Long QT Syndrome (LQTS)

Detailed pages: concepts/LQTS-Genetics-and-Pathophysiology — gene architecture, ion-channel mechanisms, TdP pathway, sex hormones and circadian variation.

Details

Long QT syndrome is the most prevalent cardiac channelopathy: delayed ventricular repolarisation prolongs the QT interval and predisposes to torsades de pointes (TdP), ventricular fibrillation and sudden cardiac death in a structurally normal heart. (sources/lqts-nejm-2025, rating: very high) Seventeen genetic subtypes are described, but KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) account for approximately 90% of genotype-positive cases in prospective cohorts. Presentation ranges from asymptomatic QT prolongation to syncope and aborted cardiac arrest, with subtype-specific triggers — exercise and swimming in LQT1, auditory stimuli and emotion in LQT2, rest and sleep in LQT3. Management is stepwise: lifestyle measures and non-selective beta-blockers first, then mexiletine, left cardiac sympathetic denervation (LCSD) and ICD for higher-risk patients. (sources/channelopathies-jaha-2025, rating: high)

Key Facts

Epidemiology

• Prevalence 1:2000 live births in a prospective study of 44,000 infants; true prevalence is probably higher because genotype-positive/phenotype-negative individuals were excluded. (sources/lqts-nejm-2025, rating: very high; sources/channelopathies-jaha-2025)
• The measured figure is 1 in 2,534 apparently healthy live births (95% CI 1 in 1,583 to 1 in 4,350) — 17 cases among 43,080 white infants in the Italian neonatal ECG study — with a working estimate of ≥1 in 2,000 once infants with QTc 450–470 ms are included. Disease-causing variants were found in 29% of infants with QTc 451–460 ms and 49% of those >470 ms. (sources/inherited-arrhythmias-nrdp-2020, rating: very high)
• Age and sex modify risk: arrhythmic risk is highest in childhood and attenuates after 60 years. Males aged 10–12 have 4× the risk of females; from ages 18–40 the ratio reverses (women 11% vs men 2%), reflecting oestrogen inhibition and testosterone potentiation of IKr. The postpartum period carries additional risk. (sources/channelopathies-jaha-2025, rating: high)
• Asymptomatic carriers are not risk-free: family members with a confirmed pathogenic variant but normal QTc carry a tenfold increased risk of cardiac events versus non-carriers, justifying variant analysis in all first-degree relatives regardless of QTc. (sources/arrhythmia-genetics-mgenetik-2025, rating: high)
• About 10% of infants who die suddenly in the first year carry an LQTS-causing variant, and a prolonged neonatal QT predicts sudden death. Without genetic testing these deaths are labelled SIDS; the corollary is both a rationale for neonatal ECG screening and a caution against assuming repeated infant deaths imply infanticide. (sources/inherited-arrhythmias-nrdp-2020)
• Latent LQTS underlies a minority of drug-induced prolongation — estimates range from 10–15% to ~30% depending on cohort and definition; see Acquired Long QT Syndrome and Contradictions. (sources/arrhythmia-genetics-mgenetik-2025; sources/drug-arrhythmia-aha-2020)

Genetics and Pathophysiology

Full detail: concepts/LQTS-Genetics-and-Pathophysiology.

Genetics

• Three major genes account for ~90% of genotype-positive cases in prospective cohorts — KCNQ1 (LQT1, ~50%), KCNH2 (LQT2, ~40%), SCN5A (LQT3, ~10%); registry-based reviews give ~80% and lower LQT1/LQT2 shares, reflecting ascertainment. (sources/lqts-nejm-2025, rating: very high; sources/lqts-jaccep-2022, rating: high)
• A 2020 Primer gives the registry-era shares as LQT1 30–35%, LQT2 25–40%, LQT3 5–10%, with 15–20% of clinically definite cases genotype-negative and 5–10% carrying multiple mutations. Double mutants present younger and more severely. (sources/inherited-arrhythmias-nrdp-2020, rating: very high)
• Variant position and functional class stratify risk within a gene: KCNQ1 transmembrane variants carry higher risk than C-terminal variants, dominant-negative alleles higher risk than haploinsufficiency, and KCNH2 pore-region missense variants more severe disease than non-pore variants. (sources/inherited-arrhythmias-nrdp-2020)
• ClinGen-definitive genes are KCNQ1, KCNH2, CALM1/2/3 and CACNA1C, with SCN5A under the broad "SCN5A-related cardiac rhythm disorder" designation. SCN4B and KCNE2 are disputed; CAV3 and KCNJ2 have limited isolated-LQTS evidence. (sources/clingen-summary-2026-05-09, rating: high)
• Recessive and syndromal forms: Jervell and Lange-Nielsen (KCNQ1/KCNE1 biallelic), Timothy syndrome (CACNA1C), Andersen-Tawil (KCNJ2) and TRDN-related recessive LQTS/CPVT. (sources/channelopathies-jaha-2025, rating: high)
• Calmodulinopathy is almost always de novo. CALM1/2/3 lie on different chromosomes, share 85% nucleotide homology and encode an identical 149-amino-acid protein, yet one mutant allele of six causes disease. In the International Calmodulinopathy Registry (74 patients), 93% of screened families had a de novo variant and the remainder showed germline mosaicism in a parent. (sources/inherited-arrhythmias-nrdp-2020)
• Modifiers matter: NOS1AP variants, KCNE1-D85N and KCNH2-K897T modify risk, and a PRS explains ~15% of susceptibility variance; 75% of marked unexplained QTc prolongation is non-genetic. (sources/modifier-genes-scd-ehj-2018, rating: high; sources/gwas-arrhythmias-cmp-genes-2025, rating: high)

Pathophysiology

• Three final pathways: IKs loss-of-function (LQT1), IKr loss-of-function (LQT2) and INaLate gain-of-function (LQT3) all prolong APD; LQT4, LQT8 and LQT9/12 act through Ca²⁺ handling, ICaL gain-of-function and Nav1.5 complex disruption respectively. (sources/channelopathies-jaha-2025, rating: high; sources/membrane-potential-physrev-2021, rating: very high)
• Common pathway to TdP: APD prolongation → disproportionate M-cell prolongation → transmural dispersion of repolarisation → early afterdepolarisation → triggered beat on the T-wave → re-entry. (sources/membrane-potential-physrev-2021)
• Repolarisation reserve explains why a latent variant plus an IKr-blocking drug unmasks TdP — the mechanistic basis of acquired LQTS. (sources/repolarisation-jaccep-2023, rating: high)
• Sex hormones and circadian regulation shift APD: oestrogen inhibits IKr, testosterone upregulates IKr/IKs and progesterone upregulates IKs; Kcnh2 is BMAL1/CLOCK-regulated, and short-half-life variants may amplify circadian APD swings. (sources/membrane-potential-physrev-2021; sources/circadian-scd-jmcc-2025, rating: high)

Diagnosis

Diagnostic criteria

(sources/VA-SCD-ESC-2022, rating: very high; sources/lqts-jaccep-2022, rating: high)

Schwartz Score — LQTS points

Interpretation: ≤1 low probability; >1–3 intermediate; ≥3.5 high probability. The score was developed ~30 years ago, before gene discovery, and genetic positivity is not a primary component — a pathogenic-variant carrier with normal QTc can score low despite confirmed disease. (sources/channelopathies-jaha-2025, rating: high; sources/lqts-jaccep-2022, rating: high)

• Updated score: QTc ≥480 ms at 4-minute exercise recovery is now a scoring criterion (100% specificity, 36% sensitivity; see the provocation table below). (sources/lqts-jaccep-2022, rating: high)
• Normal limits: QTc 440 ms in males and 460 ms in females (Bazett), with a population mean of 400 ± 20 ms. (sources/inherited-arrhythmias-nrdp-2020, rating: very high)
• Do not use the tangent method when LQTS is suspected. It can underestimate the QT interval when the descending T-wave limb has a slow component, which is common with IKs or IKr impairment — precisely the patients being assessed. (sources/inherited-arrhythmias-nrdp-2020)
• The exercise test almost never provokes arrhythmia in LQTS — the opposite of CPVT — but provides three diagnostic and prognostic signals: failure of QT to adapt to R–R shortening, T-wave changes in early recovery, and the rate of heart-rate deceleration in the first minute after exercise. (sources/inherited-arrhythmias-nrdp-2020)
• Echocardiography can show mechanical alterations in a subset of LQTS patients, an underused adjunct to the electrical phenotype. (sources/inherited-arrhythmias-nrdp-2020)
• Schwartz Score performance: ≥3.5 has 99% specificity but only 19–36% sensitivity — it confirms LQTS well but excludes it poorly. (sources/lqts-jaccep-2022, rating: high; sources/VA-SCD-ESC-2022)
• QTc alone cannot exclude LQTS: in 1,710 cases the mean QTc was 471±45 ms, and 47% of LQT1, 36% of LQT2 and 35% of LQT3 patients had QTc <460 ms. Up to 40% have QTc <450 ms at baseline. (sources/arrhythmia-genetics-mgenetik-2025; sources/repolarisation-jaccep-2023)
• Workup: 12-lead ECG, Schwartz Score, exercise treadmill test, 24-hour ambulatory ECG, and genetic testing when clinical suspicion remains despite a negative workup. (sources/channelopathies-jaha-2025)
• Genetic testing is Class I in suspected or definite LQTS; AHA 2020 additionally recommends testing for idiopathic QT prolongation with QTc >480 ms prepuberty or >500 ms in adults, even when asymptomatic. (sources/arrhythmia-genetics-mgenetik-2025; sources/genetic-test-aha-2020, rating: high)
• Epinephrine challenge and EPS are not recommended (Class III) for routine diagnosis. (sources/VA-SCD-ESC-2022)
• AI-ECG identifies concealed LQTS with AUC 0.741 and can discriminate LQT1 from LQT2; input occlusion shows T-wave features consistent with IKr inhibition. (sources/repolarisation-jaccep-2023)

ECG patterns by subtype

(sources/repolarisation-jaccep-2023, rating: high; sources/lqts-jaccep-2022, rating: high)

• Giant T-U waves in any subtype herald impending TdP — a widened terminal deflection immediately precedes the short-coupled ventricular beat that triggers the arrhythmia. (sources/lqts-jaccep-2022)
• Pattern overlap is common and morphology alone cannot assign genotype; normal T-wave morphology does not exclude LQTS. Serial ECGs at different heart rates improve sensitivity and genotype differentiation. (sources/arrhythmia-genetics-mgenetik-2025; sources/lqts-jaccep-2022)

Provocation testing

(sources/lqts-jaccep-2022, rating: high)

Acquired Long QT Syndrome

• Caused by IKr-blocking drugs (more than 200 remain marketed), hypokalaemia, bradycardia and heart block; individual repolarisation reserve determines susceptibility. (sources/drug-arrhythmia-aha-2020, rating: very high)
• Three predictors of latent congenital LQTS in apparent acquired LQTS: age <40 years; baseline QTc >440 ms before the offending drug; arrhythmic episodes. Any one should prompt molecular testing. (sources/lqts-nejm-2025, rating: very high)
• Estimates of latent LQTS differ by cohort and definition: 10–15% of QT prolongation cases in a general arrhythmia-genetics review, ~25% in an international acquired-LQTS cohort, and ~30% of patients developing drug-induced QT prolongation in the AHA statement. The discrepancy most likely reflects differing populations, gene panels, and whether the endpoint is prolongation or TdP. (sources/arrhythmia-genetics-mgenetik-2025; sources/lqts-jaccep-2022; sources/drug-arrhythmia-aha-2020)
• Recurring rare variants: KCNE1-p.D85N and SCN5A-p.S1103Y are consistently associated with acquired LQTS; testing for these can be considered. A further 61 common variants explain up to 30% of QTc variability under drug exposure, but routine polygenic testing is not recommended. (sources/lqts-nejm-2025)
• Excessive physical training can produce marked, reversible QT prolongation mimicking congenital LQTS, especially in teenagers; abnormalities resolve after 3–4 months of detraining. (sources/lqts-nejm-2025)

Risk Stratification

Risk calculators

• 1-2-3 LQTS Risk Calculator: estimates arrhythmic risk before therapy initiation and is recommended before ICD decisions — Class IIa (ESC 2022). ICD in asymptomatic high-risk patients identified by the calculator is Class IIb. (sources/VA-SCD-ESC-2022, rating: very high)
• Trigger patterns inform risk: LQT1 events occur with exercise and swimming, LQT2 with auditory stimuli, emotion and the postpartum period, LQT3 at rest and during sleep. (sources/channelopathies-jaha-2025, rating: high)

Event rates by QTc

• Annual rates: QTc <460 ms <0.1%/year severe events; QTc <500 ms 0.2–0.4%/year; QTc ≥500 ms 0.5–1.3%/year severe events and 1.9–2.1%/year cardiac events — 2–3× the risk of QTc <500 ms even on beta-blockers. Risk rises ~1.1× per 10 ms QTc increment, and the maximum QTc on serial ECGs predicts better than a single measurement. (sources/lqts-jaccep-2022, rating: high)

Event rates by genotype and variant

• Annual severe event rates to age 40: LQT1 0.2–0.5%, LQT2 0.3–0.7%, LQT3 0.3–1.1%. Peak mortality occurs at ages 1–19 in LQT1, 30–39 in LQT2 and 15–19 in LQT3. (sources/lqts-jaccep-2022)
• Variant-specific risk: KCNQ1-A341V carries 80% cardiac-event risk by age 40 versus 30% for other LQT1 variants, whereas KCNQ1-Y111C is low risk (0.05%/year over 25 years). In LQT3, ΔKPQ is higher risk while E1784K and D1790G carry less. (sources/lqts-jaccep-2022)
• Variant location hierarchy: transmembrane pore > other transmembrane > N/C terminus; dominant-negative > haploinsufficiency. (sources/lqts-jaccep-2022)

Management

Lifestyle and avoidance

• Avoid QT-prolonging drugs (CredibleMeds list), correct hypokalaemia and hypomagnesaemia, and restrict competitive sport in high-risk subtypes. (sources/channelopathies-jaha-2025, rating: high)

Beta-blockers

• Class I; only propranolol (2.0–3.5 mg/kg/day) and nadolol (1.0–1.5 mg/kg/day) are confirmed effective. Metoprolol should not be used — higher recurrence of events. (sources/lqts-nejm-2025, rating: very high; sources/VA-SCD-ESC-2022, rating: very high)
• Monitoring endpoint is 15–20% heart-rate blunting during maximal exercise, not QTc reduction. Nadolol target is ~1 mg/kg/day, given in the evening or divided. More than 50% of patients have suboptimal adherence, and most "beta-blocker failures" reflect non-adherence or co-prescribed QT-prolonging drugs. (sources/lqts-jaccep-2022, rating: high; sources/lqts-nejm-2025)

Mexiletine

• Class I in LQT3 with prolonged QTc (upgraded from IIa in ESC 2022). Mexiletine 8 mg/kg/day reduces QTc by ~60 ms and lowers cardiac events. In LQT2, ~70% of patients show clinically meaningful QTc shortening, broadening its use beyond LQT3. (sources/lqts-nejm-2025, rating: very high; sources/VA-SCD-ESC-2022)
• Acute oral drug test: 6–8 mg/kg, measure QTc at 2 hours; shortening >40 ms predicts response — start long-term therapy only in responders. (sources/lqts-jaccep-2022, rating: high)
• The test needs no mutation data. Therapeutic levels are reached 90–120 minutes after half the daily dose, so a 2-hour ECG identifies responders empirically; the >40 ms criterion was proposed for patients with baseline QTc >500 ms. Mayo and Milan now also use mexiletine routinely in LQT2. (sources/inherited-arrhythmias-nrdp-2020, rating: very high)
• Ranolazine and newer sodium-channel blockers are not supported by sufficient data. Lumacaftor–ivacaftor, a CFTR corrector, may rescue KCNH2 trafficking defects in LQT2; iPSC-CM response and early clinical data are encouraging but unconfirmed. (sources/inherited-arrhythmias-nrdp-2020)

ICD

• Class I: after cardiac arrest, and in symptomatic patients despite beta-blockers plus genotype-specific therapy. Class IIb: asymptomatic high-risk patients selected by the 1-2-3 calculator. (sources/VA-SCD-ESC-2022, rating: very high)
• Primary-prevention predictors of appropriate shock: QTc ≥500 ms and cardiogenic syncope despite beta-blockers. JLN/compound heterozygotes under 40 require shared decision-making about primary-prevention ICD or LCSD. (sources/lqts-jaccep-2022, rating: high)
• Complications (meta-analysis, n=462): 2.8%/year inappropriate shocks and 7.0%/year total complications. Dual-chamber transvenous ICD is preferred over subcutaneous ICD because it allows atrial overdrive pacing; S-ICD experience remains limited. (sources/lqts-jaccep-2022)
• In the largest LQTS device study, 31% had an adverse event within 5 years — infection, lead dislodgement or tricuspid regurgitation — and younger patients face more generator changes. Young LQT1 patients whose arrest occurred off beta-blockade may be managed with beta-blockers and/or LCSD alone; for everyone else the usual strategy is LCSD to prevent episodes with an ICD as safety net. (sources/inherited-arrhythmias-nrdp-2020, rating: very high)

Gene-specific lifestyle

(sources/inherited-arrhythmias-nrdp-2020, rating: very high)

Left cardiac sympathetic denervation

• Class I when ICD is contraindicated or declined, or when a patient on full therapy with an ICD has multiple shocks or syncope from ventricular arrhythmia. Post-LCSD QTc <500 ms predicts success; persistent QTc >500 ms prompts consideration of ICD. In selected high-risk LQT1 patients it may be preferred over primary-prevention ICD. See concepts/Left-Cardiac-Sympathetic-Denervation. (sources/VA-SCD-ESC-2022; sources/lqts-jaccep-2022)

Precision therapy

• In a 20-year Mayo Clinic cohort (n=1,304), expert management used up to 18 distinct configurations for LQT3 alone; phenotype outweighed genotype in guiding treatment. (sources/precision-lqts-tcm-2024, rating: high)
• Intentional nontherapy (18%) in post-pubertal asymptomatic patients with normal resting and recovery QTc — precautionary measures only, with zero lethal events at 7.5 years. Genotype-specific prescribing: propranolol over nadolol in LQT3 (direct INaLate inhibition), mexiletine and atrial overdrive pacing for high-risk LQT2, and flecainide for the p.Ile1768Val-SCN5A variant matched to mechanism. (sources/precision-lqts-tcm-2024)
• Escalation: LCSD monotherapy (5%, mainly beta-blocker-intolerant), right cardiac sympathetic denervation added in refractory LQT3, and cardiac transplantation in 2.6% with intractable arrhythmia. More than 50% of referred patients with a pre-existing ICD underwent extraction after specialist reassessment. Full detail: concepts/Precision-Medicine-LQTS. (sources/precision-lqts-tcm-2024)

Special Populations

Pregnancy and postpartum

• Risk paradox: pregnancy is relatively protective through physiological tachycardia, but the first 9 months postpartum carry a 2.7-fold higher cardiac-event risk and 4.1-fold higher life-threatening-event risk than the prepregnancy period, reverting to baseline thereafter. LQT2 is disproportionately affected, attributed to the postpartum fall in progesterone. (sources/lqts-pregnancy-medicina-2022, rating: medium)
• The genotype gap is wide: postpartum event rates are <1% in LQT1 but 16% in LQT2, with no LQT3 data. (sources/inherited-arrhythmias-nrdp-2020, rating: very high)
• Beta-blockers are Class I throughout pregnancy and for at least 40 weeks postpartum, reducing postpartum events from 3.7% to 0.8%; propranolol and nadolol are preferred over metoprolol. Atenolol is class D for intrauterine growth restriction, and amiodarone is contraindicated. (sources/lqts-pregnancy-medicina-2022; sources/inherited-arrhythmias-nrdp-2020)
• Fetal loss depends on which parent carries the variant: fetal death is 24.4% when the mother is affected versus 3.4% when the father is, and miscarriage and stillbirth are both increased in LQTS pregnancies. (sources/inherited-arrhythmias-nrdp-2020)
• Oxytocin can prolong QT. When indicated it should not be withheld; optimise potassium and magnesium, obtain an ECG at baseline and 1–2 h after starting, and stop if QTc exceeds 500 ms or rises >60 ms from baseline. (sources/inherited-arrhythmias-nrdp-2020)
• Delivery planning: low risk (QTc ≤470 ms, no events) → standard obstetric care; medium risk (QTc ≥470 ms or remote events) → tertiary centre; high risk (recent events on therapy) → Caesarean in a cardiac theatre. LQTS does not require intrapartum telemetry, but CPVT does. ICD before pregnancy is preferred in high-risk women. Full detail: concepts/LQTS-Pregnancy-Management. (sources/lqts-pregnancy-medicina-2022; sources/inherited-arrhythmias-nrdp-2020)
• Neonatal ECG is unreliable until after the second week because the QT is physiologically prolonged for 7–10 days, unless QTc exceeds 500 ms. Neonatal genetic screening proceeds in parallel; pre-implantation genetic testing is an option when the familial variant is known. (sources/inherited-arrhythmias-nrdp-2020)

Competitive sports

• Concealed variant-positive LQTS (gene-positive, QTc <460 ms): competitive sport is reasonable; in the largest cohort (n=494) there were zero deaths and 0.3 events/100 patient-years. Avoid QT-prolonging drugs; consider prophylactic beta-blockade. (sources/competitive-sports-aha-2025, rating: very high)
• Phenotypic LQTS is reasonable with shared decision-making under expert supervision and guideline-directed therapy; zero deaths and 1.16 events/100 athlete-years were reported. Non-selective beta-blockade, an emergency action plan and AED access are required. (sources/competitive-sports-aha-2025)
• LQT1 swimming/diving can be considered with supervision by a CPR-trained individual, a pool in preference to open water and an AED on site; most prior events occurred in undiagnosed or untreated patients. No breakthrough arrhythmia for ≥3 months before return. (sources/competitive-sports-aha-2025)
• ICD solely to enable sports participation should not be performed — ~5%/year inappropriate shocks and ~4%/year device complications. See concepts/Sports-Cardiology-SDM. (sources/competitive-sports-aha-2025)

Emerging Therapies

(sources/gene-therapy-arrhythmia-2025, rating: high; sources/lqts-nejm-2025; sources/channelopathies-jaha-2025)

Contradictions / Open Questions

• Latent LQTS in drug-induced prolongation — discrepant estimates: 10–15% in a general review, ~25% in an international acquired-LQTS cohort, and ~30% in the AHA statement. The range likely reflects different populations, panels and endpoints (QT prolongation versus TdP). None supports routine pre-prescription genetic screening. (sources/arrhythmia-genetics-mgenetik-2025; sources/lqts-jaccep-2022; sources/drug-arrhythmia-aha-2020, rating: very high)
• QTc threshold inconsistency: ESC 2022 uses QTc ≥480 ms as a Class I criterion, while many programmes and older guidelines use >450 ms in men or >470 ms in women. The Schwartz Score assigns 3 points at ≥480 ms but permits diagnosis at lower values, so who receives a diagnosis and a genetic referral varies by centre. (sources/VA-SCD-ESC-2022, rating: very high; sources/channelopathies-jaha-2025)
• Asymptomatic LQTS — ICD threshold undefined: for asymptomatic patients on full beta-blockade with persistently prolonged QTc, ICD is only Class IIb when guided by the 1-2-3 calculator. No Class I or IIa threshold exists for the largest patient group. (sources/VA-SCD-ESC-2022)
• LQT3 — mexiletine versus gene therapy: ESC 2022 upgraded mexiletine to Class I on established pharmacology and registry data, while SCN5A base editing shows strong preclinical efficacy. Both target the same late-sodium mechanism but have never been compared. (sources/VA-SCD-ESC-2022; sources/gene-therapy-arrhythmia-2025, rating: high)
• SupRep balance constraint — no validated human dosing: precise suppression-to-replacement balance is required; excess suppression worsens LQTS and excess replacement risks short QT. Demonstrated in animals but never established in humans. (sources/gene-therapy-arrhythmia-2025)
• ICD over- versus under-implantation: more than 50% of referred patients with a pre-existing ICD had it extracted after specialist reassessment, yet ICDs provide mortality benefit in LQTS. The resolution is individualised, precision-risk-stratified implantation rather than reflexive device therapy for any LQTS diagnosis. (sources/precision-lqts-tcm-2024, rating: high)
• Risk-score timing may drive excessive ICD use: ESC 2022 recommends applying the 1-2-3 calculator at the initial visit. In a 946-patient study, initial-visit scoring would have indicated 142 ICDs, but only 22 were implanted with yearly reassessment; three received appropriate shocks and none died. Because therapy modifies risk, implanting before reassessment after optimisation is hard to justify. (sources/lqts-nejm-2025, rating: very high; sources/VA-SCD-ESC-2022)
• Mexiletine in LQT2 — off-label but evidence-supported: guidelines restrict mexiletine to LQT3, but the Mayo cohort showed a 65 ms QTc reduction and elimination of breakthrough events in high-risk LQT2 with baseline QTc ~543 ms. This challenges strict genotype-to-drug assignment and supports mechanism-guided prescribing. (sources/precision-lqts-tcm-2024; sources/scn5a-jaccep-2018, rating: high)
• Andersen–Tawil may be misclassified as LQTS. Its apparent QT prolongation may result from including a prominent U wave in the QTc calculation, and the 2020 Primer argues it should not be regarded as part of the LQTS spectrum — despite carrying the LQT7 label. (sources/inherited-arrhythmias-nrdp-2020, rating: very high)
• QT measurement method changes who is diagnosed. The tangent method is widely used but can underestimate QT when the T-wave descent is slow — the patients most likely to have LQTS — so the same ECG can fall inside or outside the threshold depending on technique. No study has compared method-specific event rates. (sources/inherited-arrhythmias-nrdp-2020)
• ICD benefit and ICD harm are measured in different studies. The device prevents sudden death, but 31% have an adverse event within 5 years in the largest LQTS cohort, and younger patients accumulate more generator changes. The comparison that would settle the trade-off — device versus LCSD-based therapy in matched patients — has not been done. (sources/inherited-arrhythmias-nrdp-2020)
• Sudden infant death sits between cardiology and forensic pathology. About 10% of SIDS cases carry LQTS-causing variants, which supports neonatal ECG screening but also means recurrent infant deaths should not be assumed to be infanticide without genetic evaluation. (sources/inherited-arrhythmias-nrdp-2020)

Connections

• Phenotype and overlap: entities/Short-QT-Syndrome · entities/Brugada-Syndrome · entities/CPVT · entities/Andersen-Tawil-Syndrome
• Genes and mechanisms: entities/KCNQ1 · entities/KCNH2 · entities/SCN5A · entities/NOS1AP · concepts/Calmodulinopathy
• Electrophysiology: concepts/Cardiac-Action-Potential · concepts/Cardiac-Repolarization · concepts/Torsades-de-Pointes · concepts/Electrical-Remodeling · concepts/Circadian-Rhythm-Cardiac-Electrophysiology
• Diagnosis and variants: concepts/Drug-Induced-Arrhythmia · concepts/Variant-Reclassification · concepts/ClinGen-Gene-Disease-Validity · concepts/Genetic-Testing-in-Arrhythmias
• Therapy: concepts/Left-Cardiac-Sympathetic-Denervation · concepts/Precision-Medicine-LQTS · concepts/LQTS-Pregnancy-Management · concepts/Sports-Cardiology-SDM · concepts/SupRep-Therapy · concepts/AAV-Gene-Delivery · concepts/CRISPR-Cas9-in-Channelopathies
• Genetics and translational: concepts/Modifier-Genes · concepts/Polygenic-Risk-Score · concepts/GWAS-Cardiac-Genetics · concepts/Epigenetics-Cardiac-Arrhythmia · concepts/iPSC-Derived-Cardiomyocytes · concepts/Cardiogenetic-Centers

Sources

• sources/clingen-summary-2026-05-09
• sources/competitive-sports-aha-2025
• sources/channelopathies-jaha-2025
• sources/inherited-arrhythmias-nrdp-2020
• sources/circadian-scd-jmcc-2025
• sources/drug-arrhythmia-aha-2020
• sources/gene-therapy-arrhythmia-2025
• sources/genetic-test-aha-2020
• sources/gwas-arrhythmias-cmp-genes-2025
• sources/arrhythmia-genetics-mgenetik-2025
• sources/membrane-potential-physrev-2021
• sources/modifier-genes-scd-ehj-2018
• sources/precision-lqts-tcm-2024
• sources/repolarisation-jaccep-2023
• sources/scn5a-jaccep-2018
• sources/lqts-jaccep-2022
• sources/lqts-nejm-2025
• sources/lqts-pregnancy-medicina-2022
• sources/VA-SCD-ESC-2022