Aetiology

Monogenic (Mendelian): ~75–80%, KCNQ1, KCNH2 and SCN5A account for ~90% of genotyped cases^[1]

Acquired: acquired long QT (QT-prolonging drugs, hypokalaemia/hypomagnesaemia, bradycardia) is a separate, reversible entity to exclude^[1]

Complex (likely polygenic): ~20–25% gene-elusive, partly reflecting polygenic QT modulation^[8]

Genetics

Inheritance: Autosomal dominant (Romano-Ward syndrome, penetrance 25–75% for QTc >460ms); rare autosomal recessive (Jervell-Lange-Nielsen syndrome with congenital deafness, homozygous/compound heterozygous KCNQ1 or KCNE1 variants, nearly 100% penetrance).

Genetic yield: ~75% with comprehensive testing. Up to 25% are gene-elusive, but phenotypic severity mirrors genotype-positive LQTS in these patients (Asatryan et al 2024, Circ Arrhythm Electrophysiol)^[8]

ClinGen-validated genes:

Gene	Subtype	% Genotype+	Channel / Mechanism	Arrhythmic Triggers
KCNQ1	LQT1	~50%	IKs loss-of-function (K⁺)	Exercise, swimming, adrenergic-dependent
KCNH2	LQT2	35–40%	IKr loss-of-function (K⁺)	Auditory triggers, emotion, postpartum; higher risk in females
SCN5A	LQT3	~10%	INa gain-of-function (Na⁺ delayed inactivation)	Rest/sleep, bradycardia; mexiletine genotype-specific benefit
CALM1/2/3	Calmodulinopathy	<1%	Calmodulin (impaired Ca²⁺-channel inactivation)	Often de novo; extreme QTc; severe early-onset, high arrhythmic risk; neurodevelopmental features
TRDN	–	<1%	Triadin; autosomal recessive	Exercise-triggered; T-wave abnormalities at rest
CACNA1C	LQT8 (Timothy)	Rare	ICaL gain-of-function (Ca²⁺)	Multiorgan syndrome: ASD, autism, syndactyly; very rare

Gene-elusive LQTS (~11–25%): Multiple mechanisms, polygenic risk score contribution, environmental QTc modulators, exercise-induced repolarisation abnormalities, new causal genes not yet identified, or variant reclassification over time. Management mirrors genotype-positive LQTS. Referral to specialised cardiogenetic clinic recommended (Asatryan et al 2024)^[8].

Modifier genes: Common variants modulate QTc and arrhythmic risk in individual patients, polygenic risk scores can refine risk stratification beyond the primary pathogenic variant (Schwartz & Crotti, NEJM 2025).

Genotype-Specific Management (Zhu et al 2024, Schwartz & Crotti NEJM 2025)^[7]^[2]^[9]

Subtype	Gene	% LQTS	Triggers	ECG Pattern	Key Management Points
LQT1	KCNQ1	~50%	Exercise, swimming (adrenergic)	Broad-based T wave	Beta-blockers most effective; nadolol preferred; restrict competitive swimming
LQT2	KCNH2	35–40%	Auditory triggers, emotion, postpartum	Notched/bifid T wave	Higher risk in females; avoid alarm clocks; K⁺ supplementation; beta-blockers effective
LQT3	SCN5A	~10%	Rest/sleep, bradycardia	Long isoelectric ST segment	Mexiletine (off-label): shortens QTc, reduces events; beta-blockers less effective; pacemaker in selected cases
Calmodulinopathies	CALM1/2/3	<1%	Variable; often de novo	Extreme QTc prolongation	Very high risk; early ICD; consider LCSD; flecainide may have role; specialist centre

Prevalence

Estimated prevalence 1 in 2,000 to 1 in 2,500 in the general population; actual prevalence may be higher due to variable penetrance, silent mutation carriers, and under-diagnosis^[7]

More common in females for arrhythmic events (especially LQT2); variable penetrance, many carriers have QTc within normal range

LQTS is an important cause of autopsy-negative sudden unexplained death in the young, though reported proportions vary widely by population and ascertainment^[7]

Autosomal dominant forms (Romano-Ward): first-degree relatives have 50% probability of carrying the pathogenic variant, cascade genetic screening is therefore essential^[7]

Three definitive principal genes account for the large majority of genotype-positive LQTS: LQT1 (KCNQ1), LQT2 (KCNH2), and LQT3 (SCN5A) together account for ~80–90% of genotype-positive cases. A number of other genes have historically been reported as rare/syndromic causes or proposed modifiers, but many of these historical associations are disputed or lack definitive gene-disease validation, an unqualified "at least 17 genes" count should not be presented as if all carry equal, definitive evidence^[7]

Diagnostic Criteria

LQTS Diagnostic Criteria (Schwartz Score^[3])

Definite LQTS if ANY of the following:

QTc ≥500 ms on repeated ECGs (in absence of secondary causes)
QTc ≥480 ms with unexplained syncope
Pathogenic LQTS variant identified (regardless of QTc)
Schwartz Score ≥3.5

Schwartz Score Components:

Criterion	Points
ECG Findings
QTc ≥480 ms	3
QTc 460-479 ms	2
QTc 450-459 ms (males only)	1
Torsades de pointes	2
T-wave alternans	1
Notched T-wave in ≥3 leads	1
Clinical History
Syncope with stress/emotion	2
Syncope without stress	1
Family History
Definite LQTS in family	1
Unexplained SCD <30 years in family	0.5

Interpretation: ≥3.5 = High probability; 2-3 = Intermediate; ≤1 = Low probability

Measure QT manually in appropriate leads on repeated ECGs; Bazett's formula (QTc = QT/√RR) underlies many diagnostic thresholds, but interpret cautiously at high or low heart rates and consider Fridericia or Framingham for borderline values

Gene-Elusive LQTS: Key Pitfalls (Asatryan et al, Circ Arrhythm Electrophysiol 2024)^[8]

11–25% of LQTS patients have negative genetic testing. Severity mirrors genotype-positive LQTS, manage equally.

Most common error: Including U waves in QTc measurement → overestimation of borderline QTc. Anterior T-wave inversion in ~20% of LQTS, can mislead.
Exercise testing: QTc at 4-min recovery ≥445 ms = 90% sensitivity AND specificity for LQTS. Perform off beta-blockers for best diagnostic yield.
Do not reduce management intensity because genetics is negative, cascade ECG screening of all 1st-degree relatives still applies.
16% of patients referred to LQTS centres for second opinion ultimately did NOT have LQTS. Expert cardio-genetic review is essential.

Diagnosis

ECG patterns in Long QT Syndrome: LQT1 (broad-based T-waves), LQT2 (low amplitude/notched T-waves), LQT3 (late-onset peaked T-waves), LQT8 (Timothy syndrome). Source: ECGpedia.org

ESC 2022 Guidelines - LQTS Diagnostic Criteria

Diagnostic Criteria (ESC 2022):

LQTS is diagnosed (Class I) if:

QTc ≥480 ms in repeated 12-lead ECGs (with or without symptoms), OR
Pathogenic mutation present (irrespective of QT duration)

LQTS should be considered (Class IIa) if:

QTc ≥460 ms and <480 ms in repeated ECGs + arrhythmic syncope (excluding secondary causes)

Testing not recommended (Class III):

Routine epinephrine challenge testing
Invasive electrophysiologic study

Reference: Zeppenfeld K et al. 2022 ESC Guidelines for management of patients with ventricular arrhythmias and prevention of sudden cardiac death. Eur Heart J 2022;43:3997-4126^[1] (management recommendations are covered in the Treatments section).

Clinical Presentation:

Often asymptomatic - diagnosed on screening or incidental ECG
Syncope (often misdiagnosed as seizure)
Cardiac arrest / sudden death
Palpitations (may precede syncope)

Genotype-specific triggers:

LQT1: Exercise (especially swimming)
LQT2: Auditory triggers (alarm clock, phone), emotions, postpartum
LQT3: Rest, sleep

Important: Exclude secondary causes before diagnosing congenital LQTS (electrolyte abnormalities, medications)

Investigations

First-line:

Resting 12-lead ECG (QTc measurement, T-wave morphology)
Repeat ECGs (QTc can vary)
24-hour Holter monitoring (QTc during sleep, T-wave alternans)
Exercise stress test (QTc during recovery, paradoxical QT prolongation in LQT1)

Provocation tests (specialist centres):

Epinephrine challenge test (can unmask LQTS, particularly LQT1)

Genetic testing:

Recommended in all with high clinical suspicion
Enables genotype-specific management
Facilitates family cascade screening

Exclude secondary causes of QT prolongation:

Medications (check www.crediblemeds.org)
Electrolyte abnormalities (K+, Mg2+, Ca2+)
Hypothyroidism, bradycardia, structural heart disease

Treatments

1. General measures:

Avoid QT-prolonging drugs (check www.crediblemeds.org)
Maintain normal electrolytes (target K⁺ 4–5 mmol/L; 4.5–5 mmol/L in LQT2, where IKr current is hypersensitive to hypokalaemia); oral KCl supplements or dietary advice, IV replacement if hospitalised
Avoid loud alarms/sudden awakening (LQT2)
Genotype-specific restrictions (avoid swimming in LQT1)
Clinical expert evaluation for competitive sports (see Exercise tab)
Avoid hypokalaemia, hypomagnesaemia, high-dose diuretics, sudden bradycardia

2. Medical therapy:

Beta-blockers (Class I, all symptomatic; Class IIa, asymptomatic high-risk^[1]): Highly effective in LQT1/LQT2; less so in LQT3. Reassess annually (Schwartz & Crotti, NEJM 2025^[2]).
- Nadolol (preferred, long-acting, once/twice daily, consistent levels^[4]):
  - Start 40 mg once daily → target 80–160 mg once daily (up to 3 mg/kg/day in children)
  - UK: Available via SPECIALS / named patient import, arrange in advance through hospital pharmacy^[6]
  - Renally cleared, reduce dose if eGFR <50 ml/min; avoid if eGFR <30
- Propranolol (alternative, especially in children or if nadolol unavailable):
  - Start 20–40 mg two to three times daily → target 80–160 mg twice daily (total 160–320 mg/day)
  - Paediatric: 2–4 mg/kg/day in 3–4 divided doses
  - Short-acting formulation available; longer-acting (LA/SR) preferred for compliance
- Bisoprolol (alternative if nadolol/propranolol not tolerated): 2.5–10 mg once daily, note less evidence specifically for LQTS
Mexiletine (LQT3-specific, Class IIa, off-label^[1]): Sodium channel blocker, reduces persistent INa, shortens QTc in SCN5A-positive LQT3.
- Start 50–100 mg three times daily with food → target 150–200 mg three times daily
- Maximum 900 mg/day; check QTc after dose changes (should shorten in LQT3)
- Monitor LFTs; avoid if significant hepatic impairment

3. Device therapy / surgery:

ICD: secondary prevention after cardiac arrest; primary prevention if syncope on beta-blockers or very high-risk features
Left cardiac sympathetic denervation (LCSD): for patients with recurrent events despite beta-blockers, or if ICD refused/contraindicated or beta-blockers ineffective

Related Resources

Complications

Torsades de pointes: causing syncope, seizures, aborted cardiac arrest and sudden death, with genotype-specific triggers (LQT1 exertion and swimming, LQT2 auditory and postpartum, LQT3 rest and sleep)^[1]
Postpartum arrhythmia surge: particularly in LQT2
ICD-related complications: inappropriate shocks and lead failure over decades in young patients

Risk Stratification

High-risk features (consider ICD):

Cardiac arrest survivor (secondary prevention)
Syncope despite adequate beta-blocker therapy
Marked QTc prolongation, typically >500ms, which raises risk but is not on its own an indication for an ICD
LQT2 or LQT3 genotype with high-risk features
Female with LQT2 in postpartum period

These features should be integrated (with the risk calculator below and specialist shared decision-making) rather than treated individually as automatic ICD indications; beta-blockade and trigger avoidance remain the foundation of therapy.

Beta-blocker therapy indicated:

All symptomatic patients (syncope, cardiac arrest)
Asymptomatic with QTc >470ms (females) or >450ms (males)
Some advocate beta-blockers for ALL genotype-positive individuals

Risk modifiers:

LQT1: Male sex protective; events common during exercise/swimming
LQT2: Female sex higher risk; postpartum period very high risk (continue beta-blockers)
LQT3: Male sex higher risk; events during sleep
QTc >500ms marks substantially higher risk across genotypes, though it is one factor among several rather than a standalone determinant

Risk calculator: the 1-2-3 LQTS Risk Calculator can be used to estimate individualized SCD risk and inform ICD decisions in genotype-positive patients, alongside the factors above^[1]

Pregnancy Management

Pregnancy in LQTS - individualized risk assessment (2025 ESC pregnancy approach)

PRECONCEPTION COUNSELLING:

Risk stratification: genotype, symptom history, QTc and beta-blocker therapy all inform risk, but should be weighed together by a Pregnancy Heart Team rather than mapped onto a single fixed mWHO class^[5]. As a general pattern, LQT1 with no prior symptoms, QTc <500ms and established beta-blocker therapy tends to carry lower risk; LQT2, symptomatic disease, marked QTc prolongation or an ICD are associated with materially higher risk, particularly LQT2 in the postpartum period
- LQT1: generally lower risk when asymptomatic, QTc <500ms and on beta-blocker therapy
- LQT2: generally higher risk, with the highest cardiac event risk in pregnancy and especially postpartum
- LQT3, symptomatic LQTS, marked QTc prolongation, or an ICD: generally higher risk
Pregnancy-specific risks:
- LQT2: 2.7-fold increased arrhythmic event risk during pregnancy; 4.6-fold in first 9 months postpartum (HIGHEST RISK GENOTYPE)
- LQT1: Generally lower risk during pregnancy (progesterone shortens QT), and postpartum risk is lower than in LQT2, but it is not eliminated, so continue beta-blockade and maintain surveillance
- LQT3: Intermediate risk; bradycardia during sleep may worsen arrhythmia substrate
Baseline assessment:
- 12-lead ECG with manual QTc calculation (Bazett formula acceptable)
- Exercise test (unmask QT behaviour, assess beta-blocker efficacy)
- Holter monitoring if palpitations/presyncope history
- Review ICD if present (programming, battery, lead integrity)
Medications:
- Beta-blockers: ESSENTIAL - do NOT stop (nadolol preferred for LQT1/LQT2; metoprolol acceptable)
- Mexiletine (LQT3): pregnancy data are limited; use only where clearly indicated, with specialist input and fetal monitoring
- Avoid ALL QT-prolonging drugs - check www.crediblemeds.org
Genetic counselling: each child has a 50% chance of inheriting the familial variant (autosomal dominant); whether and how severely disease develops depends on penetrance and variable expression; prenatal testing available

PREGNANCY MANAGEMENT:

Monitoring frequency:
- LQT2: Monthly cardiology review (high risk)
- LQT1/LQT3: Each trimester if stable and asymptomatic
- ECG each visit (monitor QTc evolution)
- Holter if palpitations, presyncope, or any symptoms
QTc evolution in pregnancy:
- Generally SHORTENS slightly in 2nd/3rd trimester (progesterone effect)
- BUT some LQT2 women have PARADOXICAL QTc prolongation
- Monitor closely if QTc increasing or >500ms
Beta-blocker management:
- DO NOT STOP - essential for arrhythmia prevention
- Nadolol 40-160mg/day (preferred, long half-life) OR metoprolol 100-200mg/day
- Monitor heart rate - target resting HR 60-70 bpm
- May need dose increase in pregnancy (increased drug metabolism)
Electrolyte management:
- Check potassium and magnesium each trimester
- Maintain K+ 4-5 mmol/L (supplement if <4.0)
- Supplement Mg2+ if levels low or if hyperemesis/frequent vomiting
Avoid triggers:
- QT-prolonging medications (antibiotics, antiemetics, antihistamines) - check ALL drugs
- LQT2 specific: Avoid sudden loud noises/alarms

LABOUR & DELIVERY:

Delivery planning:
- Deliver at tertiary centre (high-risk, especially LQT2)
- MDT planning ahead of expected delivery, timing individualized rather than fixed
- External defibrillator immediately available
Mode of delivery:
- Delivery mode is normally obstetric (vaginal delivery preferred if stable); an ICD in place is not by itself an indication for elective caesarean section
- Caesarean section may be considered for significant cardiac instability (e.g. recurrent syncope, very prolonged QTc) or standard obstetric indications, decided individually rather than by a fixed rule
- Assisted second stage to reduce sympathetic surge
Anaesthesia:
- Epidural generally preferred (reduces catecholamine surge from pain)
- Avoid QT-prolonging drugs: ondansetron carries a recognised QT-prolongation risk; metoclopramide and cyclizine are not established as electrically neutral alternatives either, check any antiemetic against a current QT-risk resource (e.g. CredibleMeds) and the BNF/SmPC, with pharmacy or anaesthetic input
- GA if needed: propofol generally considered compatible; avoid volatile anaesthetics (some prolong QT)
Intrapartum monitoring:
- Continuous ECG monitoring throughout labour
- Have IV magnesium sulphate available (torsades treatment)
- ICD: Reprogram if concerned about T-wave oversensing; keep magnet available
Continue beta-blockers THROUGHOUT labour - do not skip doses

POSTPARTUM - HIGHEST RISK PERIOD (ESPECIALLY LQT2):

Critical first 9 months postpartum (LQT2):
- 4.6-fold increased arrhythmic event risk compared to non-pregnant state
- Hormonal withdrawal (falling progesterone) → QT prolongation
- Sleep deprivation, emotional stress, fatigue
Immediate postpartum management:
- Monitor 24-48 hours postpartum (CCU/telemetry if LQT2)
- DO NOT STOP BETA-BLOCKERS - this is CRITICAL
- ECG on day 1 postpartum and at discharge (monitor QTc)
Outpatient monitoring (LQT2):
- Cardiology review individualized to risk, with a lower threshold for more frequent review through the first 9 months postpartum for LQT2
- ECG at each visit
- Holter if any palpitations/symptoms
- Patient education: Report immediately - palpitations, lightheadedness, syncope
Beta-blocker compliance:
- Counsel extensively about arrhythmia risk if stopped
- Continue same dose as pregnancy (or increase if QTc rising)
- Nadolol/metoprolol compatible with breastfeeding
Sleep deprivation management:
- Particularly important for LQT3 (events during sleep)
- Encourage partner assistance with night feeds
Breastfeeding: generally encouraged; beta-blockers compatible
Contraception: no specific method is excluded; progesterone-only methods may be preferred (shorten QT)

VERY HIGH-RISK SCENARIOS WARRANTING DETAILED MDT DISCUSSION:

Recurrent cardiac arrest despite beta-blockers and ICD
Recent electrical storm

These represent the highest-risk end of the spectrum and warrant individualized, detailed Pregnancy Heart Team discussion rather than being treated as an automatic bar to pregnancy.

GENOTYPE-SPECIFIC SUMMARY:

LQT1: Generally lower risk in pregnancy (progesterone protective); postpartum risk lower than LQT2 but not absent, continue beta-blockade
LQT2: HIGHEST RISK - close monitoring pregnancy + 9 months postpartum essential
LQT3: Intermediate risk; sleep deprivation postpartum may increase events

Follow-up

Pragmatic surveillance approach informed by ESC 2022 Ventricular Arrhythmia guidelines (which do not mandate fixed monitoring intervals)^[1].

Advanced / complicated = prior cardiac arrest or syncope, markedly prolonged QTc, breakthrough events on therapy, or appropriate ICD therapy.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

	Genotype+ / Phenotype−	Uncomplicated / Stable	Advanced / Complicated
Frequency	Annual (concealed LQTS)	Annual	Every 6 months
Clinical review	Symptoms; QT-drug & adherence counselling	Symptoms, syncope, adherence, QT-drug review	As above + device check
ECG	Annual (QTc may be normal)	Annual 12-lead (QTc trend)	Each visit
Holter / ambulatory	As indicated	Periodic / symptom-directed	As indicated
Exercise / stress test	Consider (may unmask LQT1)	As indicated (paradoxical QT response, esp. LQT1)	As indicated
Echocardiography	Baseline	Baseline (exclude structural disease)	If symptoms change
Family screening	–	Cascade ECG ± genetic testing	–

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

Key Points

Normal QTc does NOT exclude LQTS if genotype-positive
Screen first-degree relatives with ECG and consider genetic testing if variant identified
Check www.crediblemeds.org before prescribing ANY medication^[1]
Do NOT stop beta-blockers abruptly (rebound tachycardia can be fatal)^[1]
Maintain K+ 4-5 mmol/L; replace promptly if low^[1]
Genotype guides triggers: LQT1 avoid competitive swimming; LQT2 avoid sudden loud noises
ICD does NOT replace beta-blocker therapy
LQT2: increased pregnancy and postpartum arrhythmic risk (especially with prior symptoms); continue beta-blockers and maintain close follow-up for ~9 months postpartum

References & Review Date

Last reviewed: July 2026

Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. doi:10.1093/eurheartj/ehac262
Schwartz PJ, Crotti L. Long QT syndrome. N Engl J Med. 2025;393:2023–2034. PubMed
Schwartz PJ, et al. Diagnostic criteria for the long QT syndrome: an update. Circulation. 1993;88(2):782–784. doi:10.1161/01.CIR.88.2.782
van der Werf C, et al. Nadolol versus propranolol in patients with long QT syndrome. Heart Rhythm. 2013;10(11):1692–1698. doi:10.1016/j.hrthm.2013.07.034
2025 ESC Guidelines for the management of cardiovascular disease during pregnancy. Eur Heart J. 2025. doi:10.1093/eurheartj/ehaf193
Joint Formulary Committee. British National Formulary (BNF). bnf.nice.org.uk
Zhu W, Bian X, Lv J. From genes to clinical management: a comprehensive review of long QT syndrome pathogenesis and treatment. Heart Rhythm O2. 2024;5(8):573–586. doi:10.1016/j.hroo.2024.07.006
Asatryan B, Murray B, Gasperetti A, et al. Unraveling complexities in genetically elusive long QT syndrome. Circ Arrhythm Electrophysiol. 2024;17(2):e012356. doi:10.1161/CIRCEP.123.012356
Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–1874. doi:10.1056/NEJMoa022147

Long QT Syndrome (LQTS)