deaths are autopsy-normal, and only about 10% of SIDS yields an LQTS variant — yet the family benefit is measured in cascade yield, which is higher after postmortem testing than after testing the living. (sources/genetic-test-aha-2020; sources/inherited-arrhythmias-nrdp-2020; sources/genetic-yield-jama-card-2022)
Equity is not addressed by any of the recommendations. Non-European patients have higher VUS rates because variant databases are Eurocentric, and cardiogenetic centres are concentrated in academic institutions — so the populations least likely to receive an interpretable result are also least likely to access the service. (sources/genetic-test-aha-2020; sources/arrhythmia-genetics-mgenetik-2025)

Connections

Syndromes: entities/Long-QT-Syndrome · entities/Brugada-Syndrome · entities/CPVT · entities/Short-QT-Syndrome · entities/Early-Repolarization-Syndrome · entities/Idiopathic-Ventricular-Fibrillation
Class overview and phenotype definitions: concepts/Channelopathies · concepts/LQTS-Genetics-and-Pathophysiology · concepts/Calmodulinopathy
Genes: entities/SCN5A · entities/KCNQ1 · entities/KCNH2 · entities/KCNJ2 · entities/RYR2 · entities/CASQ2
Framework and adjacent pages: concepts/Genetic-Testing-in-Cardiomyopathy · concepts/Genetic-Testing-in-AF · concepts/Cascade-Family-Screening · concepts/Variant-Reclassification · concepts/ClinGen-Gene-Disease-Validity · concepts/Incidental-Cardiovascular-Variants · concepts/DTC-Genetic-Testing
Delivery and outcomes: concepts/Cardiogenetic-Centers · concepts/Sudden-Cardiac-Death · concepts/Polygenic-Risk-Score · concepts/Pharmacological-Provocation-Testing