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Classifications

Channelopathy

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Mappings

MONDO

MONDO:0019171 familial long QT syndrome

Orphanet ORPHA:101016 maps Romano-Ward syndrome to the same inherited familial long QT syndrome concept used by MONDO:0019171.

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Definitions

1

QT-prolonging-drug-associated torsade/marked-QTc case-finding query for latent congenital LQTS carriers

EHR/OMOP case-finding query: identify individuals who develop marked QTc prolongation or torsades de pointes after exposure to a known QT-prolonging (IKr/hERG-blocking) drug, without a prior LQTS diagnosis, as candidates for latent congenital LQTS warranting off-drug QTc reassessment and genetic evaluation. This is the pharmacological-trigger member of the trigger-provoked-latent-disease archetype (cf. the Timothy and Brugada fever queries); because drug-unmasking is established, derivation_basis is ESTABLISHED_CRITERIA.

PHENOTYPE_ALGORITHM EHR/OMOP case-finding for latent congenital LQTS carriers; grounded in the established drug-unmasking / reduced-repolarization-reserve mechanism but not yet validated as a computable phenotype.

Drug-associated marked QTc prolongation or torsade

Marked QTc prolongation (or documented torsades de pointes) during exposure to a known QT-prolonging drug, in a patient without a prior LQTS diagnosis; reassess QTc off the drug and refer for LQTS genetic testing.

Inclusion criteria

QT-prolonging drug exposure Active exposure to a drug on a recognized QT-prolonging/torsadogenic list (index exposure).
Marked QTc prolongation or torsades de pointes Marked QTc prolongation on ECG, or a documented torsade/polymorphic VT, during the drug exposure.

Exclusion criteria

Pre-existing LQTS diagnosis Already-diagnosed congenital LQTS (not a latent-case-finding hit).

Show evidence (1 reference)

PMID:11997281 SUPPORT Human Clinical

"DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in approximately 10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits."

Empirical basis for the query: ~10-15% of drug-associated torsade patients carry a congenital LQTS gene variant, so drug-provoked torsade enriches for latent carriers.

Notes: Pharmacological-trigger counterpart to the Timothy (MECHANISTIC_HYPOTHESIS) and Brugada (ESTABLISHED_CRITERIA, fever) queries — same trigger-provoked-latent-disease archetype with a drug as the provocation. See docs/hypothesis-based-phenotype-algorithms.md and docs/reports/hypothesis-driven-ehr-case-finding-2026-07-12.md.

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Inheritance

1

Autosomal dominant HP:0000006

The disease root is centered on the usually autosomal dominant inherited spectrum rather than recessive syndromic JLNS.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:10348966 SUPPORT Other

"The majority of cases are inherited by autosomal dominant transmission."

Supports using autosomal dominant inheritance for the familial long-QT root entry.

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Subtypes

16

Long QT Syndrome 1 MONDO:0100316

KCNQ1 hgnc:6294

KCNQ1-related form driven by reduced IKs-mediated repolarization reserve.

Long QT Syndrome 2 MONDO:0013367

KCNH2 hgnc:6251

KCNH2-related form driven by reduced IKr-mediated repolarization reserve.

Long QT Syndrome 3 MONDO:0011377

SCN5A hgnc:10593

SCN5A-related form driven by persistent late sodium current and especially relevant to mexiletine precision therapy.

Long QT Syndrome 4 MONDO:0800323

ANK2 hgnc:493

Historical ANK2-related LQT4 designation; detailed ankyrin-B syndrome curation remains in the separate ANK2-focused entry.

Long QT Syndrome 5 MONDO:0013372

KCNE1 hgnc:6240

KCNE1-related familial LQTS subtype.

Long QT Syndrome 6 MONDO:0013370

KCNE2 hgnc:6242

KCNE2-related familial LQTS subtype.

Long QT Syndrome 8 MONDO:0032756

CACNA1C hgnc:1390

CACNA1C-related LQTS subtype, with syndromic Timothy syndrome overlap curated separately.

Long QT Syndrome 9 MONDO:0012736

CAV3 hgnc:1529

CAV3-related familial LQTS subtype.

Long QT Syndrome 10 MONDO:0012737

SCN4B hgnc:10592

SCN4B-related familial LQTS subtype.

Long QT Syndrome 11 MONDO:0012738

AKAP9 hgnc:379

AKAP9-related familial LQTS subtype.

Long QT Syndrome 12 MONDO:0013062

SNTA1 hgnc:11167

SNTA1-related familial LQTS subtype.

Long QT Syndrome 13 MONDO:0013279

KCNJ5 hgnc:6266

KCNJ5-related familial LQTS subtype.

Long QT Syndrome 14 MONDO:0014548

CALM1 hgnc:1442

CALM1-related familial LQTS subtype.

Long QT Syndrome 15 MONDO:0014550

CALM2 hgnc:1445

CALM2-related familial LQTS subtype.

Long QT Syndrome 16 MONDO:0032915

TRDN hgnc:12261

TRDN-related familial LQTS subtype with catecholaminergic ventricular tachycardia overlap.

Other rare-gene familial LQTS

CALM3 hgnc:1449 KCNJ2 hgnc:6263 ALG10B hgnc:31088

Other inherited ion-channel or regulatory-gene forms retained at the disease root unless they define a separately curated clinically distinct syndrome. The three genes bound here have a ClinGen gene-disease validity assertion against long QT syndrome but no numbered LQTS subtype of their own in this entry: CALM3 (definitive), KCNJ2 (limited, and the gene of Andersen-Tawil syndrome, which is curated separately) and ALG10B (limited).

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Discussions and Knowledge Gaps

1

Can New Approach Methodologies functionally confirm and risk-stratify the latent congenital LQTS carriers surfaced by the drug-induced-torsade EHR case-finding query — distinguishing true reduced-repolarization-reserve carriers from incidental variants — using the CiPA in-vitro/in-silico paradigm and patient iPSC-cardiomyocytes?

OPEN QUESTION OPEN q_lqt_drug_query_nam_confirmation

Attached to

pathophysiology#QT-Prolonging Drug Unmasking of Reduced Repolarization Reserve

The EHR query (see this entry's definitions) surfaces candidates but cannot say whether a given variant actually reduces repolarization reserve. CiPA — the Comprehensive in vitro Proarrhythmia Assay — is a mature regulatory NAM that pairs in-vitro multi-ion-channel (notably hERG/IKr) measurement with an in-silico human ventricular action-potential model to predict torsade risk; this entry already curates such an O'Hara-Rudy-derived model. Applying CiPA to a candidate's variant, plus a patient-iPSC-cardiomyocyte drug challenge, is the mechanistic complement to the population EHR arm and a route to resolving variants of uncertain significance.

Proposed experiments

CiPA in-vitro/in-silico and iPSC-cardiomyocyte confirmation of query hits

CiPA in-vitro/in-silico proarrhythmia assay with iPSC-cardiomyocytes

exp_lqt_cipa_nam_confirmation

For candidate carriers surfaced by the drug-induced-torsade query, express the candidate KCNH2/KCNQ1/SCN5A variant heterologously and measure IKr (and the CiPA multi-channel panel); challenge patient-derived (and isogenic control) iPSC-cardiomyocytes with a QT-prolonging drug; and integrate the channel data into an in-silico human ventricular action-potential model (O'Hara-Rudy/ToR-ORd) to predict torsade risk. Concordant loss of repolarizing current, drug-induced APD prolongation/EADs, and an elevated in-silico torsade metric would confirm reduced repolarization reserve.

Model systems

Heterologous ion-channel expression (CiPA multi-channel panel)

Candidate variant expressed in a mammalian cell line; IKr/hERG and the CiPA multi-channel panel measured by patch clamp.

CELL LINE

human NCBITaxon:9606

Patient iPSC-derived cardiomyocytes

Patient-derived and isogenic-corrected iPSC-cardiomyocytes challenged with a QT-prolonging drug.

IPSC DERIVED MODEL

human NCBITaxon:9606

In-silico human ventricular action-potential model

O'Hara-Rudy/ToR-ORd human ventricular model integrating the measured channel block to predict torsade risk (CiPA in-silico arm).

OTHER

Perturbations

QT-prolonging drug challenge

pathophysiology#QT-Prolonging Drug Unmasking of Reduced Repolarization Reserve

Apply a QT-prolonging (IKr-blocking) drug across the in-vitro and in-silico systems.

Readouts

Repolarizing current, APD prolongation and EADs

pathophysiology#Prolonged Ventricular Action Potential Duration

IKr density, drug-induced APD prolongation and early afterdepolarizations in iPSC-cardiomyocytes, and the in-silico torsade metric.

Torsade propensity

pathophysiology#Torsades de Pointes

In-silico/iPSC torsade-risk classification for the candidate variant.

Decision criterion

Concordant reduction of repolarizing current, drug-induced APD prolongation/EADs, and an elevated in-silico torsade metric for a candidate variant versus isogenic control.

Supporting outcome

The variant genuinely reduces repolarization reserve, confirming a query hit as a true latent congenital LQTS carrier.

Refuting outcome

No functional deficit, indicating the query hit is not explained by that variant (incidental finding).

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Pathophysiology

9

Reduced Repolarizing Potassium Current

Many inherited long-QT subtypes reduce outward delayed rectifier potassium currents in cardiomyocytes, diminishing repolarization reserve and delaying completion of the ventricular action potential.

cardiomyocyte CL:0000746

KCNQ1 hgnc:6294 KCNH2 hgnc:6251

potassium ion transmembrane transport GO:0071805 ↓ DECREASED membrane repolarization during cardiac muscle cell action potential GO:0086013 ↕ DYSREGULATED

monoatomic ion channel activity GO:0005216 ⚠ ABNORMAL

heart UBERON:0000948

Downstream

Prolonged Ventricular Action Potential Duration Reduced repolarization reserve prolongs the ventricular action potential and creates an arrhythmogenic substrate.

Show evidence (2 references)

PMID:16001794 SUPPORT Other

"Loss of function in the slow component of the delayed rectifier potassium current (I(Ks)) channels (KCNQ1, KCNE1), the rapid component of the potassium current (I(Kr)) channels (KCNH2, KCNE2)"

Supports the core disease mechanism in which reduced repolarizing potassium current underlies common inherited LQTS subtypes.

PMID:42154296 SUPPORT In Vitro

"variant p.F68C causes a severe trafficking defect and exerts a dominant-negative effect on wild-type hERG channels, leading to markedly reduced rapid delayed rectifier potassium current (IKr)"

Demonstrates KCNH2 p.F68C causes loss-of-function through trafficking defect and dominant-negative effects, reducing IKr current density in LQT2.

Persistent Late Sodium Current in LQT3

In the SCN5A-mediated subtype, defective sodium-channel inactivation leaves a small persistent inward current during depolarization, further delaying myocardial repolarization.

cardiomyocyte CL:0000746

SCN5A hgnc:10593

sodium ion transmembrane transport GO:0035725 ⚠ ABNORMAL membrane repolarization during cardiac muscle cell action potential GO:0086013 ↕ DYSREGULATED

monoatomic ion channel activity GO:0005216 ⚠ ABNORMAL

heart UBERON:0000948

Downstream

Prolonged Ventricular Action Potential Duration Persistent inward sodium current prolongs ventricular repolarization and feeds the common arrhythmogenic substrate.

Sinus Bradycardia LQTS3 sodium-channel dysfunction can affect sinoatrial-node pacemaker activity and present with sinus bradycardia.

Show evidence (2 references)

PMID:10377081 SUPPORT In Vitro

"Two-electrode voltage-clamp recordings of a recombinant E1784K mutant channel expressed in Xenopus oocytes revealed a defect in fast inactivation characterized by a small, persistent current during long membrane depolarizations."

Shows the late inward sodium current mechanism characteristic of the SCN5A/LQT3 branch of inherited long QT syndrome.

PMID:10377081 SUPPORT In Vitro

"The functional defect exhibited by the mutant channel causes delayed myocardial repolarization"

Directly links persistent late sodium current to delayed myocardial repolarization in LQT3.

Impaired Calcium-Dependent Inactivation of the L-Type Calcium Current

The second route to a prolonged plateau, alongside reduced repolarizing potassium current and persistent late sodium current. Calmodulin, encoded identically by CALM1, CALM2 and CALM3, pre-associates with the IQ motif of the Cav1.2 pore-forming alpha-1C subunit (CACNA1C) and, on binding calcium, drives calcium-dependent inactivation of the channel. Variants on either side of that interaction leave the channel open longer than it should be: CACNA1C gain-of-function variants impair inactivation directly, while arrhythmogenic calmodulin variants disrupt the calcium-sensing step that triggers it. Either way calcium influx during the plateau is prolonged and the ventricular action potential lengthens. Calmodulin variants can act on the repolarizing side as well, reducing activation of Kv7.1 (KCNQ1), so a single calmodulin lesion can reach the action potential by both routes.

cardiomyocyte CL:0000746

CALM1 hgnc:1442 CALM2 hgnc:1445 CALM3 hgnc:1449 CACNA1C hgnc:1390

membrane depolarization during cardiac muscle cell action potential GO:0086012 ↑ INCREASED

calmodulin binding GO:0005516 ↓ DECREASED voltage-gated calcium channel activity involved in cardiac muscle cell action potential GO:0086007 ↑ INCREASED

heart UBERON:0000948

Downstream

Prolonged Ventricular Action Potential Duration Failure to terminate L-type calcium influx during the plateau lengthens the ventricular action potential, the same endpoint reached by reduced repolarizing potassium current and by persistent late sodium current.

Show evidence (5 references)

PMID:41294816 SUPPORT In Vitro

"In cardiomyocytes, it mediates Ca2+-dependent inactivation (CDI) of Cav1.2"

States the normal calmodulin function whose loss this node describes.

PMID:41294816 SUPPORT BACKGROUND Human Clinical

"It is encoded by three independent genes (CALM1–3), which produce identical proteins"

Why all three CALM genes are bound to one node rather than to three. Graded HUMAN_CLINICAL with `quote_role: BACKGROUND` because the sentence states an established fact about the human genes in this paper's introduction rather than reporting the mouse-myocyte and recombinant-protein work the paper did.

PMID:41294816 SUPPORT In Vitro

"Electrophysiological recordings demonstrated that CaM D133H impairs Ca2+-dependent inactivation (CDI) of Cav1.2, prolonging Ca2+ influx, while also reducing activation of Kv7.1, thereby limiting repolarising K+ currents. Together, these dual defects converge to prolong action potential duration,..."

The paper's own electrophysiological result for one arrhythmogenic calmodulin variant, and the step from impaired inactivation to a prolonged action potential that this node's downstream edge asserts.

+ 2 more references

Prolonged Ventricular Action Potential Duration

Reduced repolarization reserve and persistent inward sodium current prolong ventricular action potential duration and delay ventricular repolarization.

cardiomyocyte CL:0000746

membrane repolarization during cardiac muscle cell action potential GO:0086013 ↕ DYSREGULATED

heart UBERON:0000948

Computational models

O'Hara-Rudy (ORd) Human Ventricular Action Potential Model KINETIC APD90 computed from the simulated action potential is the single-cell correlate of prolonged ventricular repolarization in LQTS.

ToR-ORd Human Ventricular Myocyte Model KINETIC Multiscale validation includes repolarization abnormalities and drug-induced I_Kr block relevant to LQTS.

Downstream

Early Afterdepolarizations Prolonged ventricular action potential duration permits early afterdepolarizations to emerge from the plateau.

Prolonged QTc Interval Delayed ventricular repolarization is recorded clinically as QT-interval prolongation on basal electrocardiography.

Abnormal T-Wave Abnormal ventricular repolarization can produce abnormal T-wave morphology on the electrocardiogram.

Show evidence (1 reference)

PMID:28670758 SUPPORT Other

"This together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarizations (EADs), provides the substrate of ventricular tachyarrhythmia associated with LQTS, usually referred to as torsade de pointes (TdP) VT."

Review abstract identifies prolonged action potential duration as the proximal repolarization abnormality that precedes early afterdepolarizations in congenital LQTS.

Early Afterdepolarizations

Prolonged ventricular action potential duration promotes plateau oscillations and early afterdepolarizations that trigger torsades de pointes.

cardiomyocyte CL:0000746

cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL cardiac conduction GO:0061337 ↕ DYSREGULATED

heart UBERON:0000948

Computational models

O'Hara-Rudy (ORd) Human Ventricular Action Potential Model KINETIC I_Kr block during slow pacing induces early afterdepolarizations in the model, reproducing the arrhythmogenic trigger.

Downstream

Torsades de Pointes Early afterdepolarization-triggered ventricular tachyarrhythmias produce syncope, cardiac arrest, and sudden death.

Show evidence (2 references)

PMID:28670758 SUPPORT Other

"This together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarizations (EADs), provides the substrate of ventricular tachyarrhythmia associated with LQTS, usually referred to as torsade de pointes (TdP) VT."

Review abstract directly links prolonged action potential duration to plateau oscillations termed early afterdepolarizations in congenital LQTS.

PMID:10348966 SUPPORT Other

"The delayed recovery predisposes individuals to the development of early afterdepolarizations and initiation of torsade de pointes arrhythmias."

Supports the disease-level causal chain from delayed repolarization to early afterdepolarizations and torsades.

Adrenergic Trigger Susceptibility

Life-threatening events in familial LQTS are shaped by genotype-specific triggering circumstances. The classical LQT1-LQT3 subtypes differ in whether episodes cluster during exercise or rest/sleep, which informs risk stratification and anti-adrenergic management.

Downstream

Torsades de Pointes Genotype-specific triggering circumstances precipitate malignant ventricular arrhythmias against the repolarization substrate.

Show evidence (1 reference)

PMID:11136691 SUPPORT Human Clinical

"LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep..."

Supports subtype-aware trigger heterogeneity within the inherited LQTS root and justifies retaining LQT1-LQT3 as named subtypes under one disease entry.

QT-Prolonging Drug Unmasking of Reduced Repolarization Reserve

A QT-prolonging drug — most often an IKr/hERG (KCNH2) blocker — superimposed on a subclinical reduction in repolarization reserve precipitates marked QT prolongation and torsades de pointes. Individuals with a latent congenital LQTS genotype have diminished reserve, so a QT-prolonging drug can unmask an otherwise subclinical channelopathy. Drug-associated ("acquired") LQTS thus acts as a pharmacological provocation that surfaces latent congenital LQTS carriers; congenital LQTS gene variants are enriched among such patients. Unlike the Timothy-syndrome fever hypothesis, this drug-unmasking mechanism is well established.

cardiomyocyte CL:0000746

KCNH2 hgnc:6251

KCNE1 hgnc:6240 KCNE2 hgnc:6242

membrane repolarization during cardiac muscle cell action potential GO:0086013 ↓ DECREASED

monoatomic ion channel activity GO:0005216 ⚠ ABNORMAL

heart UBERON:0000948

Downstream

Prolonged Ventricular Action Potential Duration A QT-prolonging drug reduces net repolarizing current on a background of diminished reserve, prolonging the ventricular action potential.

Torsades de Pointes Marked drug-induced QT prolongation on a susceptible substrate precipitates torsades de pointes.

Show evidence (3 references)

PMID:11997281 SUPPORT Human Clinical

"DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in approximately 10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits."

In a large cohort of drug-associated (acquired) LQTS/torsades patients, 10-15% carry congenital long-QT gene variants, establishing that QT-prolonging drugs unmask a latent congenital substrate.

PMID:24561134 SUPPORT Human Clinical

"diLQTS patients were more burdened by rare AAC variants in cLQTS genes encoding potassium channel modulators, supporting the idea that multiple rare variants, notably across cLQTS genes, predispose to diLQTS."

Whole-exome sequencing shows drug-induced LQTS patients carry an excess of rare variants in congenital LQTS genes, supporting drug exposure as a provocation that surfaces latent genetic predisposition.

DOI:10.1161/CIRCULATIONAHA.119.043132 SUPPORT Human Clinical

"Although KCNE1 was classified as having only limited evidence and KCNE2 as having disputed evidence for causality in LQTS, both genes were classified as having strong evidence for specific risk alleles in predisposing to aLQTS"

The basis for binding KCNE1 and KCNE2 at this acquired/drug-provoked node rather than at the inherited repolarization node, and for the split grading their `genetic:` records carry.

Torsades de Pointes

Torsades de pointes is the characteristic malignant ventricular tachyarrhythmia of inherited LQTS, arising from prolonged repolarization, early afterdepolarizations, and permissive trigger conditions.

cardiomyocyte CL:0000746

cardiac conduction GO:0061337 ⚠ ABNORMAL

Computational models

CiPA IKr-Dynamic ORd Proarrhythmia Model KINETIC The qNet metric derived from this model classifies drug-induced torsades de pointes risk.

Downstream

Syncope Torsades de pointes commonly presents as transient loss of consciousness from arrhythmic cerebral hypoperfusion.

Seizure Arrhythmic loss-of-consciousness events in LQTS can present clinically as seizure or seizure-like episodes before the cardiac diagnosis is recognized.

Cardiac Arrest Sustained torsades de pointes or degeneration to ventricular fibrillation can progress to cardiac arrest.

Sudden Cardiac Death Untreated torsades de pointes can degenerate to a fatal ventricular arrhythmia.

Syncope and Sudden Cardiac Death Sustained torsades de pointes abolishes effective cardiac output, causing arrhythmic syncope and, when the rhythm does not terminate, sudden cardiac death.

Show evidence (2 references)

PMID:9272508 SUPPORT Other

"The familial long QT syndrome (LQTS) is now recognized as a genetic channelopathy with a propensity to arrhythmogenic syncope and sudden death."

Establishes the disease-level tendency toward syncope and sudden death in familial LQTS.

PMID:10348966 SUPPORT Other

"The torsade produces the syncope and sudden death."

Directly links torsades de pointes to the defining severe clinical outcomes.

Syncope and Sudden Cardiac Death

Loss of effective cardiac output during sustained torsades de pointes causes transient cerebral hypoperfusion (syncope) and, when the malignant ventricular arrhythmia does not terminate, sudden cardiac death. These are the shared sentinel clinical endpoints of inherited long QT syndrome.

cardiomyocyte CL:0000746

heart UBERON:0000948

Show evidence (2 references)

PMID:9272508 SUPPORT Other

"The familial long QT syndrome (LQTS) is now recognized as a genetic channelopathy with a propensity to arrhythmogenic syncope and sudden death."

Establishes arrhythmogenic syncope and sudden death as the shared clinical endpoint of familial long QT syndrome.

PMID:10348966 SUPPORT Other

"The torsade produces the syncope and sudden death."

Directly attributes the syncope and sudden-death endpoint to the torsades de pointes arrhythmia in inherited LQTS.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Cardiovascular 7

Prolonged QTc Interval OBLIGATE HP:0005184

Show evidence (2 references)

PMID:18606002 SUPPORT Other

"Congenital long QT syndrome (LQTS) is a hereditary cardiac disease characterized by a prolongation of the QT interval at basal ECG and by a high risk of life-threatening arrhythmias."

Supports QT prolongation as the defining electrocardiographic phenotype of inherited long QT syndrome.

ORPHA:101016 SUPPORT Other

"HP:0005184 | Prolonged QTc interval | Obligate (100%)"

Orphanet records prolonged QTc interval as obligate in Romano-Ward/familial LQTS.

Syncope FREQUENT HP:0001279

Show evidence (2 references)

PMID:18606002 SUPPORT Other

"The two cardinal manifestations of LQTS are syncopal episodes, that may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities, including prolongation of the QT interval and T wave abnormalities."

Review abstract identifies syncope as one of the cardinal manifestations of congenital long QT syndrome.

ORPHA:101016 SUPPORT Other

"HP:0001279 | Syncope | Frequent (79-30%)"

Orphanet frequency data supports syncope as frequent in Romano-Ward/familial LQTS.

Cardiac Arrest HP:0001695

Show evidence (1 reference)

PMID:18606002 SUPPORT Other

"The two cardinal manifestations of LQTS are syncopal episodes, that may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities, including prolongation of the QT interval and T wave abnormalities."

The cardinal-manifestation summary explicitly includes cardiac arrest as a major outcome of LQTS syncopal episodes.

Torsades de Pointes OCCASIONAL Torsade de pointes HP:0001664

Show evidence (2 references)

PMID:28670758 SUPPORT Other

"This together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarizations (EADs), provides the substrate of ventricular tachyarrhythmia associated with LQTS, usually referred to as torsade de pointes (TdP) VT."

Supports torsades de pointes ventricular tachycardia as the characteristic ventricular arrhythmia of LQTS.

ORPHA:101016 SUPPORT Other

"HP:0001664 | Torsade de pointes | Occasional (29-5%)"

Orphanet frequency data supports torsade de pointes as an occasional recorded phenotype.

Sudden Cardiac Death OCCASIONAL HP:0001645

Show evidence (2 references)

PMID:9272508 SUPPORT Other

"The familial long QT syndrome (LQTS) is now recognized as a genetic channelopathy with a propensity to arrhythmogenic syncope and sudden death."

Supports sudden cardiac death as a core disease manifestation of familial long QT syndrome.

ORPHA:101016 SUPPORT Other

"HP:0001645 | Sudden cardiac death | Occasional (29-5%)"

Orphanet frequency data supports sudden cardiac death as an occasional recorded outcome in Romano-Ward/familial LQTS.

Sinus Bradycardia FREQUENT HP:0001688

Show evidence (1 reference)

ORPHA:101016 SUPPORT Other

"HP:0001688 | Sinus bradycardia | Frequent (79-30%)"

Orphanet frequency data supports sinus bradycardia as frequent in Romano-Ward/familial LQTS.

Abnormal T-Wave FREQUENT HP:0005135

Show evidence (2 references)

PMID:10348966 SUPPORT Other

"The signs of long QT syndrome are prolongation of the QT interval on the electrocardiogram and abnormalities of T wave morphology."

Review abstract supports abnormal T-wave morphology as a diagnostic ECG feature of inherited LQTS.

ORPHA:101016 SUPPORT Other

"HP:0005135 | Abnormal T-wave | Frequent (79-30%)"

Orphanet frequency data supports abnormal T-wave as frequent in Romano-Ward/familial LQTS.

Nervous System 1

Seizure OCCASIONAL HP:0001250

Show evidence (1 reference)

ORPHA:101016 SUPPORT Other

"HP:0001250 | Seizure | Occasional (29-5%)"

Orphanet frequency data supports seizure as an occasional recorded phenotype in Romano-Ward/familial LQTS.

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Genetic Associations

18

KCNQ1 (Causative)

Gene: KCNQ1 hgnc:6294 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:16001794 SUPPORT Other

"Loss of function in the slow component of the delayed rectifier potassium current (I(Ks)) channels (KCNQ1, KCNE1)"

This supports KCNQ1 as a causative gene in the inherited LQT1 branch of long QT syndrome.

CGGV:assertion_dff8874e-98a1-472b-9cc2-3f441b1c1064-2018-09-25T040000.000Z SUPPORT Other

ClinGen classifies the KCNQ1-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

KCNH2 (Causative)

Gene: KCNH2 hgnc:6251 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:16001794 SUPPORT Other

"Loss of function in the slow component of the delayed rectifier potassium current (I(Ks)) channels (KCNQ1, KCNE1), the rapid component of the potassium current (I(Kr)) channels (KCNH2, KCNE2)"

This supports KCNH2 as a core causative gene for the inherited LQT2 subtype series.

CGGV:assertion_462eeb4e-357d-4c3d-89f0-e386ac0d011b-2018-09-25T040000.000Z SUPPORT Other

ClinGen classifies the KCNH2-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

SCN5A (Causative)

Gene: SCN5A hgnc:10593 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:16001794 SUPPORT Other

"Changes of function in the alpha-subunit of cardiac sodium channels (SCN5A) is also linked to the LQTS type 3 and the BrS."

This supports SCN5A as the defining causative gene for LQT3 within inherited long QT syndrome.

ALG10B (Pathogenic Variants)

Gene: ALG10B hgnc:31088

Show evidence (1 reference)

CGGV:assertion_6499e6e2-af96-4868-bfd5-18ab35f61847-2026-01-15T010000.000Z SUPPORT Other

ClinGen classifies the ALG10B-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.

CACNA1C (Pathogenic Variants)

Gene: CACNA1C hgnc:1390 gene page

Show evidence (1 reference)

CGGV:assertion_c496551d-c7a7-4e49-ad41-8cfd49840dc1-2020-04-24T040000.000Z SUPPORT Other

ClinGen classifies the CACNA1C-long QT syndrome gene-disease relationship as moderate with autosomal dominant inheritance.

CALM1 (Pathogenic Variants)

Gene: CALM1 hgnc:1442 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

CGGV:assertion_4a150cd9-e16b-4992-8cc7-5ccec44b4d6b-2018-09-25T160000.000Z SUPPORT Other

ClinGen classifies the CALM1-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

CALM2 (Pathogenic Variants)

Gene: CALM2 hgnc:1445 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

CGGV:assertion_86e4b783-3b60-4a1d-ab34-e61d27751ca6-2018-09-25T160000.000Z SUPPORT Other

ClinGen classifies the CALM2-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

CALM3 (Pathogenic Variants)

Gene: CALM3 hgnc:1449 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

CGGV:assertion_3cc2a1ae-5f3d-445c-b124-f3d38fdd070a-2018-09-25T160000.000Z SUPPORT Other

ClinGen classifies the CALM3-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

CAV3 (Pathogenic Variants)

Gene: CAV3 hgnc:1529 gene page

Show evidence (1 reference)

CGGV:assertion_74aabddc-3402-46de-ba1e-f66aa273cd9c-2020-12-15T002855.870Z SUPPORT Other

ClinGen classifies the CAV3-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.

KCNJ2 (Pathogenic Variants)

Gene: KCNJ2 hgnc:6263 gene page

Show evidence (1 reference)

CGGV:assertion_5dc2acbc-8dbe-4142-8f71-89f1576dde08-2020-12-15T002535.799Z SUPPORT Other

ClinGen classifies the KCNJ2-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.

TRDN (Pathogenic Variants)

Gene: TRDN hgnc:12261 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

CGGV:assertion_1278bd6a-6ac7-4556-87ea-f860027b2da5-2020-04-24T040000.000Z SUPPORT Other

ClinGen classifies the TRDN-long QT syndrome gene-disease relationship as strong with autosomal recessive inheritance.

KCNE1 (Limited evidence for unprovoked congenital LQTS; strong for acquired)

Gene: KCNE1 hgnc:6240 gene page

Show evidence (2 references)

CGGV:assertion_957550ae-d91c-49e7-be7c-ff5a13faa3ff-2020-12-15T002142.973Z SUPPORT Other

ClinGen's assertion, and the only one in this entry recorded against a numbered LQTS class (MONDO:0013372) rather than against the parent long QT syndrome term.

CGGV:assertion_957550ae-d91c-49e7-be7c-ff5a13faa3ff-2020-12-15T002142.973Z REFUTE Other

"There is strong evidence associating KCNE1 with acquired LQTS, however, only limited evidence for its association with unprovoked LQTS."

REFUTE against the claim this entry is scoped to - KCNE1 as a cause of inherited, unprovoked long QT syndrome. The same sentence supports the acquired-LQTS role, which is curated at the drug-unmasking node instead.

KCNE2 (Disputed as a cause of unprovoked congenital LQTS)

Gene: KCNE2 hgnc:6242 gene page relationship_type: DISPUTED

Show evidence (2 references)

CGGV:assertion_9912be79-b172-46ca-a67c-99698de5590b-2020-12-15T002341.412Z SUPPORT Other

The ClinGen validity row behind the DISPUTED typing of this record.

CGGV:assertion_9912be79-b172-46ca-a67c-99698de5590b-2020-12-15T002341.412Z REFUTE Other

"KCNE2 variants reported for LQTS routinely require secondary provocation to induce phenotype, persuading the Expert Panel to conclude that KCNE2 has no supportive evidence as a cause of LQTS in the absence of provoking factors"

The panel's reasoning, quoted because the DISPUTED value alone does not say why - and the reason here is specific and reusable.

SCN4B (Disputed as a cause of congenital LQTS)

Gene: SCN4B hgnc:10592 relationship_type: DISPUTED

Show evidence (2 references)

CGGV:assertion_0e276096-21ab-42bc-866a-b1b4dcb01753-2018-09-25T160000.000Z SUPPORT Other

The ClinGen validity row behind the DISPUTED typing of this record.

CGGV:assertion_0e276096-21ab-42bc-866a-b1b4dcb01753-2018-09-25T160000.000Z REFUTE Other

"Because of the candidate gene approach, lack of segregation or case-control data and paucity of additional genetic and experimental data, this gene-disease association was classified as disputed."

The panel's stated grounds for disputing the SCN4B-LQTS association.

AKAP9 (Disputed as a cause of congenital LQTS)

Gene: AKAP9 hgnc:379 relationship_type: DISPUTED

Show evidence (2 references)

CGGV:assertion_786eac72-8014-4fdf-b279-10a5faaa09b8-2020-12-15T002607.349Z SUPPORT Other

The ClinGen validity row behind the DISPUTED typing of this record.

CGGV:assertion_786eac72-8014-4fdf-b279-10a5faaa09b8-2020-12-15T002607.349Z REFUTE Other

"The first study to associate this gene with LQTS used a candidate gene approach and identified a missense variant in AKAP9 in a single patient with LQTS"

The whole of the genetic evidence the panel found for this association, and the reason it is disputed rather than merely limited.

SNTA1 (Disputed as a cause of congenital LQTS)

Gene: SNTA1 hgnc:11167 relationship_type: DISPUTED

Show evidence (2 references)

CGGV:assertion_03c758a6-9290-4e14-9501-0ffb0fbfe8ce-2020-04-24T040000.000Z SUPPORT Other

The ClinGen validity row behind the DISPUTED typing of this record.

CGGV:assertion_03c758a6-9290-4e14-9501-0ffb0fbfe8ce-2020-04-24T040000.000Z REFUTE Other

"One of these variants, however, is now known to be present in ~1:150 individuals of European descent, making it an unlikely cause of a rare disease."

The population-frequency argument against the SNTA1-LQTS association, quoted because it is a different and stronger kind of refutation than a study-design objection.

KCNJ5 (Disputed as a cause of congenital LQTS)

Gene: KCNJ5 hgnc:6266 gene page relationship_type: DISPUTED

Show evidence (2 references)

CGGV:assertion_6fa6a520-ae6b-4638-a092-a61831d481bf-2020-12-15T002641.568Z SUPPORT Other

The ClinGen validity row behind the DISPUTED typing of this record.

CGGV:assertion_6fa6a520-ae6b-4638-a092-a61831d481bf-2020-12-15T002641.568Z REFUTE Other

"The Gly387Arg variant identified in this family, however, is now recognized to be present in 1/200 individuals of East Asian descent, making it very unlikely to be a rare cause of a rare disease."

The population-frequency argument the panel used to dispute the KCNJ5-LQTS association.

ANK2 (Disputed as a cause of congenital LQTS; curated as its own entity elsewhere)

Gene: ANK2 hgnc:493 gene page relationship_type: DISPUTED

Show evidence (2 references)

CGGV:assertion_dd577817-d668-413c-95f9-d3e08a8cf5d3-2020-12-15T002719.834Z SUPPORT Other

The ClinGen validity row behind the DISPUTED typing of this record.

DOI:10.1161/CIRCULATIONAHA.119.043132 REFUTE Human Clinical

"Six genes, AKAP9, ANK2, KCNE2, KCNJ5, SCN4B, and SNTA1, were classified as disputed, defined as the absence of sufficient genetic evidence to support causation of LQTS"

The published reappraisal naming all six disputed genes together, which is the single source behind the DISPUTED typing on this record and on the five others in this entry.

🗃️

External Assertions

1

Orphanet Romano-Ward syndrome disease record

Orphanet structured disease record ORPHA:101016

Orphanet's ORPHA:101016 structured record for Romano-Ward syndrome provides the familial LQTS definition, inheritance, epidemiology, gene table, HPO phenotype frequencies, and cross-references used to align this inherited LQTS root entry.

Show evidence (1 reference)

ORPHA:101016 SUPPORT Other

"A form of familial long QT syndrome (LQTS) characterized by syncopal episodes and electrocardiographic abnormalities (QT prolongation, T-wave abnormalities and torsade de pointes (TdP) ventricular tachycardia)."

Orphanet defines Romano-Ward syndrome as a familial LQTS form with the core electrocardiographic and syncopal phenotype.

💊

Medical Actions

5

Beta-Blocker Therapy

Action: beta-blocker therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576

First-line anti-adrenergic therapy for most patients with inherited long QT syndrome.

Mechanism Target:

INHIBITS Adrenergic Trigger Susceptibility — Anti-adrenergic therapy reduces the likelihood that subtype-specific exercise or emotion-related triggers will precipitate malignant ventricular arrhythmias.

Show evidence (1 reference)

PMID:10673253 SUPPORT Human Clinical

"beta-blockers are associated with a significant reduction in cardiac events in LQTS patients."

Supports beta-blocker therapy as effective anti-adrenergic risk reduction in congenital long QT syndrome.

Show evidence (2 references)

PMID:18606002 SUPPORT Other

"Treatment should always begin with beta-blockers, unless there are valid contraindications."

Review abstract states that beta-blockers are the mandatory first-line treatment for congenital long QT syndrome.

PMID:10673253 SUPPORT Human Clinical

"beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers"

Defines both the benefit and the residual risk that prompt escalation beyond beta-blockers in higher-risk patients.

Left Cardiac Sympathetic Denervation

Action: left cardiac sympathetic denervation Ontology label: Surgical Procedure NCIT:C15329

Surgical anti-adrenergic escalation when recurrent syncope or major events persist despite full-dose beta-blockade.

Mechanism Target:

INHIBITS Adrenergic Trigger Susceptibility — Left cardiac sympathetic denervation reduces arrhythmia-provoking sympathetic input when pharmacologic anti-adrenergic therapy is insufficient.

Show evidence (1 reference)

PMID:18606002 SUPPORT Other

"If the patient has one more syncope despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation"

Supports LCSD as the preferred escalation step after recurrent syncope despite adequate beta-blockade.

Show evidence (1 reference)

PMID:18606002 SUPPORT Other

"If the patient has one more syncope despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation"

Review abstract explicitly recommends LCSD after recurrent syncope on full-dose beta-blockade.

Implantable Cardioverter-Defibrillator Placement

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Device therapy for high-risk patients, especially after cardiac arrest or when malignant events recur despite optimal medical therapy.

Show evidence (1 reference)

PMID:15191637 SUPPORT Other

"For high-risk patients, the implantable cardioverter-defibrillator (ICD) offer an effective therapeutic option to reduce mortality."

Supports ICD placement as mortality-reducing therapy in high-risk congenital long QT syndrome.

Mexiletine

Action: Pharmacotherapy NCIT:C15986

Agent: mexiletine CHEBI:6916

Precision pharmacotherapy most relevant to the SCN5A/LQT3 subtype, where late sodium current blockade shortens QTc and lowers arrhythmic event burden.

Mechanism Target:

INHIBITS Persistent Late Sodium Current in LQT3 — Mexiletine blocks late sodium current in the SCN5A-mediated subtype, shortening QTc and reducing malignant arrhythmic events.

Show evidence (1 reference)

PMID:26940925 SUPPORT Human Clinical

"Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy."

Supports mexiletine as subtype-targeted pharmacotherapy for the LQT3 branch of inherited long QT syndrome.

Allele-Specific RNA Interference

Action: allele-specific RNA interference therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: siRNA therapeutic agent NCIT:C201688

Emerging precision therapeutic strategy targeting loss-of-function KCNH2 variants in LQT2 patients. RNA interference selectively suppresses mutant KCNH2 transcript while preserving wild-type expression, alleviating dominant-negative effects and restoring hERG current density.

Mechanism Target:

INHIBITS Reduced Repolarizing Potassium Current — Allele-specific RNA interference suppresses the expression of mutant KCNH2 transcripts carrying loss-of-function variants, reducing their dominant-negative interference with wild-type hERG channels and partially restoring IKr current density.

Show evidence (1 reference)

PMID:42154296 SUPPORT In Vitro

"allele-specific RNA interference selectively suppressed mutant hERG expression, alleviated dominant-negative interference, and partially restored hERG current density without detectable cytotoxicity"

Demonstrates that allele-specific RNAi is effective at rescuing loss-of-function by suppressing mutant KCNH2 expression.

🔬

Diagnosis

3

Resting electrocardiography with QTc and T-wave assessment

Baseline 12-lead ECG remains the core diagnostic procedure for identifying QT prolongation and genotype-patterned T-wave abnormalities in suspected inherited long QT syndrome.

clinical assessment NCIT:C124351

QTc LOINC:8636-3

Reference Ranges

Q-T interval corrected (Guideline diagnostic QTc cut-off, as applied by Vink et al. (Circulation 2018) to 1484 genotyped individuals from 265 families with LQT1, LQT2 or LQT3)

QTc at or above the guideline diagnostic cut-off (≥ 480 ms)

QTc at or above the guideline diagnostic cut-off: Meets the guideline QTc cut-off for diagnosing LQTS; below it, LQTS is not excluded, since a share of gene carriers have a normal QTc.

LOINC:8636-3 names no correction formula; the formula-specific codes LOINC:76635-2 (Bazett) and LOINC:76634-5 (Fridericia) exist and are not bound, because the cited abstract reports that cut-off performance depends on the correction formula as well as on the QT measurement method, age and sex. The abstract calls 480 ms "the current guideline cutoff" without naming the guideline or writing an inequality; the band treats 480 ms as the lower, included boundary. The QTc point bands of the Schwartz score and the HRS/EHRA/APHRS 2013 QTc criterion are not recorded as ranges, because no cached text carries them: the Schwartz and Crotti review (PMID:18606002, full text) describes the point score and its probability categories but its Table 2 with the QTc points is not in the cached text; the Schwartz diagnostic-criteria update (PMID:8339437), the HRS/EHRA/APHRS consensus statement and its two executive summaries (PMID:24011539, PMID:23994779, PMID:23916535) and two ESC ventricular arrhythmia guidelines (PMID:26320108, PMID:36017572) returned no abstract text, and PubMed searches for LQTS abstracts quoting the Schwartz QTc bands returned none. Searched 2026-10-07.

Show evidence (2 references)

PMID:30571576 SUPPORT Human Clinical

"Using the current guideline cutoff (QTc interval 480 ms), both methods had similar specificity but yielded a different sensitivity."

States the guideline diagnostic QTc cut-off of 480 ms, applied in a genotyped LQTS family cohort.

PMID:30571576 SUPPORT Human Clinical

"Adjusted cutoff values are therefore specified for method, correction formula, age, and sex."

The reason the method-less QTc code is bound rather than a formula-specific one.

Results: Prolonged QTc with characteristic T-wave abnormalities supports inherited LQTS, but a normal QTc does not exclude the diagnosis in concealed carriers.

NCIT does not provide an ECG-specific diagnostic term here, so the preferred term is narrowed in the name and description.

Show evidence (2 references)

PMID:10348966 SUPPORT Other

"The signs of long QT syndrome are prolongation of the QT interval on the electrocardiogram and abnormalities of T wave morphology."

Supports ECG-based recognition of QT prolongation and T-wave morphology as the primary diagnostic assessment.

PMID:10348966 SUPPORT Other

"Approximately 12% of long QT gene carriers have a normal QTc, < or =0. 44 seconds. Thus, a normal QTc interval does not exclude long QT syndrome."

Clarifies why concealed disease remains possible despite a normal resting QTc.

Integrated clinical criteria and family-history review

Borderline presentations require formal integration of electrocardiographic, clinical, and familial findings rather than reliance on QTc alone.

clinical assessment NCIT:C124351

Results: Specific diagnostic criteria help resolve borderline or intermittently expressed phenotypes when ECG findings are not unequivocal.

Show evidence (1 reference)

PMID:18606002 SUPPORT Other

"However, borderline cases are more complex and require the evaluation of various electrocardiographic, clinical, and familial findings, as proposed in specific diagnostic criteria."

Directly supports formal multicomponent diagnostic criteria for borderline inherited LQTS.

Molecular genetic testing

Molecular testing is used to confirm the inherited diagnosis, define the subtype, and support cascade family screening when a pathogenic variant is identified.

molecular genetic testing NCIT:C19770

Results: Detection of a pathogenic variant in a validated LQTS gene supports the inherited diagnosis and refines subtype-aware counseling and management.

Show evidence (1 reference)

PMID:18606002 SUPPORT Other

"Additionally, molecular screening is now part of the diagnostic process."

Supports routine integration of molecular testing into modern inherited LQTS diagnosis.

📊

Prevalence

1

Live births

Birth Prevalence 40.0 per 100,000 1–9 per 10,000 (births)

Estimated prevalence is close to 1 in 2,500 live births.

Show evidence (1 reference)

PMID:18606002 SUPPORT Other

"Disease prevalence is estimated at close to 1 in 2,500 live births."

Provides a disease-level prevalence estimate for inherited long QT syndrome.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Familial Long QT Syndrome:

Acquired long QT syndrome

Overlapping Features Drug-induced or metabolic QT prolongation can closely mimic congenital LQTS and must be excluded before an inherited diagnosis is finalized.

Distinguishing Features

Reversible exposure to QT-prolonging drugs, bradycardia, or electrolyte disturbance favors an acquired cause
Inherited LQTS is diagnosed from persistent clinical and electrocardiographic features rather than an isolated exposure history

Show evidence (2 references)

PMID:15191637 SUPPORT Other

"For acquired LQTS, it is generally believed that the main issue is the blockade of the slow component of the delayed rectifier K+ current (IKr)."

Supports acquired long QT syndrome as the major mechanistic and clinical mimic that must be separated from inherited disease.

PMID:15191637 SUPPORT Other

"For patients with a history of drug-induced LQTS, care must be taken to avoid further exposure to QT-prolonging drugs or conditions."

Highlights a reversible exposure history as a distinguishing feature of acquired rather than congenital LQTS.

Brugada syndrome MONDO:0015263

Overlapping Features Sodium-channel overlap syndromes can blur the boundary between LQT3 and Brugada syndrome, especially in SCN5A-mediated disease.

Distinguishing Features

Brugada syndrome is defined by right precordial ST-segment elevation rather than baseline QT prolongation
Some SCN5A variants can create mixed phenotypes, so both repolarization and depolarization signatures should be reviewed

Show evidence (1 reference)

PMID:18451998 SUPPORT Human Clinical

"Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A."

Directly supports Brugada syndrome as a clinically important differential diagnosis and overlap state for SCN5A-mediated LQT3.

📊

Related Datasets

1

Modeling long QT syndrome using gene-edited pigs geo:GSE288082

Bulk RNA-seq dataset from left ventricular tissue of a KCNH2-mutant miniature pig model developed to recapitulate LQT2-associated electrophysiology and remodeling.

pig BULK RNA SEQ n=8

left ventricular myocardium UBERON:0002084

Conditions: KCNH2-mutant long QT syndrome type 2 miniature pig wild-type left ventricular control tissue

GEO summary describes transcriptomic comparison of KCNH2-mutant versus wild type ventricular tissue in a large-animal LQT2 model.

Show evidence (1 reference)

GEO:GSE288082 SUPPORT Model Organism

"To explore the mechanism underlying mutation of KCNH2 caused LQT, we compared the transcriptomes of KCNH2-mut pigs and WT controls"

This supports GSE288082 as a disease-relevant large-animal transcriptomic dataset for KCNH2-mediated long QT syndrome biology.

🔬

Clinical Trials

2

NCT01648205 PHASE_II COMPLETED

Single-blinded phase II study of ranolazine in genotyped LQT3 patients to test whether late sodium current blockade can shorten QTc over longitudinal follow-up.

Target Phenotypes: prolonged QT interval HP:0001657

Show evidence (1 reference)

clinicaltrials:NCT01648205 SUPPORT Human Clinical

"The purpose of this study is to determine whether late sodium channel blockade might be effective in shortening the QTc interval in various LQT3 mutations and be considered as a safe therapeutic option for LQT3 patients."

Supports a subtype-specific ranolazine trial directly targeting late sodium current physiology in LQT3.

NCT05906732 NOT_APPLICABLE TERMINATED

Combined phase 1b/2a study of the SGK1 inhibitor LQT-1213, pairing a dofetilide challenge in healthy adults with safety and pharmacodynamic testing in patients with LQT2 or LQT3.

Target Phenotypes: prolonged QT interval HP:0001657

Show evidence (1 reference)

clinicaltrials:NCT05906732 SUPPORT Human Clinical

"Part 2: This is a Phase 2a, single-blind, placebo run-in, multiple-dose safety study to evaluate the safety, tolerability, and PK of LQT-1213 in patients diagnosed with LQT2 or LQT3."

Supports an actively developed precision-therapy program for inherited LQT2/LQT3 biology.

🧮

Computational Models

3

O'Hara-Rudy (ORd) Human Ventricular Action Potential Model CellML KINETIC

Foundational system of ordinary differential equations for the undiseased human ventricular cardiomyocyte action potential, fit to human myocyte data for the major ionic currents (I_CaL, I_Kr, I_Ks, I_K1, I_to, late I_Na, I_NaCa, I_NaK) with intracellular Ca2+ and CaMKII handling. Long QT syndrome is simulated by reducing repolarizing K+ conductance (I_Kr for LQT2, I_Ks for LQT1) or increasing the persistent late Na+ current (LQT3); each perturbation prolongs action potential duration and, during slow pacing, generates early afterdepolarizations, the cellular substrate for torsades de pointes.

Repository ↗ PMID:21637795

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Membrane potential Transmembrane potential of the ventricular cardiomyocyte, the primary ODE state variable.	`v`	mV
Action potential duration at 90% repolarization (APD90) Time from action potential upstroke to 90% repolarization; the single-cell correlate of the QT interval and the principal LQTS readout.	`APD90`	ms		Prolonged QTc interval above 300 mild 300 moderate 400 severe 500

Pathograph links

Prolonged Ventricular Action Potential Duration APD90 computed from the simulated action potential is the single-cell correlate of prolonged ventricular repolarization in LQTS.

Early Afterdepolarizations I_Kr block during slow pacing induces early afterdepolarizations in the model, reproducing the arrhythmogenic trigger.

Findings

I_Kr block during slow pacing induces early afterdepolarizations in the model, the cellular trigger for torsades de pointes in LQT2 and drug-induced long QT

Show evidence (1 reference)

PMID:21637795 SUPPORT Computational

"Early afterdepolarizations were induced by I(Kr) block during slow pacing, and AP and Ca(2+) alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle."

Confirms the model reproduces I_Kr-block-induced early afterdepolarizations, the arrhythmogenic mechanism shared by LQT2 and acquired (drug-induced) long QT syndrome.

CellML encoding in the Physiome Model Repository (exposure e/71); original MATLAB from the Rudy Lab. Endocardial, midmyocardial, and epicardial cell variants are provided. Base model for the CiPA IKr-dynamic ORd and ToR-ORd refinements below.

Show evidence (1 reference)

PMID:21637795 SUPPORT Computational

"an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed"

Establishes ORd as the reference undiseased human ventricular action potential ODE model, the baseline for simulating LQTS ion-channel perturbations.

CiPA IKr-Dynamic ORd Proarrhythmia Model KINETIC

Regulatory in-silico proarrhythmia model built on the O'Hara-Rudy ORd model by replacing the I_Kr formulation with a Markov model of dynamic drug-hERG (I_Kr) binding. Combined with multi-channel pharmacology (up to seven currents), it computes the net-charge metric qNet to stratify drug-induced torsades de pointes (TdP) risk. This is the acquired (drug-induced) long QT / proarrhythmia arm and is the consensus cell model of the FDA/HESI CiPA initiative.

Repository ↗ PMID:28878692 Base model: O'Hara-Rudy ORd human ventricular action potential model (PMID:21637795)

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
qNet Net electronic charge carried by the major inward and outward ionic currents over a steady-state action potential; lower qNet indicates higher drug-induced torsades de pointes risk.	`qNet`	microC/microF	Torsade de pointes

Pathograph links

Torsades de Pointes The qNet metric derived from this model classifies drug-induced torsades de pointes risk.

Findings

The CiPA initiative uses an in-silico cell model with multi-channel pharmacology to predict drug-induced torsades de pointes risk

Show evidence (1 reference)

PMID:28878692 SUPPORT Computational

"The Comprehensive in vitro Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using in silico models and in vitro multi-channel pharmacology data as integral parts of this initiative."

Establishes the regulatory purpose of the model: in-silico prediction of drug-induced TdP risk.

The qNet net-charge metric classifies drug-induced TdP risk across a range of concentrations and pacing rates

Show evidence (1 reference)

PMID:28878692 SUPPORT Computational

"we developed an updated version of the metric that quantifies the net electronic charge carried by major inward and outward ionic currents during the steady state action potential, which could classify the level of drug-induced TdP risk across a wide range of concentrations and pacing rates"

Defines qNet as the model output used to stratify drug-induced TdP risk.

Consensus in-silico model of the FDA/HESI Comprehensive in vitro Proarrhythmia Assay (CiPA); reference implementation at github.com/FDA/CiPA. Optimized by Dutta et al. 2017 from the IKr-dynamic ORd model.

Show evidence (1 reference)

PMID:28878692 SUPPORT Computational

"we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model)"

Documents that the CiPA proarrhythmia model is the ORd model extended with a dynamic drug-I_Kr (hERG) Markov model, tying acquired long QT and TdP risk to the same repolarization-reserve mechanism as congenital LQTS.

ToR-ORd Human Ventricular Myocyte Model CellML KINETIC

Tomek-Rodriguez-O'Hara-Rudy refinement of the ORd model, recalibrated and independently validated across health, disease, and drug block, with a reformulated L-type Ca2+ current and a replaced hERG (I_Kr) current. It scales from single-cell ionic dynamics to whole-organ simulation including the electrocardiogram, and is a current reference human ventricular model for LQTS repolarization and drug-block studies.

Repository ↗ PMID:31868580 Base model: O'Hara-Rudy ORd human ventricular action potential model (PMID:21637795)

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Membrane potential Transmembrane potential of the ventricular cardiomyocyte, the primary ODE state variable.	`v`	mV
Action potential duration at 90% repolarization (APD90) ToR-ORd recalibrated action potential duration at 90% repolarization; the single-cell correlate of the QT interval and the principal LQTS readout, computed with the reformulated I_CaL and replaced hERG (I_Kr) formulations.	`APD90`	ms		Prolonged QTc interval above 300 mild 300 moderate 400 severe 500

Pathograph links

Prolonged Ventricular Action Potential Duration Multiscale validation includes repolarization abnormalities and drug-induced I_Kr block relevant to LQTS.

Findings

ToR-ORd is validated under healthy and key disease conditions and under drug blockade, supporting its use for LQTS and drug-induced repolarization studies

Show evidence (1 reference)

PMID:31868580 SUPPORT Computational

"Validation based on substantial multiscale simulations supports the credibility of the ToR-ORd model under healthy and key disease conditions, as well as drug blockade."

Confirms disease- and drug-block validation, the basis for applying the model to congenital and acquired long QT syndrome.

Code (MATLAB and CellML), the validation pipeline, and human AP morphology data at github.com/jtmff/torord; a CellML exposure is also in the Physiome Model Repository.

Show evidence (1 reference)

PMID:31868580 SUPPORT Computational

"we present the design, development, calibration and independent validation of a human-based ventricular model (ToR-ORd) for simulations of electrophysiology and excitation-contraction coupling, from ionic to whole-organ dynamics, including the electrocardiogram"

Describes ToR-ORd as a multiscale (cell to ECG) human ventricular model suitable for linking LQTS ion-channel defects to the QT interval.

{ }

Source YAML

click to show

name: Familial Long QT Syndrome
creation_date: '2026-04-14T05:37:14Z'
description: >-
  Familial long QT syndrome (LQTS) is a heritable cardiac channelopathy of
  ventricular repolarization characterized by QT prolongation, torsades de
  pointes, syncope, cardiac arrest, and sudden cardiac death. This entry serves
  as the disease-level inherited LQTS root for the classical subtype series and
  related non-syndromic multigene forms. It intentionally separates acquired
  long QT syndrome and avoids duplicating detailed entries for clinically
  distinct syndromic or overlap descendants such as Jervell and Lange-Nielsen
  syndrome, ankyrin-B syndrome, Andersen-Tawil syndrome, and Timothy syndrome.
category: Genetic
disease_term:
  preferred_term: familial long QT syndrome
  term:
    id: MONDO:0019171
    label: familial long QT syndrome
synonyms:
- Long QT syndrome
- LQTS
- inherited long QT syndrome
- congenital long QT syndrome
- Romano-Ward syndrome
- Romano-Ward long QT syndrome
- Ward-Romano syndrome
parents:
- Cardiac Arrhythmia
- Channelopathy
notes: >-
  Curated as the disease-level inherited long-QT root so that canonical
  LQT1-LQT16 and related rare-gene familial forms can be lumped under one
  mechanistic entry without duplicating separately curated syndromic or
  gene-specific entries.

  Reading the gene records. The LQT numbering and the strength of the
  gene-disease evidence are two different things, and this entry keeps them in
  two different slots. A `has_subtypes` row's `genes:` list says which gene the
  numbered designation refers to; it is not an endorsement. The `genetic:`
  record for that gene carries the grading, and for six of them the grading is
  `relationship_type: DISPUTED`. In 2020 ClinGen's long QT expert panel
  reappraised the 17 genes then reported as LQTS causes and found, of those 17,
  only KCNQ1, KCNH2 and SCN5A definitive, six disputed (AKAP9, ANK2, KCNE2,
  KCNJ5, SCN4B, SNTA1) and three limited (CAV3, KCNE1, KCNJ2). That is the 2020
  reappraisal's verdict on that set of 17, not ClinGen's current roster: the
  gene-validity download read on 2026-09-19 also carries CALM1, CALM2 and CALM3
  as definitive, TRDN as strong, CACNA1C as moderate and ALG10B as limited, all
  of which this entry curates. The numbered subtypes for the disputed and limited
  genes are retained because the designations remain in wide use and are what
  MONDO keys on - not because this entry treats them as established.

  Disagreement with MONDO. MONDO asserts a causal gene (RO:0004003) on
  MONDO:0013370 (LQT6, KCNE2), MONDO:0012737 (LQT10, SCN4B), MONDO:0012738
  (LQT11, AKAP9), MONDO:0013062 (LQT12, SNTA1), MONDO:0013279 (LQT13, KCNJ5) and
  MONDO:0013372 (LQT5, KCNE1). Five of those six pairs are the ones ClinGen
  disputes and the sixth is graded limited, so the assertions are recorded here
  with their gradings rather than as plain causal relationships. This is a
  disagreement about evidence strength, not about identity: the gene MONDO names
  for each numbered type is the gene this entry binds.

  Where MONDO records the gene is not uniform either, which matters to anyone
  reading these terms programmatically. LQT1, LQT2, LQT5, LQT6, LQT9, LQT10,
  LQT11, LQT12, LQT13, LQT14 and LQT15 carry an asserted `relationship:
  RO:0004003` line. LQT3 carries the gene only inside its equivalence axiom
  (`intersection_of: RO:0004003 HGNC:10593`) with no asserted relationship, so a
  query that reads asserted relationships alone will miss SCN5A. LQT4
  (MONDO:0800323), LQT8 (MONDO:0032756) and LQT16 (MONDO:0032915) carry no causal
  gene at all in either form; the ANK2, CACNA1C and TRDN bindings on those rows
  rest on this entry's own sources. Read from the MONDO build on 2026-09-19.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019171
      label: familial long QT syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:101016
    mapping_justification: >-
      Orphanet ORPHA:101016 maps Romano-Ward syndrome to the same inherited
      familial long QT syndrome concept used by MONDO:0019171.
external_assertions:
- name: Orphanet Romano-Ward syndrome disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:101016
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=101016
  description: >-
    Orphanet's ORPHA:101016 structured record for Romano-Ward syndrome provides
    the familial LQTS definition, inheritance, epidemiology, gene table, HPO
    phenotype frequencies, and cross-references used to align this inherited
    LQTS root entry.
  evidence:
  - reference: ORPHA:101016
    reference_title: "Romano-Ward syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A form of familial long QT syndrome (LQTS) characterized by syncopal episodes and electrocardiographic abnormalities (QT prolongation, T-wave abnormalities and torsade de pointes (TdP) ventricular tachycardia)."
    explanation: Orphanet defines Romano-Ward syndrome as a familial LQTS form with the core electrocardiographic and syncopal phenotype.
classifications:
  channelopathy_category:
    classification_value: cardiac channelopathy
has_subtypes:
- name: Type 1
  display_name: Long QT Syndrome 1
  subtype_term:
    preferred_term: long QT syndrome 1
    term:
      id: MONDO:0100316
      label: long QT syndrome 1
  genes:
  - preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  description: >-
    KCNQ1-related form driven by reduced IKs-mediated repolarization reserve.
- name: Type 2
  display_name: Long QT Syndrome 2
  subtype_term:
    preferred_term: long QT syndrome 2
    term:
      id: MONDO:0013367
      label: long QT syndrome 2
  genes:
  - preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  description: >-
    KCNH2-related form driven by reduced IKr-mediated repolarization reserve.
- name: Type 3
  display_name: Long QT Syndrome 3
  subtype_term:
    preferred_term: long QT syndrome 3
    term:
      id: MONDO:0011377
      label: long QT syndrome 3
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  description: >-
    SCN5A-related form driven by persistent late sodium current and especially
    relevant to mexiletine precision therapy.
- name: Type 4
  display_name: Long QT Syndrome 4
  subtype_term:
    preferred_term: long QT syndrome 4
    term:
      id: MONDO:0800323
      label: long QT syndrome 4
  genes:
  - preferred_term: ANK2
    term:
      id: hgnc:493
      label: ANK2
  description: >-
    Historical ANK2-related LQT4 designation; detailed ankyrin-B syndrome
    curation remains in the separate ANK2-focused entry.
- name: Type 5
  display_name: Long QT Syndrome 5
  subtype_term:
    preferred_term: long QT syndrome 5
    term:
      id: MONDO:0013372
      label: long QT syndrome 5
  genes:
  - preferred_term: KCNE1
    term:
      id: hgnc:6240
      label: KCNE1
  description: KCNE1-related familial LQTS subtype.
- name: Type 6
  display_name: Long QT Syndrome 6
  subtype_term:
    preferred_term: long QT syndrome 6
    term:
      id: MONDO:0013370
      label: long QT syndrome 6
  genes:
  - preferred_term: KCNE2
    term:
      id: hgnc:6242
      label: KCNE2
  description: KCNE2-related familial LQTS subtype.
- name: Type 8
  display_name: Long QT Syndrome 8
  subtype_term:
    preferred_term: long QT syndrome 8
    term:
      id: MONDO:0032756
      label: long QT syndrome 8
  genes:
  - preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  description: >-
    CACNA1C-related LQTS subtype, with syndromic Timothy syndrome overlap
    curated separately.
- name: Type 9
  display_name: Long QT Syndrome 9
  subtype_term:
    preferred_term: long QT syndrome 9
    term:
      id: MONDO:0012736
      label: long QT syndrome 9
  genes:
  - preferred_term: CAV3
    term:
      id: hgnc:1529
      label: CAV3
  description: CAV3-related familial LQTS subtype.
- name: Type 10
  display_name: Long QT Syndrome 10
  subtype_term:
    preferred_term: long QT syndrome 10
    term:
      id: MONDO:0012737
      label: long QT syndrome 10
  genes:
  - preferred_term: SCN4B
    term:
      id: hgnc:10592
      label: SCN4B
  description: SCN4B-related familial LQTS subtype.
- name: Type 11
  display_name: Long QT Syndrome 11
  subtype_term:
    preferred_term: long QT syndrome 11
    term:
      id: MONDO:0012738
      label: long QT syndrome 11
  genes:
  - preferred_term: AKAP9
    term:
      id: hgnc:379
      label: AKAP9
  description: AKAP9-related familial LQTS subtype.
- name: Type 12
  display_name: Long QT Syndrome 12
  subtype_term:
    preferred_term: long QT syndrome 12
    term:
      id: MONDO:0013062
      label: long QT syndrome 12
  genes:
  - preferred_term: SNTA1
    term:
      id: hgnc:11167
      label: SNTA1
  description: SNTA1-related familial LQTS subtype.
- name: Type 13
  display_name: Long QT Syndrome 13
  subtype_term:
    preferred_term: long QT syndrome 13
    term:
      id: MONDO:0013279
      label: long QT syndrome 13
  genes:
  - preferred_term: KCNJ5
    term:
      id: hgnc:6266
      label: KCNJ5
  description: KCNJ5-related familial LQTS subtype.
- name: Type 14
  display_name: Long QT Syndrome 14
  subtype_term:
    preferred_term: long QT syndrome 14
    term:
      id: MONDO:0014548
      label: long QT syndrome 14
  genes:
  - preferred_term: CALM1
    term:
      id: hgnc:1442
      label: CALM1
  description: CALM1-related familial LQTS subtype.
- name: Type 15
  display_name: Long QT Syndrome 15
  subtype_term:
    preferred_term: long QT syndrome 15
    term:
      id: MONDO:0014550
      label: long QT syndrome 15
  genes:
  - preferred_term: CALM2
    term:
      id: hgnc:1445
      label: CALM2
  description: CALM2-related familial LQTS subtype.
- name: Type 16
  display_name: Long QT Syndrome 16
  subtype_term:
    preferred_term: long QT syndrome 16
    term:
      id: MONDO:0032915
      label: long QT syndrome 16
  genes:
  - preferred_term: TRDN
    term:
      id: hgnc:12261
      label: TRDN
  description: TRDN-related familial LQTS subtype with catecholaminergic ventricular tachycardia overlap.
- name: Other rare-gene familial LQTS
  genes:
  - preferred_term: CALM3
    term:
      id: hgnc:1449
      label: CALM3
  - preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  - preferred_term: ALG10B
    term:
      id: hgnc:31088
      label: ALG10B
  description: >-
    Other inherited ion-channel or regulatory-gene forms retained at the
    disease root unless they define a separately curated clinically distinct
    syndrome. The three genes bound here have a ClinGen gene-disease validity
    assertion against long QT syndrome but no numbered LQTS subtype of their
    own in this entry: CALM3 (definitive), KCNJ2 (limited, and the gene of
    Andersen-Tawil syndrome, which is curated separately) and ALG10B
    (limited).
prevalence:
- population: Live births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 40.0
  percentage: '0.04'
  notes: Estimated prevalence is close to 1 in 2,500 live births.
  evidence:
  - reference: PMID:18606002
    reference_title: Congenital long QT syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Disease prevalence is estimated at close to 1 in 2,500 live births.
    explanation: Provides a disease-level prevalence estimate for inherited long QT syndrome.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The disease root is centered on the usually autosomal dominant inherited
    spectrum rather than recessive syndromic JLNS.
  evidence:
  - reference: PMID:10348966
    reference_title: "The inherited long QT syndrome: from ion channel to bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The majority of cases are inherited by autosomal dominant transmission.
    explanation: Supports using autosomal dominant inheritance for the familial long-QT root entry.
definitions:
- name: >-
    QT-prolonging-drug-associated torsade/marked-QTc case-finding query for latent
    congenital LQTS carriers
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: ESTABLISHED_CRITERIA
  validation_status:
    status: UNVALIDATED
    rationale: >-
      Drug-induced (acquired) LQTS is an established provocation that enriches for
      congenital LQTS gene variants (~10-15% of drug-associated torsade patients),
      so the query is well grounded — but this specific computable EHR phenotype
      has not been evaluated against a genotyped gold standard for PPV/yield.
      Natural validation substrate: genotype-linked EHR biobanks where these
      studies originated (e.g. Vanderbilt BioVU / eMERGE, All of Us).
  attaches_to:
  - pathophysiology#QT-Prolonging Drug Unmasking of Reduced Repolarization Reserve
  description: >-
    EHR/OMOP case-finding query: identify individuals who develop marked QTc
    prolongation or torsades de pointes after exposure to a known QT-prolonging
    (IKr/hERG-blocking) drug, without a prior LQTS diagnosis, as candidates for
    latent congenital LQTS warranting off-drug QTc reassessment and genetic
    evaluation. This is the pharmacological-trigger member of the
    trigger-provoked-latent-disease archetype (cf. the Timothy and Brugada fever
    queries); because drug-unmasking is established, derivation_basis is
    ESTABLISHED_CRITERIA.
  scope: >-
    EHR/OMOP case-finding for latent congenital LQTS carriers; grounded in the
    established drug-unmasking / reduced-repolarization-reserve mechanism but not
    yet validated as a computable phenotype.
  criteria_sets:
  - name: Drug-associated marked QTc prolongation or torsade
    description: >-
      Marked QTc prolongation (or documented torsades de pointes) during exposure
      to a known QT-prolonging drug, in a patient without a prior LQTS diagnosis;
      reassess QTc off the drug and refer for LQTS genetic testing.
    inclusion_criteria:
    - preferred_term: QT-prolonging drug exposure
      description: Active exposure to a drug on a recognized QT-prolonging/torsadogenic list (index exposure).
    - preferred_term: Marked QTc prolongation or torsades de pointes
      description: >-
        Marked QTc prolongation on ECG, or a documented torsade/polymorphic VT,
        during the drug exposure.
    exclusion_criteria:
    - preferred_term: Pre-existing LQTS diagnosis
      description: Already-diagnosed congenital LQTS (not a latent-case-finding hit).
  evidence:
  - reference: PMID:11997281
    reference_title: >-
      Allelic variants in long-QT disease genes in patients with drug-associated
      torsades de pointes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA variants in the coding regions of congenital long-QT disease genes
      predisposing to aLQTS can be identified in approximately 10% to 15% of
      affected subjects, predominantly in genes encoding ancillary subunits.
    explanation: >-
      Empirical basis for the query: ~10-15% of drug-associated torsade patients
      carry a congenital LQTS gene variant, so drug-provoked torsade enriches for
      latent carriers.
  notes: >-
    Pharmacological-trigger counterpart to the Timothy (MECHANISTIC_HYPOTHESIS)
    and Brugada (ESTABLISHED_CRITERIA, fever) queries — same
    trigger-provoked-latent-disease archetype with a drug as the provocation. See
    docs/hypothesis-based-phenotype-algorithms.md and
    docs/reports/hypothesis-driven-ehr-case-finding-2026-07-12.md.
pathophysiology:
- name: Reduced Repolarizing Potassium Current
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  description: >-
    Many inherited long-QT subtypes reduce outward delayed rectifier potassium
    currents in cardiomyocytes, diminishing repolarization reserve and delaying
    completion of the ventricular action potential.
  genes:
  - preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  - preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  - preferred_term: membrane repolarization during cardiac muscle cell action potential
    term:
      id: GO:0086013
      label: membrane repolarization during cardiac muscle cell action potential
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: monoatomic ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
    modifier: ABNORMAL
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:16001794
    reference_title: "[The genetic disorders responsible for sudden cardiac death]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Loss of function in the slow component of the delayed rectifier potassium
      current (I(Ks)) channels (KCNQ1, KCNE1), the rapid component of the
      potassium current (I(Kr)) channels (KCNH2, KCNE2)
    explanation: Supports the core disease mechanism in which reduced repolarizing potassium current underlies common inherited LQTS subtypes.
  - reference: PMID:42154296
    reference_title: "Functional characterization and allele-specific RNA interference-based rescue of KCNH2 p.F68C variant associated with long QT syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "variant p.F68C causes a severe trafficking defect and exerts a dominant-negative effect on wild-type hERG channels, leading to markedly reduced rapid delayed rectifier potassium current (IKr)"
    explanation: Demonstrates KCNH2 p.F68C causes loss-of-function through trafficking defect and dominant-negative effects, reducing IKr current density in LQT2.
  downstream:
  - target: Prolonged Ventricular Action Potential Duration
    description: >-
      Reduced repolarization reserve prolongs the ventricular action potential
      and creates an arrhythmogenic substrate.
- name: Persistent Late Sodium Current in LQT3
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  description: >-
    In the SCN5A-mediated subtype, defective sodium-channel inactivation leaves
    a small persistent inward current during depolarization, further delaying
    myocardial repolarization.
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
    modifier: ABNORMAL
  - preferred_term: membrane repolarization during cardiac muscle cell action potential
    term:
      id: GO:0086013
      label: membrane repolarization during cardiac muscle cell action potential
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: monoatomic ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
    modifier: ABNORMAL
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:10377081
    reference_title: Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Two-electrode voltage-clamp recordings of a recombinant E1784K mutant
      channel expressed in Xenopus oocytes revealed a defect in fast
      inactivation characterized by a small, persistent current during long
      membrane depolarizations.
    explanation: Shows the late inward sodium current mechanism characteristic of the SCN5A/LQT3 branch of inherited long QT syndrome.
  - reference: PMID:10377081
    reference_title: Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The functional defect exhibited by the mutant channel causes delayed
      myocardial repolarization
    explanation: Directly links persistent late sodium current to delayed myocardial repolarization in LQT3.
  downstream:
  - target: Prolonged Ventricular Action Potential Duration
    description: >-
      Persistent inward sodium current prolongs ventricular repolarization and
      feeds the common arrhythmogenic substrate.
  - target: Sinus Bradycardia
    description: >-
      LQTS3 sodium-channel dysfunction can affect sinoatrial-node pacemaker
      activity and present with sinus bradycardia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired sinoatrial-node pacemaker activity
    evidence:
    - reference: PMID:30123799
      reference_title: "Long QT Syndrome and Sinus Bradycardia-A Mini Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Interestingly, almost all of the ion channels affected by the various
        types of LQTS gene mutations are also expressed in the human sinoatrial
        node (SAN).
      explanation: Review evidence supports sinoatrial-node involvement by LQTS-associated ion-channel defects.
    - reference: PMID:30123799
      reference_title: "Long QT Syndrome and Sinus Bradycardia-A Mini Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Furthermore, a clear causative role of this sinus bradycardia in
        cardiac events seems reserved to mutations underlying LQT3.
      explanation: Review evidence specifically links LQT3 mutations to causative sinus bradycardia in cardiac events.
- name: Impaired Calcium-Dependent Inactivation of the L-Type Calcium Current
  biological_scale: MOLECULAR
  description: >-
    The second route to a prolonged plateau, alongside reduced repolarizing
    potassium current and persistent late sodium current. Calmodulin, encoded
    identically by CALM1, CALM2 and CALM3, pre-associates with the IQ motif of
    the Cav1.2 pore-forming alpha-1C subunit (CACNA1C) and, on binding calcium,
    drives calcium-dependent inactivation of the channel. Variants on either
    side of that interaction leave the channel open longer than it should be:
    CACNA1C gain-of-function variants impair inactivation directly, while
    arrhythmogenic calmodulin variants disrupt the calcium-sensing step that
    triggers it. Either way calcium influx during the plateau is prolonged and
    the ventricular action potential lengthens. Calmodulin variants can act on
    the repolarizing side as well, reducing activation of Kv7.1 (KCNQ1), so a
    single calmodulin lesion can reach the action potential by both routes.
  genes:
  - preferred_term: CALM1
    term:
      id: hgnc:1442
      label: CALM1
  - preferred_term: CALM2
    term:
      id: hgnc:1445
      label: CALM2
  - preferred_term: CALM3
    term:
      id: hgnc:1449
      label: CALM3
  - preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: calmodulin binding
    term:
      id: GO:0005516
      label: calmodulin binding
    modifier: DECREASED
  - preferred_term: voltage-gated calcium channel activity involved in cardiac muscle cell action potential
    term:
      id: GO:0086007
      label: voltage-gated calcium channel activity involved in cardiac muscle cell action potential
    modifier: INCREASED
  biological_processes:
  - preferred_term: membrane depolarization during cardiac muscle cell action potential
    term:
      id: GO:0086012
      label: membrane depolarization during cardiac muscle cell action potential
    modifier: INCREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:41294816
    reference_title: "Calmodulin D133H Disrupts Ca(v)1.2 and K(v)7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In cardiomyocytes, it mediates Ca2+-dependent inactivation (CDI) of Cav1.2"
    explanation: States the normal calmodulin function whose loss this node describes.
  - reference: PMID:41294816
    reference_title: "Calmodulin D133H Disrupts Ca(v)1.2 and K(v)7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "It is encoded by three independent genes (CALM1–3), which produce identical proteins"
    explanation: >-
      Why all three CALM genes are bound to one node rather than to three. Graded
      HUMAN_CLINICAL with `quote_role: BACKGROUND` because the sentence states an
      established fact about the human genes in this paper's introduction rather
      than reporting the mouse-myocyte and recombinant-protein work the paper did.
  - reference: PMID:41294816
    reference_title: "Calmodulin D133H Disrupts Ca(v)1.2 and K(v)7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Electrophysiological recordings demonstrated that CaM D133H impairs Ca2+-dependent inactivation (CDI) of Cav1.2, prolonging Ca2+ influx, while also reducing activation of Kv7.1, thereby limiting repolarising K+ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS."
    explanation: >-
      The paper's own electrophysiological result for one arrhythmogenic calmodulin
      variant, and the step from impaired inactivation to a prolonged action
      potential that this node's downstream edge asserts.
  - reference: PMID:41294816
    reference_title: "Calmodulin D133H Disrupts Ca(v)1.2 and K(v)7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional Cav1.2 channels comprise the pore-forming α1C subunit (CACNA1C)"
    explanation: >-
      The basis for binding CACNA1C at this node alongside the calmodulin genes: it
      encodes the subunit whose inactivation calmodulin controls.
  - reference: PMID:41294816
    reference_title: "Calmodulin D133H Disrupts Ca(v)1.2 and K(v)7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations that disrupt these interactions abolish CDI, resulting in excessive Ca2+ entry"
    explanation: >-
      The generalisation this node rests on: it is the calmodulin-to-channel
      interaction that fails, so a lesion on either side of it produces the same
      excess calcium entry.
  downstream:
  - target: Prolonged Ventricular Action Potential Duration
    causal_link_type: DIRECT
    description: >-
      Failure to terminate L-type calcium influx during the plateau lengthens the
      ventricular action potential, the same endpoint reached by reduced
      repolarizing potassium current and by persistent late sodium current.
  notes: >-
    CAV3, KCNJ2, ALG10B and TRDN are deliberately not bound here. CAV3 and
    ALG10B are graded Limited by ClinGen and this entry curates no mechanism for
    either; KCNJ2 carries the IK1 current and is the gene of Andersen-Tawil
    syndrome, curated separately; and TRDN acts on the calcium release unit and
    the ryanodine receptor rather than on L-type inactivation, which is a
    different mechanism from the one this node describes and is not curated in
    this entry. Each of those would need its own node and its own evidence, not a
    seat at this one.
- name: Prolonged Ventricular Action Potential Duration
  conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
  role: central_effector
  description: >-
    Reduced repolarization reserve and persistent inward sodium current
    prolong ventricular action potential duration and delay ventricular
    repolarization.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: membrane repolarization during cardiac muscle cell action potential
    term:
      id: GO:0086013
      label: membrane repolarization during cardiac muscle cell action potential
    modifier: DYSREGULATED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:28670758
    reference_title: Congenital Long QT syndrome and torsade de pointes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This together with the tendency of prolonged APD to be associated with
      oscillations at the plateau level, termed early afterdepolarizations
      (EADs), provides the substrate of ventricular tachyarrhythmia associated
      with LQTS, usually referred to as torsade de pointes (TdP) VT.
    explanation: Review abstract identifies prolonged action potential duration as the proximal repolarization abnormality that precedes early afterdepolarizations in congenital LQTS.
  downstream:
  - target: Early Afterdepolarizations
    description: >-
      Prolonged ventricular action potential duration permits early
      afterdepolarizations to emerge from the plateau.
  - target: Prolonged QTc Interval
    description: >-
      Delayed ventricular repolarization is recorded clinically as QT-interval
      prolongation on basal electrocardiography.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18606002
      reference_title: Congenital long QT syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Congenital long QT syndrome (LQTS) is a hereditary cardiac disease
        characterized by a prolongation of the QT interval at basal ECG and by a
        high risk of life-threatening arrhythmias.
      explanation: Review evidence links inherited LQTS ventricular repolarization abnormality to basal ECG QT prolongation.
  - target: Abnormal T-Wave
    description: >-
      Abnormal ventricular repolarization can produce abnormal T-wave morphology
      on the electrocardiogram.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10348966
      reference_title: "The inherited long QT syndrome: from ion channel to bedside."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The signs of long QT syndrome are prolongation of the QT interval on the
        electrocardiogram and abnormalities of T wave morphology.
      explanation: Review evidence directly links LQTS to T-wave morphology abnormalities on ECG.
- name: Early Afterdepolarizations
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  role: amplifier
  description: >-
    Prolonged ventricular action potential duration promotes plateau
    oscillations and early afterdepolarizations that trigger torsades de
    pointes.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DYSREGULATED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:28670758
    reference_title: Congenital Long QT syndrome and torsade de pointes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This together with the tendency of prolonged APD to be associated with
      oscillations at the plateau level, termed early afterdepolarizations
      (EADs), provides the substrate of ventricular tachyarrhythmia associated
      with LQTS, usually referred to as torsade de pointes (TdP) VT.
    explanation: Review abstract directly links prolonged action potential duration to plateau oscillations termed early afterdepolarizations in congenital LQTS.
  - reference: PMID:10348966
    reference_title: "The inherited long QT syndrome: from ion channel to bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The delayed recovery predisposes individuals to the development of early
      afterdepolarizations and initiation of torsade de pointes arrhythmias.
    explanation: Supports the disease-level causal chain from delayed repolarization to early afterdepolarizations and torsades.
  downstream:
  - target: Torsades de Pointes
    description: >-
      Early afterdepolarization-triggered ventricular tachyarrhythmias produce
      syncope, cardiac arrest, and sudden death.
- name: Adrenergic Trigger Susceptibility
  description: >-
    Life-threatening events in familial LQTS are shaped by genotype-specific
    triggering circumstances. The classical LQT1-LQT3 subtypes differ in
    whether episodes cluster during exercise or rest/sleep, which informs risk
    stratification and anti-adrenergic management.
  evidence:
  - reference: PMID:11136691
    reference_title: "Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LQT1 patients experienced the majority of their events (62%) during
      exercise, and only 3% occurred during rest/sleep. These percentages were
      almost reversed among LQT2 and LQT3 patients, who were less likely to
      have events during exercise (13%) and more likely to have events during
      rest/sleep (29% and 39%).
    explanation: Supports subtype-aware trigger heterogeneity within the inherited LQTS root and justifies retaining LQT1-LQT3 as named subtypes under one disease entry.
  downstream:
  - target: Torsades de Pointes
    description: >-
      Genotype-specific triggering circumstances precipitate malignant
      ventricular arrhythmias against the repolarization substrate.
- name: QT-Prolonging Drug Unmasking of Reduced Repolarization Reserve
  conforms_to: "xenobiotic_cardiac_channel_perturbation#Xenobiotic Cardiac Ion-Channel Perturbation"
  role: trigger
  description: >-
    A QT-prolonging drug — most often an IKr/hERG (KCNH2) blocker — superimposed
    on a subclinical reduction in repolarization reserve precipitates marked QT
    prolongation and torsades de pointes. Individuals with a latent congenital
    LQTS genotype have diminished reserve, so a QT-prolonging drug can unmask an
    otherwise subclinical channelopathy. Drug-associated ("acquired") LQTS thus
    acts as a pharmacological provocation that surfaces latent congenital LQTS
    carriers; congenital LQTS gene variants are enriched among such patients.
    Unlike the Timothy-syndrome fever hypothesis, this drug-unmasking mechanism
    is well established.
  gene:
    preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  genes:
  - preferred_term: KCNE1
    term:
      id: hgnc:6240
      label: KCNE1
  - preferred_term: KCNE2
    term:
      id: hgnc:6242
      label: KCNE2
  notes: >-
    KCNE1 and KCNE2 are bound here rather than at the inherited repolarization
    node, and that placement is the finding rather than a convenience. Both encode
    ancillary beta subunits - minK on IKs, MiRP1 on IKr - and ClinGen's long QT
    expert panel reached a split verdict on them: limited (KCNE1) or disputed
    (KCNE2) evidence as causes of unprovoked congenital LQTS, but strong evidence
    for specific risk alleles predisposing to the acquired, drug-provoked form
    that this node models. The cohort evidence already on this node points the
    same way, locating the congenital variants found in drug-associated torsades
    patients "predominantly in genes encoding ancillary subunits".

    Their `genetic:` records carry the LQT5 and LQT6 subtype keys and the
    corresponding ClinGen gradings; this binding adds the mechanism node where the
    evidence for them is strongest, and does not assert that either gene is an
    established cause of inherited LQTS.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: membrane repolarization during cardiac muscle cell action potential
    term:
      id: GO:0086013
      label: membrane repolarization during cardiac muscle cell action potential
    modifier: DECREASED
  molecular_functions:
  - preferred_term: monoatomic ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
    modifier: ABNORMAL
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:11997281
    reference_title: >-
      Allelic variants in long-QT disease genes in patients with drug-associated
      torsades de pointes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA variants in the coding regions of congenital long-QT disease genes
      predisposing to aLQTS can be identified in approximately 10% to 15% of
      affected subjects, predominantly in genes encoding ancillary subunits.
    explanation: >-
      In a large cohort of drug-associated (acquired) LQTS/torsades patients,
      10-15% carry congenital long-QT gene variants, establishing that
      QT-prolonging drugs unmask a latent congenital substrate.
  - reference: PMID:24561134
    reference_title: >-
      Exome sequencing implicates an increased burden of rare potassium channel
      variants in the risk of drug-induced long QT interval syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diLQTS patients were more burdened by rare AAC variants in cLQTS genes
      encoding potassium channel modulators, supporting the idea that multiple
      rare variants, notably across cLQTS genes, predispose to diLQTS.
    explanation: >-
      Whole-exome sequencing shows drug-induced LQTS patients carry an excess of
      rare variants in congenital LQTS genes, supporting drug exposure as a
      provocation that surfaces latent genetic predisposition.
  - reference: DOI:10.1161/CIRCULATIONAHA.119.043132
    reference_title: An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although KCNE1 was classified as having only limited evidence and KCNE2 as having disputed evidence for causality in LQTS, both genes were classified as having strong evidence for specific risk alleles in predisposing to aLQTS"
    explanation: >-
      The basis for binding KCNE1 and KCNE2 at this acquired/drug-provoked node
      rather than at the inherited repolarization node, and for the split grading
      their `genetic:` records carry.
  downstream:
  - target: Prolonged Ventricular Action Potential Duration
    description: >-
      A QT-prolonging drug reduces net repolarizing current on a background of
      diminished reserve, prolonging the ventricular action potential.
    causal_link_type: DIRECT
  - target: Torsades de Pointes
    description: >-
      Marked drug-induced QT prolongation on a susceptible substrate precipitates
      torsades de pointes.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - early afterdepolarizations
- name: Torsades de Pointes
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  role: effector
  description: >-
    Torsades de pointes is the characteristic malignant ventricular
    tachyarrhythmia of inherited LQTS, arising from prolonged repolarization,
    early afterdepolarizations, and permissive trigger conditions.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:9272508
    reference_title: "Clinical management of patients with the long QT syndrome: drugs, devices, and gene-specific therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The familial long QT syndrome (LQTS) is now recognized as a genetic
      channelopathy with a propensity to arrhythmogenic syncope and sudden
      death.
    explanation: Establishes the disease-level tendency toward syncope and sudden death in familial LQTS.
  - reference: PMID:10348966
    reference_title: "The inherited long QT syndrome: from ion channel to bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The torsade produces the syncope and sudden death.
    explanation: Directly links torsades de pointes to the defining severe clinical outcomes.
  downstream:
  - target: Syncope
    description: >-
      Torsades de pointes commonly presents as transient loss of consciousness
      from arrhythmic cerebral hypoperfusion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18606002
      reference_title: Congenital long QT syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The two cardinal manifestations of LQTS are syncopal episodes, that may
        lead to cardiac arrest and sudden cardiac death, and electrocardiographic
        abnormalities, including prolongation of the QT interval and T wave
        abnormalities.
      explanation: This supports syncope as a direct clinical consequence of malignant ventricular arrhythmias in LQTS.
  - target: Seizure
    description: >-
      Arrhythmic loss-of-consciousness events in LQTS can present clinically as
      seizure or seizure-like episodes before the cardiac diagnosis is recognized.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19282063
      reference_title: "Misdiagnosis of long QT syndrome as epilepsy at first presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thirteen patients (39%) experienced diagnostic delay after presentation with syncope or seizure: median delay 2.4 years (2 months to 23 years)."
      explanation: Genetically confirmed LQTS cases presented with syncope or seizure before diagnosis.
    - reference: ORPHA:101016
      reference_title: "Romano-Ward syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
      explanation: Orphanet records seizure as an occasional phenotype in Romano-Ward/familial LQTS.
  - target: Cardiac Arrest
    description: >-
      Sustained torsades de pointes or degeneration to ventricular fibrillation
      can progress to cardiac arrest.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18606002
      reference_title: Congenital long QT syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The two cardinal manifestations of LQTS are syncopal episodes, that may
        lead to cardiac arrest and sudden cardiac death, and electrocardiographic
        abnormalities, including prolongation of the QT interval and T wave
        abnormalities.
      explanation: This supports cardiac arrest as a downstream outcome of LQTS syncopal arrhythmias.
  - target: Sudden Cardiac Death
    description: >-
      Untreated torsades de pointes can degenerate to a fatal ventricular
      arrhythmia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10348966
      reference_title: "The inherited long QT syndrome: from ion channel to bedside."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The torsade produces the syncope and sudden death.
      explanation: This directly supports sudden cardiac death as the terminal phenotype outcome of torsades in inherited LQTS.
  - target: Syncope and Sudden Cardiac Death
    description: >-
      Sustained torsades de pointes abolishes effective cardiac output, causing
      arrhythmic syncope and, when the rhythm does not terminate, sudden
      cardiac death.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10348966
      reference_title: "The inherited long QT syndrome: from ion channel to bedside."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The torsade produces the syncope and sudden death.
      explanation: Directly links the torsades de pointes arrhythmia to the shared syncope/sudden-death clinical endpoint.
- name: Syncope and Sudden Cardiac Death
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  role: outcome
  description: >-
    Loss of effective cardiac output during sustained torsades de pointes causes
    transient cerebral hypoperfusion (syncope) and, when the malignant
    ventricular arrhythmia does not terminate, sudden cardiac death. These are
    the shared sentinel clinical endpoints of inherited long QT syndrome.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:9272508
    reference_title: "Clinical management of patients with the long QT syndrome: drugs, devices, and gene-specific therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The familial long QT syndrome (LQTS) is now recognized as a genetic
      channelopathy with a propensity to arrhythmogenic syncope and sudden
      death.
    explanation: Establishes arrhythmogenic syncope and sudden death as the shared clinical endpoint of familial long QT syndrome.
  - reference: PMID:10348966
    reference_title: "The inherited long QT syndrome: from ion channel to bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The torsade produces the syncope and sudden death.
    explanation: Directly attributes the syncope and sudden-death endpoint to the torsades de pointes arrhythmia in inherited LQTS.
phenotypes:
- category: Cardiovascular
  name: Prolonged QTc Interval
  diagnostic: true
  frequency: OBLIGATE
  description: >-
    Baseline QT prolongation on ECG is the defining diagnostic sign of
    inherited long QT syndrome, although some gene carriers may have borderline
    or intermittently normal QTc measurements.
  phenotype_term:
    preferred_term: prolonged QTc interval
    term:
      id: HP:0005184
      label: Prolonged QTc interval
  evidence:
  - reference: PMID:18606002
    reference_title: Congenital long QT syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital long QT syndrome (LQTS) is a hereditary cardiac disease
      characterized by a prolongation of the QT interval at basal ECG and by a
      high risk of life-threatening arrhythmias.
    explanation: Supports QT prolongation as the defining electrocardiographic phenotype of inherited long QT syndrome.
  - reference: ORPHA:101016
    reference_title: "Romano-Ward syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005184 | Prolonged QTc interval | Obligate (100%)"
    explanation: Orphanet records prolonged QTc interval as obligate in Romano-Ward/familial LQTS.
- category: Cardiovascular
  name: Syncope
  frequency: FREQUENT
  description: >-
    Recurrent syncopal episodes reflect transient hemodynamic compromise from
    torsades de pointes or related malignant ventricular arrhythmias.
  phenotype_term:
    preferred_term: syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:18606002
    reference_title: Congenital long QT syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The two cardinal manifestations of LQTS are syncopal episodes, that may
      lead to cardiac arrest and sudden cardiac death, and electrocardiographic
      abnormalities, including prolongation of the QT interval and T wave
      abnormalities.
    explanation: Review abstract identifies syncope as one of the cardinal manifestations of congenital long QT syndrome.
  - reference: ORPHA:101016
    reference_title: "Romano-Ward syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001279 | Syncope | Frequent (79-30%)"
    explanation: Orphanet frequency data supports syncope as frequent in Romano-Ward/familial LQTS.
- category: Cardiovascular
  name: Cardiac Arrest
  description: >-
    Sustained torsades de pointes or degeneration to ventricular fibrillation
    can cause resuscitated or fatal cardiac arrest.
  phenotype_term:
    preferred_term: cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:18606002
    reference_title: Congenital long QT syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The two cardinal manifestations of LQTS are syncopal episodes, that may
      lead to cardiac arrest and sudden cardiac death, and electrocardiographic
      abnormalities, including prolongation of the QT interval and T wave
      abnormalities.
    explanation: The cardinal-manifestation summary explicitly includes cardiac arrest as a major outcome of LQTS syncopal episodes.
- category: Cardiovascular
  name: Torsades de Pointes
  frequency: OCCASIONAL
  description: >-
    The signature malignant ventricular tachyarrhythmia of long QT syndrome is
    torsades de pointes, arising from prolonged repolarization and early
    afterdepolarizations.
  phenotype_term:
    preferred_term: torsade de pointes
    term:
      id: HP:0001664
      label: Torsade de pointes
  evidence:
  - reference: PMID:28670758
    reference_title: Congenital Long QT syndrome and torsade de pointes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This together with the tendency of prolonged APD to be associated with
      oscillations at the plateau level, termed early afterdepolarizations
      (EADs), provides the substrate of ventricular tachyarrhythmia associated
      with LQTS, usually referred to as torsade de pointes (TdP) VT.
    explanation: Supports torsades de pointes ventricular tachycardia as the characteristic ventricular arrhythmia of LQTS.
  - reference: ORPHA:101016
    reference_title: "Romano-Ward syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001664 | Torsade de pointes | Occasional (29-5%)"
    explanation: Orphanet frequency data supports torsade de pointes as an occasional recorded phenotype.
- category: Cardiovascular
  name: Sudden Cardiac Death
  frequency: OCCASIONAL
  description: >-
    Sudden cardiac death results from untreated or refractory torsades de
    pointes degenerating to ventricular fibrillation.
  phenotype_term:
    preferred_term: sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:9272508
    reference_title: "Clinical management of patients with the long QT syndrome: drugs, devices, and gene-specific therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The familial long QT syndrome (LQTS) is now recognized as a genetic
      channelopathy with a propensity to arrhythmogenic syncope and sudden
      death.
    explanation: Supports sudden cardiac death as a core disease manifestation of familial long QT syndrome.
  - reference: ORPHA:101016
    reference_title: "Romano-Ward syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001645 | Sudden cardiac death | Occasional (29-5%)"
    explanation: Orphanet frequency data supports sudden cardiac death as an occasional recorded outcome in Romano-Ward/familial LQTS.
- category: Cardiovascular
  name: Sinus Bradycardia
  frequency: FREQUENT
  description: >-
    Sinus bradycardia can occur in familial LQTS and is captured as a frequent
    Orphanet phenotype for Romano-Ward syndrome.
  phenotype_term:
    preferred_term: sinus bradycardia
    term:
      id: HP:0001688
      label: Sinus bradycardia
  evidence:
  - reference: ORPHA:101016
    reference_title: "Romano-Ward syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001688 | Sinus bradycardia | Frequent (79-30%)"
    explanation: Orphanet frequency data supports sinus bradycardia as frequent in Romano-Ward/familial LQTS.
- category: Cardiovascular
  name: Abnormal T-Wave
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Abnormal T-wave morphology on ECG is a frequent electrocardiographic feature
    of familial LQTS and contributes to clinical recognition.
  phenotype_term:
    preferred_term: abnormal T-wave
    term:
      id: HP:0005135
      label: Abnormal T-wave
  evidence:
  - reference: PMID:10348966
    reference_title: "The inherited long QT syndrome: from ion channel to bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The signs of long QT syndrome are prolongation of the QT interval on the
      electrocardiogram and abnormalities of T wave morphology.
    explanation: Review abstract supports abnormal T-wave morphology as a diagnostic ECG feature of inherited LQTS.
  - reference: ORPHA:101016
    reference_title: "Romano-Ward syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005135 | Abnormal T-wave | Frequent (79-30%)"
    explanation: Orphanet frequency data supports abnormal T-wave as frequent in Romano-Ward/familial LQTS.
- category: Neurologic
  name: Seizure
  frequency: OCCASIONAL
  description: >-
    Seizure-like episodes can be recorded in familial LQTS, often reflecting
    cerebral hypoperfusion during malignant arrhythmia rather than primary
    epilepsy.
  phenotype_term:
    preferred_term: seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:101016
    reference_title: "Romano-Ward syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
    explanation: Orphanet frequency data supports seizure as an occasional recorded phenotype in Romano-Ward/familial LQTS.
genetic:
- name: KCNQ1
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  association: Causative
  subtype: Type 1
  notes: Encodes the IKs channel alpha subunit for the canonical LQT1 subtype.
  evidence:
  - reference: PMID:16001794
    reference_title: "[The genetic disorders responsible for sudden cardiac death]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Loss of function in the slow component of the delayed rectifier potassium
      current (I(Ks)) channels (KCNQ1, KCNE1)
    explanation: This supports KCNQ1 as a causative gene in the inherited LQT1 branch of long QT syndrome.
  - reference: CGGV:assertion_dff8874e-98a1-472b-9cc2-3f441b1c1064-2018-09-25T040000.000Z
    reference_title: "KCNQ1 / long QT syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNQ1 | HGNC:6294 | long QT syndrome | MONDO:0002442 | AD | Definitive"
    explanation: ClinGen classifies the KCNQ1-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: KCNH2
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  association: Causative
  subtype: Type 2
  notes: Encodes the IKr channel alpha subunit for the canonical LQT2 subtype.
  evidence:
  - reference: PMID:16001794
    reference_title: "[The genetic disorders responsible for sudden cardiac death]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Loss of function in the slow component of the delayed rectifier potassium
      current (I(Ks)) channels (KCNQ1, KCNE1), the rapid component of the
      potassium current (I(Kr)) channels (KCNH2, KCNE2)
    explanation: This supports KCNH2 as a core causative gene for the inherited LQT2 subtype series.
  - reference: CGGV:assertion_462eeb4e-357d-4c3d-89f0-e386ac0d011b-2018-09-25T040000.000Z
    reference_title: "KCNH2 / long QT syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNH2 | HGNC:6251 | long QT syndrome | MONDO:0002442 | AD | Definitive"
    explanation: ClinGen classifies the KCNH2-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: SCN5A
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  association: Causative
  subtype: Type 3
  notes: Encodes the cardiac sodium-channel alpha subunit that defines the LQT3 branch.
  evidence:
  - reference: PMID:16001794
    reference_title: "[The genetic disorders responsible for sudden cardiac death]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Changes of function in the alpha-subunit of cardiac sodium channels
      (SCN5A) is also linked to the LQTS type 3 and the BrS.
    explanation: This supports SCN5A as the defining causative gene for LQT3 within inherited long QT syndrome.
- name: ALG10B
  subtype: Other rare-gene familial LQTS
  gene_term:
    preferred_term: ALG10B
    term:
      id: hgnc:31088
      label: ALG10B
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_6499e6e2-af96-4868-bfd5-18ab35f61847-2026-01-15T010000.000Z
    reference_title: "ALG10B / long QT syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALG10B | HGNC:31088 | long QT syndrome | MONDO:0002442 | AD | Limited"
    explanation: ClinGen classifies the ALG10B-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.
- name: CACNA1C
  subtype: Type 8
  gene_term:
    preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_c496551d-c7a7-4e49-ad41-8cfd49840dc1-2020-04-24T040000.000Z
    reference_title: "CACNA1C / long QT syndrome (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CACNA1C | HGNC:1390 | long QT syndrome | MONDO:0002442 | AD | Moderate"
    explanation: ClinGen classifies the CACNA1C-long QT syndrome gene-disease relationship as moderate with autosomal dominant inheritance.
- name: CALM1
  subtype: Type 14
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CALM1
    term:
      id: hgnc:1442
      label: CALM1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_4a150cd9-e16b-4992-8cc7-5ccec44b4d6b-2018-09-25T160000.000Z
    reference_title: "CALM1 / long QT syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CALM1 | HGNC:1442 | long QT syndrome | MONDO:0002442 | AD | Definitive"
    explanation: ClinGen classifies the CALM1-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: CALM2
  subtype: Type 15
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CALM2
    term:
      id: hgnc:1445
      label: CALM2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_86e4b783-3b60-4a1d-ab34-e61d27751ca6-2018-09-25T160000.000Z
    reference_title: "CALM2 / long QT syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CALM2 | HGNC:1445 | long QT syndrome | MONDO:0002442 | AD | Definitive"
    explanation: ClinGen classifies the CALM2-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: CALM3
  subtype: Other rare-gene familial LQTS
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CALM3
    term:
      id: hgnc:1449
      label: CALM3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_3cc2a1ae-5f3d-445c-b124-f3d38fdd070a-2018-09-25T160000.000Z
    reference_title: "CALM3 / long QT syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CALM3 | HGNC:1449 | long QT syndrome | MONDO:0002442 | AD | Definitive"
    explanation: ClinGen classifies the CALM3-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: CAV3
  subtype: Type 9
  gene_term:
    preferred_term: CAV3
    term:
      id: hgnc:1529
      label: CAV3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_74aabddc-3402-46de-ba1e-f66aa273cd9c-2020-12-15T002855.870Z
    reference_title: "CAV3 / long QT syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CAV3 | HGNC:1529 | long QT syndrome | MONDO:0002442 | AD | Limited"
    explanation: ClinGen classifies the CAV3-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.
- name: KCNJ2
  subtype: Other rare-gene familial LQTS
  gene_term:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_5dc2acbc-8dbe-4142-8f71-89f1576dde08-2020-12-15T002535.799Z
    reference_title: "KCNJ2 / long QT syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNJ2 | HGNC:6263 | long QT syndrome | MONDO:0002442 | AD | Limited"
    explanation: ClinGen classifies the KCNJ2-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.
- name: TRDN
  subtype: Type 16
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TRDN
    term:
      id: hgnc:12261
      label: TRDN
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_1278bd6a-6ac7-4556-87ea-f860027b2da5-2020-04-24T040000.000Z
    reference_title: "TRDN / long QT syndrome (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TRDN | HGNC:12261 | long QT syndrome | MONDO:0002442 | AR | Strong"
    explanation: ClinGen classifies the TRDN-long QT syndrome gene-disease relationship as strong with autosomal recessive inheritance.
- name: KCNE1
  subtype: Type 5
  gene_term:
    preferred_term: KCNE1
    term:
      id: hgnc:6240
      label: KCNE1
  association: Limited evidence for unprovoked congenital LQTS; strong for acquired
  notes: >-
    KCNE1 encodes minK, the beta subunit that assembles with KCNQ1 to form the
    IKs channel, and it is the gene of the LQT5 designation. No
    `relationship_type` is set on this record. ClinGen grades the relationship
    Limited, which the `GeneDiseaseRelationshipEnum` has no value for - CAUSATIVE
    is documented as corresponding to Definitive or Strong, and DISPUTED to
    Disputed or Refuted - so the honest state is to leave the slot empty rather
    than round Limited up or down. This follows the treatment already given to
    CAV3, KCNJ2 and ALG10B in this entry, which ClinGen also grades Limited.

    Note the split verdict that makes this gene interesting: the same expert
    panel found strong evidence for KCNE1 in acquired LQTS while finding only
    limited evidence for it in unprovoked congenital LQTS. That is why this gene
    is also bound at the drug-unmasking pathophysiology node.
  evidence:
  - reference: CGGV:assertion_957550ae-d91c-49e7-be7c-ff5a13faa3ff-2020-12-15T002142.973Z
    reference_title: "KCNE1 / long QT syndrome 5 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNE1 | HGNC:6240 | long QT syndrome 5 | MONDO:0013372 | AD | Limited"
    explanation: >-
      ClinGen's assertion, and the only one in this entry recorded against a
      numbered LQTS class (MONDO:0013372) rather than against the parent long QT
      syndrome term.
  - reference: CGGV:assertion_957550ae-d91c-49e7-be7c-ff5a13faa3ff-2020-12-15T002142.973Z
    reference_title: "KCNE1 / long QT syndrome 5 (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "There is strong evidence associating KCNE1 with acquired LQTS, however, only limited evidence for its association with unprovoked LQTS."
    explanation: >-
      REFUTE against the claim this entry is scoped to - KCNE1 as a cause of
      inherited, unprovoked long QT syndrome. The same sentence supports the
      acquired-LQTS role, which is curated at the drug-unmasking node instead.
- name: KCNE2
  subtype: Type 6
  relationship_type: DISPUTED
  gene_term:
    preferred_term: KCNE2
    term:
      id: hgnc:6242
      label: KCNE2
  association: Disputed as a cause of unprovoked congenital LQTS
  notes: >-
    KCNE2 encodes MiRP1, the beta subunit that assembles with KCNH2 to form the
    IKr channel, and is the gene of the LQT6 designation. ClinGen's expert panel
    classifies the KCNE2-LQTS relationship as Disputed on the specific ground
    that reported KCNE2 variants require a secondary provocation to produce a
    phenotype - which is a statement about penetrance without a trigger, not a
    claim that the gene has nothing to do with repolarization. As with KCNE1, the
    panel found strong evidence for KCNE2 in acquired LQTS, and this entry binds
    the gene at its drug-unmasking node accordingly.
  evidence:
  - reference: CGGV:assertion_9912be79-b172-46ca-a67c-99698de5590b-2020-12-15T002341.412Z
    reference_title: "KCNE2 / long QT syndrome (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNE2 | HGNC:6242 | long QT syndrome | MONDO:0002442 | AD | Disputed"
    explanation: The ClinGen validity row behind the DISPUTED typing of this record.
  - reference: CGGV:assertion_9912be79-b172-46ca-a67c-99698de5590b-2020-12-15T002341.412Z
    reference_title: "KCNE2 / long QT syndrome (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "KCNE2 variants reported for LQTS routinely require secondary provocation to induce phenotype, persuading the Expert Panel to conclude that KCNE2 has no supportive evidence as a cause of LQTS in the absence of provoking factors"
    explanation: >-
      The panel's reasoning, quoted because the DISPUTED value alone does not say
      why - and the reason here is specific and reusable.
- name: SCN4B
  subtype: Type 10
  relationship_type: DISPUTED
  gene_term:
    preferred_term: SCN4B
    term:
      id: hgnc:10592
      label: SCN4B
  association: Disputed as a cause of congenital LQTS
  notes: >-
    SCN4B encodes a beta subunit of the cardiac sodium channel and carries the
    LQT10 designation. ClinGen classifies the relationship Disputed: the
    association rests on a single candidate-gene study reporting one missense
    variant in one genotype-negative LQTS family, with no segregation or
    case-control data behind it.
  evidence:
  - reference: CGGV:assertion_0e276096-21ab-42bc-866a-b1b4dcb01753-2018-09-25T160000.000Z
    reference_title: "SCN4B / long QT syndrome (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCN4B | HGNC:10592 | long QT syndrome | MONDO:0002442 | AD | Disputed"
    explanation: The ClinGen validity row behind the DISPUTED typing of this record.
  - reference: CGGV:assertion_0e276096-21ab-42bc-866a-b1b4dcb01753-2018-09-25T160000.000Z
    reference_title: "SCN4B / long QT syndrome (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "Because of the candidate gene approach, lack of segregation or case-control data and paucity of additional genetic and experimental data, this gene-disease association was classified as disputed."
    explanation: The panel's stated grounds for disputing the SCN4B-LQTS association.
- name: AKAP9
  subtype: Type 11
  relationship_type: DISPUTED
  gene_term:
    preferred_term: AKAP9
    term:
      id: hgnc:379
      label: AKAP9
  association: Disputed as a cause of congenital LQTS
  notes: >-
    AKAP9 encodes yotiao, the A-kinase anchoring protein that scaffolds PKA onto
    the IKs channel and mediates its response to sympathetic stimulation, and it
    carries the LQT11 designation. The protein's role in the IKs macromolecular
    complex is not what ClinGen disputes; the disputed claim is that AKAP9
    variants cause LQTS, which rests on a candidate-gene study reporting a single
    missense variant in a single patient.
  evidence:
  - reference: CGGV:assertion_786eac72-8014-4fdf-b279-10a5faaa09b8-2020-12-15T002607.349Z
    reference_title: "AKAP9 / long QT syndrome (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AKAP9 | HGNC:379 | long QT syndrome | MONDO:0002442 | AD | Disputed"
    explanation: The ClinGen validity row behind the DISPUTED typing of this record.
  - reference: CGGV:assertion_786eac72-8014-4fdf-b279-10a5faaa09b8-2020-12-15T002607.349Z
    reference_title: "AKAP9 / long QT syndrome (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "The first study to associate this gene with LQTS used a candidate gene approach and identified a missense variant in AKAP9 in a single patient with LQTS"
    explanation: >-
      The whole of the genetic evidence the panel found for this association, and
      the reason it is disputed rather than merely limited.
- name: SNTA1
  subtype: Type 12
  relationship_type: DISPUTED
  gene_term:
    preferred_term: SNTA1
    term:
      id: hgnc:11167
      label: SNTA1
  association: Disputed as a cause of congenital LQTS
  notes: >-
    SNTA1 encodes alpha-1-syntrophin, a cytoskeletal protein reported to interact
    with the cardiac sodium channel, and carries the LQT12 designation. ClinGen
    disputes the association on a population-frequency argument as well as a
    study-design one: one of the two reported missense variants turned out to be
    common enough in the general European-ancestry population to be an unlikely
    cause of a rare disease.
  evidence:
  - reference: CGGV:assertion_03c758a6-9290-4e14-9501-0ffb0fbfe8ce-2020-04-24T040000.000Z
    reference_title: "SNTA1 / long QT syndrome (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SNTA1 | HGNC:11167 | long QT syndrome | MONDO:0002442 | AD | Disputed"
    explanation: The ClinGen validity row behind the DISPUTED typing of this record.
  - reference: CGGV:assertion_03c758a6-9290-4e14-9501-0ffb0fbfe8ce-2020-04-24T040000.000Z
    reference_title: "SNTA1 / long QT syndrome (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "One of these variants, however, is now known to be present in ~1:150 individuals of European descent, making it an unlikely cause of a rare disease."
    explanation: >-
      The population-frequency argument against the SNTA1-LQTS association, quoted
      because it is a different and stronger kind of refutation than a study-design
      objection.
- name: KCNJ5
  subtype: Type 13
  relationship_type: DISPUTED
  gene_term:
    preferred_term: KCNJ5
    term:
      id: hgnc:6266
      label: KCNJ5
  association: Disputed as a cause of congenital LQTS
  notes: >-
    KCNJ5 encodes an inward-rectifying potassium channel and carries the LQT13
    designation. ClinGen disputes the association: the locus came from linkage in
    one large family, the implicated variant is too common in the relevant
    ancestry group to cause a rare disease, and little else supports the pair.
    KCNJ5 does have a definitive ClinGen relationship, but with familial
    hyperaldosteronism type III rather than with any arrhythmia syndrome.
  evidence:
  - reference: CGGV:assertion_6fa6a520-ae6b-4638-a092-a61831d481bf-2020-12-15T002641.568Z
    reference_title: "KCNJ5 / long QT syndrome (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNJ5 | HGNC:6266 | long QT syndrome | MONDO:0002442 | AD | Disputed"
    explanation: The ClinGen validity row behind the DISPUTED typing of this record.
  - reference: CGGV:assertion_6fa6a520-ae6b-4638-a092-a61831d481bf-2020-12-15T002641.568Z
    reference_title: "KCNJ5 / long QT syndrome (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "The Gly387Arg variant identified in this family, however, is now recognized to be present in 1/200 individuals of East Asian descent, making it very unlikely to be a rare cause of a rare disease."
    explanation: The population-frequency argument the panel used to dispute the KCNJ5-LQTS association.
- name: ANK2
  subtype: Type 4
  relationship_type: DISPUTED
  gene_term:
    preferred_term: ANK2
    term:
      id: hgnc:493
      label: ANK2
  association: Disputed as a cause of congenital LQTS; curated as its own entity elsewhere
  notes: >-
    ANK2 encodes ankyrin-B and carries the historical LQT4 designation. Two
    things have to be held apart here. ClinGen disputes ANK2 as a cause of long
    QT syndrome specifically - and separately disputes it for catecholaminergic
    polymorphic ventricular tachycardia and for Brugada syndrome - while
    classifying ANK2 as definitive for a complex neurodevelopmental disorder. The
    cardiac phenotype attributed to ankyrin-B loss is curated in dismech as its
    own entry, `ANK2_Ankyrin_B_Syndrome.yaml`, anchored on
    MONDO:0010958 (cardiac arrhythmia, ankyrin-B-related) rather than on an LQTS
    class. This record therefore exists to make the LQT4 row's gene explicit and
    to carry the disputed grading, not to duplicate that entry's mechanism.

    The ClinGen cache file for this assertion carries only the validity row and no
    narrative evidence summary. That is not a curation shortcut: the assertion's
    report page returned HTTP 500 when the cache was built on 2026-09-19, so there
    was no narrative to ingest. The Adler et al. reappraisal quoted below is the
    published account of the same panel's reasoning.
  evidence:
  - reference: CGGV:assertion_dd577817-d668-413c-95f9-d3e08a8cf5d3-2020-12-15T002719.834Z
    reference_title: "ANK2 / long QT syndrome (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANK2 | HGNC:493 | long QT syndrome | MONDO:0002442 | AD | Disputed"
    explanation: The ClinGen validity row behind the DISPUTED typing of this record.
  - reference: DOI:10.1161/CIRCULATIONAHA.119.043132
    reference_title: An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Six genes, AKAP9, ANK2, KCNE2, KCNJ5, SCN4B, and SNTA1, were classified as disputed, defined as the absence of sufficient genetic evidence to support causation of LQTS"
    explanation: >-
      The published reappraisal naming all six disputed genes together, which is
      the single source behind the DISPUTED typing on this record and on the five
      others in this entry.
treatments:
- name: Beta-Blocker Therapy
  description: >-
    First-line anti-adrenergic therapy for most patients with inherited long QT
    syndrome.
  treatment_term:
    preferred_term: beta-blocker therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  target_mechanisms:
  - target: Adrenergic Trigger Susceptibility
    treatment_effect: INHIBITS
    description: >-
      Anti-adrenergic therapy reduces the likelihood that subtype-specific
      exercise or emotion-related triggers will precipitate malignant
      ventricular arrhythmias.
    evidence:
    - reference: PMID:10673253
      reference_title: Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        beta-blockers are associated with a significant reduction in cardiac
        events in LQTS patients.
      explanation: Supports beta-blocker therapy as effective anti-adrenergic risk reduction in congenital long QT syndrome.
  evidence:
  - reference: PMID:18606002
    reference_title: Congenital long QT syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment should always begin with beta-blockers, unless there are valid
      contraindications.
    explanation: Review abstract states that beta-blockers are the mandatory first-line treatment for congenital long QT syndrome.
  - reference: PMID:10673253
    reference_title: Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      beta-blockers are associated with a significant reduction in cardiac
      events in LQTS patients. However, syncope, aborted cardiac arrest, and
      LQTS-related death continue to occur while patients are on prescribed
      beta-blockers
    explanation: Defines both the benefit and the residual risk that prompt escalation beyond beta-blockers in higher-risk patients.
- name: Left Cardiac Sympathetic Denervation
  description: >-
    Surgical anti-adrenergic escalation when recurrent syncope or major events
    persist despite full-dose beta-blockade.
  treatment_term:
    preferred_term: left cardiac sympathetic denervation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Adrenergic Trigger Susceptibility
    treatment_effect: INHIBITS
    description: >-
      Left cardiac sympathetic denervation reduces arrhythmia-provoking
      sympathetic input when pharmacologic anti-adrenergic therapy is
      insufficient.
    evidence:
    - reference: PMID:18606002
      reference_title: Congenital long QT syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        If the patient has one more syncope despite a full dose beta-blockade,
        left cardiac sympathetic denervation (LCSD) should be performed without
        hesitation
      explanation: Supports LCSD as the preferred escalation step after recurrent syncope despite adequate beta-blockade.
  evidence:
  - reference: PMID:18606002
    reference_title: Congenital long QT syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If the patient has one more syncope despite a full dose beta-blockade,
      left cardiac sympathetic denervation (LCSD) should be performed without
      hesitation
    explanation: Review abstract explicitly recommends LCSD after recurrent syncope on full-dose beta-blockade.
- name: Implantable Cardioverter-Defibrillator Placement
  description: >-
    Device therapy for high-risk patients, especially after cardiac arrest or
    when malignant events recur despite optimal medical therapy.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:15191637
    reference_title: Congenital and acquired long QT syndrome. Current concepts and management.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For high-risk patients, the implantable cardioverter-defibrillator (ICD)
      offer an effective therapeutic option to reduce mortality.
    explanation: Supports ICD placement as mortality-reducing therapy in high-risk congenital long QT syndrome.
- name: Mexiletine
  description: >-
    Precision pharmacotherapy most relevant to the SCN5A/LQT3 subtype, where
    late sodium current blockade shortens QTc and lowers arrhythmic event
    burden.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mexiletine
      term:
        id: CHEBI:6916
        label: mexiletine
  target_mechanisms:
  - target: Persistent Late Sodium Current in LQT3
    treatment_effect: INHIBITS
    description: >-
      Mexiletine blocks late sodium current in the SCN5A-mediated subtype,
      shortening QTc and reducing malignant arrhythmic events.
    evidence:
    - reference: PMID:26940925
      reference_title: Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Besides shortening QTc interval, mexiletine caused a major reduction of
        life-threatening arrhythmic events in LQT3 patients, thus representing
        an efficacious therapeutic strategy.
      explanation: Supports mexiletine as subtype-targeted pharmacotherapy for the LQT3 branch of inherited long QT syndrome.
  notes: Particularly relevant for the Type 3 subtype rather than the full disease root.
- name: Allele-Specific RNA Interference
  description: >-
    Emerging precision therapeutic strategy targeting loss-of-function KCNH2 variants in LQT2 patients. RNA interference selectively suppresses mutant KCNH2 transcript while preserving wild-type expression, alleviating dominant-negative effects and restoring hERG current density.
  treatment_term:
    preferred_term: allele-specific RNA interference therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: siRNA therapeutic agent
      term:
        id: NCIT:C201688
        label: siRNA Therapeutic Agent
  target_mechanisms:
  - target: Reduced Repolarizing Potassium Current
    treatment_effect: INHIBITS
    description: >-
      Allele-specific RNA interference suppresses the expression of mutant KCNH2 transcripts carrying loss-of-function variants, reducing their dominant-negative interference with wild-type hERG channels and partially restoring IKr current density.
    evidence:
    - reference: PMID:42154296
      reference_title: "Functional characterization and allele-specific RNA interference-based rescue of KCNH2 p.F68C variant associated with long QT syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "allele-specific RNA interference selectively suppressed mutant hERG expression, alleviated dominant-negative interference, and partially restored hERG current density without detectable cytotoxicity"
      explanation: Demonstrates that allele-specific RNAi is effective at rescuing loss-of-function by suppressing mutant KCNH2 expression.
  notes: Experimental variant-directed therapeutic strategy particularly relevant for KCNH2 loss-of-function variants with dominant-negative effects in LQT2.
diagnosis:
- name: Resting electrocardiography with QTc and T-wave assessment
  description: >-
    Baseline 12-lead ECG remains the core diagnostic procedure for identifying
    QT prolongation and genotype-patterned T-wave abnormalities in suspected
    inherited long QT syndrome.
  results: >-
    Prolonged QTc with characteristic T-wave abnormalities supports inherited
    LQTS, but a normal QTc does not exclude the diagnosis in concealed carriers.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  measurements:
  - preferred_term: QTc
    term:
      id: LOINC:8636-3
      label: Q-T interval corrected
  reference_ranges:
  - loinc_term:
      id: LOINC:8636-3
      label: Q-T interval corrected
    unit: ms
    population: >-
      Guideline diagnostic QTc cut-off, as applied by Vink et al. (Circulation
      2018) to 1484 genotyped individuals from 265 families with LQT1, LQT2 or LQT3
    notes: >-
      LOINC:8636-3 names no correction formula; the formula-specific codes
      LOINC:76635-2 (Bazett) and LOINC:76634-5 (Fridericia) exist and are not
      bound, because the cited abstract reports that cut-off performance depends
      on the correction formula as well as on the QT measurement method, age and
      sex. The abstract calls 480 ms "the current guideline cutoff" without naming
      the guideline or writing an inequality; the band treats 480 ms as the
      lower, included boundary. The QTc point bands of the Schwartz score and the
      HRS/EHRA/APHRS 2013 QTc criterion are not recorded as ranges, because no
      cached text carries them:
      the Schwartz and Crotti review (PMID:18606002, full text) describes the
      point score and its probability categories but its Table 2 with the QTc
      points is not in the cached text; the Schwartz diagnostic-criteria update
      (PMID:8339437), the HRS/EHRA/APHRS consensus statement and its two
      executive summaries (PMID:24011539, PMID:23994779, PMID:23916535) and two
      ESC ventricular arrhythmia guidelines (PMID:26320108, PMID:36017572)
      returned no abstract text, and PubMed searches for LQTS abstracts quoting
      the Schwartz QTc bands returned none. Searched 2026-10-07.
    evidence:
    - reference: PMID:30571576
      reference_title: "Determination and Interpretation of the QT Interval."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Using the current guideline cutoff (QTc interval 480 ms), both methods had similar specificity but yielded a different sensitivity."
      explanation: States the guideline diagnostic QTc cut-off of 480 ms, applied in a genotyped LQTS family cohort.
    - reference: PMID:30571576
      reference_title: "Determination and Interpretation of the QT Interval."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Adjusted cutoff values are therefore specified for method, correction formula, age, and sex."
      explanation: The reason the method-less QTc code is bound rather than a formula-specific one.
    interpretation_bands:
    - name: QTc at or above the guideline diagnostic cut-off
      lower_bound: 480
      unit: ms
      abnormal_flag: HIGH
      interpretation: >-
        Meets the guideline QTc cut-off for diagnosing LQTS; below it, LQTS is not
        excluded, since a share of gene carriers have a normal QTc.
  notes: >-
    NCIT does not provide an ECG-specific diagnostic term here, so the
    preferred term is narrowed in the name and description.
  evidence:
  - reference: PMID:10348966
    reference_title: "The inherited long QT syndrome: from ion channel to bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The signs of long QT syndrome are prolongation of the QT interval on the
      electrocardiogram and abnormalities of T wave morphology.
    explanation: Supports ECG-based recognition of QT prolongation and T-wave morphology as the primary diagnostic assessment.
  - reference: PMID:10348966
    reference_title: "The inherited long QT syndrome: from ion channel to bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 12% of long QT gene carriers have a normal QTc, < or
      =0. 44 seconds. Thus, a normal QTc interval does not exclude long QT
      syndrome.
    explanation: Clarifies why concealed disease remains possible despite a normal resting QTc.
- name: Integrated clinical criteria and family-history review
  description: >-
    Borderline presentations require formal integration of electrocardiographic,
    clinical, and familial findings rather than reliance on QTc alone.
  results: >-
    Specific diagnostic criteria help resolve borderline or intermittently
    expressed phenotypes when ECG findings are not unequivocal.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:18606002
    reference_title: Congenital long QT syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, borderline cases are more complex and require the evaluation of
      various electrocardiographic, clinical, and familial findings, as
      proposed in specific diagnostic criteria.
    explanation: Directly supports formal multicomponent diagnostic criteria for borderline inherited LQTS.
- name: Molecular genetic testing
  description: >-
    Molecular testing is used to confirm the inherited diagnosis, define the
    subtype, and support cascade family screening when a pathogenic variant is
    identified.
  results: >-
    Detection of a pathogenic variant in a validated LQTS gene supports the
    inherited diagnosis and refines subtype-aware counseling and management.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:18606002
    reference_title: Congenital long QT syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Additionally, molecular screening is now part of the diagnostic process.
    explanation: Supports routine integration of molecular testing into modern inherited LQTS diagnosis.
differential_diagnoses:
- name: Acquired long QT syndrome
  description: >-
    Drug-induced or metabolic QT prolongation can closely mimic congenital LQTS
    and must be excluded before an inherited diagnosis is finalized.
  distinguishing_features:
  - Reversible exposure to QT-prolonging drugs, bradycardia, or electrolyte disturbance favors an acquired cause
  - Inherited LQTS is diagnosed from persistent clinical and electrocardiographic features rather than an isolated exposure history
  evidence:
  - reference: PMID:15191637
    reference_title: Congenital and acquired long QT syndrome. Current concepts and management.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For acquired LQTS, it is generally believed that the main issue is the
      blockade of the slow component of the delayed rectifier K+ current (IKr).
    explanation: Supports acquired long QT syndrome as the major mechanistic and clinical mimic that must be separated from inherited disease.
  - reference: PMID:15191637
    reference_title: Congenital and acquired long QT syndrome. Current concepts and management.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with a history of drug-induced LQTS, care must be taken to
      avoid further exposure to QT-prolonging drugs or conditions.
    explanation: Highlights a reversible exposure history as a distinguishing feature of acquired rather than congenital LQTS.
- name: Brugada syndrome
  description: >-
    Sodium-channel overlap syndromes can blur the boundary between LQT3 and
    Brugada syndrome, especially in SCN5A-mediated disease.
  disease_term:
    preferred_term: Brugada syndrome
    term:
      id: MONDO:0015263
      label: Brugada syndrome
  distinguishing_features:
  - Brugada syndrome is defined by right precordial ST-segment elevation rather than baseline QT prolongation
  - Some SCN5A variants can create mixed phenotypes, so both repolarization and depolarization signatures should be reviewed
  evidence:
  - reference: PMID:18451998
    reference_title: The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada
      syndrome (BrS) is observed in some carriers of mutations in the Na
      channel SCN5A.
    explanation: Directly supports Brugada syndrome as a clinically important differential diagnosis and overlap state for SCN5A-mediated LQT3.
clinical_trials:
- name: NCT01648205
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Single-blinded phase II study of ranolazine in genotyped LQT3 patients to
    test whether late sodium current blockade can shorten QTc over longitudinal
    follow-up.
  target_phenotypes:
  - preferred_term: prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: clinicaltrials:NCT01648205
    reference_title: "Efficacy of Ranolazine in LQT3 Patients"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to determine whether late sodium channel
      blockade might be effective in shortening the QTc interval in various
      LQT3 mutations and be considered as a safe therapeutic option for LQT3
      patients.
    explanation: Supports a subtype-specific ranolazine trial directly targeting late sodium current physiology in LQT3.
- name: NCT05906732
  phase: NOT_APPLICABLE
  status: TERMINATED
  description: >-
    Combined phase 1b/2a study of the SGK1 inhibitor LQT-1213, pairing a
    dofetilide challenge in healthy adults with safety and pharmacodynamic
    testing in patients with LQT2 or LQT3.
  target_phenotypes:
  - preferred_term: prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  notes: ClinicalTrials.gov classifies this as a combined Phase 1b/2a program.
  evidence:
  - reference: clinicaltrials:NCT05906732
    reference_title: "A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 in Patients Diagnosed With Type 2 or 3 Long QT Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Part 2: This is a Phase 2a, single-blind, placebo run-in, multiple-dose
      safety study to evaluate the safety, tolerability, and PK of LQT-1213 in
      patients diagnosed with LQT2 or LQT3.
    explanation: Supports an actively developed precision-therapy program for inherited LQT2/LQT3 biology.
datasets:
- accession: geo:GSE288082
  title: Modeling long QT syndrome using gene-edited pigs
  description: >-
    Bulk RNA-seq dataset from left ventricular tissue of a KCNH2-mutant
    miniature pig model developed to recapitulate LQT2-associated
    electrophysiology and remodeling.
  organism:
    preferred_term: pig
    term:
      id: NCBITaxon:9823
      label: Sus scrofa
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: left ventricular myocardium
    term:
      id: UBERON:0002084
      label: heart left ventricle
    tissue_term:
      preferred_term: left ventricular myocardium
      term:
        id: UBERON:0002084
        label: heart left ventricle
  sample_count: 8
  conditions:
  - KCNH2-mutant long QT syndrome type 2 miniature pig
  - wild-type left ventricular control tissue
  notes: >-
    GEO summary describes transcriptomic comparison of KCNH2-mutant versus wild
    type ventricular tissue in a large-animal LQT2 model.
  evidence:
  - reference: GEO:GSE288082
    reference_title: "Modeling long QT syndrome using gene-edited pigs"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To explore the mechanism underlying mutation of KCNH2 caused LQT, we
      compared the transcriptomes of KCNH2-mut pigs and WT controls
    explanation: This supports GSE288082 as a disease-relevant large-animal transcriptomic dataset for KCNH2-mediated long QT syndrome biology.
computational_models:
- name: O'Hara-Rudy (ORd) Human Ventricular Action Potential Model
  description: >-
    Foundational system of ordinary differential equations for the undiseased
    human ventricular cardiomyocyte action potential, fit to human myocyte data
    for the major ionic currents (I_CaL, I_Kr, I_Ks, I_K1, I_to, late I_Na,
    I_NaCa, I_NaK) with intracellular Ca2+ and CaMKII handling. Long QT syndrome
    is simulated by reducing repolarizing K+ conductance (I_Kr for LQT2, I_Ks for
    LQT1) or increasing the persistent late Na+ current (LQT3); each perturbation
    prolongs action potential duration and, during slow pacing, generates early
    afterdepolarizations, the cellular substrate for torsades de pointes.
  model_type: KINETIC
  repository_url: https://models.cellml.org/e/71
  model_id: ohara_rudy_2011
  model_format: CellML
  publication: PMID:21637795
  perturbations:
  - preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  - preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  modeled_mechanisms:
  - target: Prolonged Ventricular Action Potential Duration
    description: >-
      APD90 computed from the simulated action potential is the single-cell
      correlate of prolonged ventricular repolarization in LQTS.
  - target: Early Afterdepolarizations
    description: >-
      I_Kr block during slow pacing induces early afterdepolarizations in the
      model, reproducing the arrhythmogenic trigger.
  evidence:
  - reference: PMID:21637795
    reference_title: "Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      an accurate model for the undiseased human ventricular action potential
      (AP) which reproduces a broad range of physiological behaviors is needed
    explanation: >-
      Establishes ORd as the reference undiseased human ventricular action
      potential ODE model, the baseline for simulating LQTS ion-channel
      perturbations.
  findings:
  - statement: I_Kr block during slow pacing induces early afterdepolarizations in the model, the cellular trigger for torsades de pointes in LQT2 and drug-induced long QT
    evidence:
    - reference: PMID:21637795
      reference_title: "Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Early afterdepolarizations were induced by I(Kr) block during slow
        pacing, and AP and Ca(2+) alternans appeared at rates >200 bpm, as
        observed in the nonfailing human ventricle.
      explanation: >-
        Confirms the model reproduces I_Kr-block-induced early
        afterdepolarizations, the arrhythmogenic mechanism shared by LQT2 and
        acquired (drug-induced) long QT syndrome.
  variables:
  - name: Membrane potential
    dataset_identifier: v
    description: Transmembrane potential of the ventricular cardiomyocyte, the primary ODE state variable.
    unit: mV
  - name: Action potential duration at 90% repolarization (APD90)
    dataset_identifier: APD90
    description: >-
      Time from action potential upstroke to 90% repolarization; the single-cell
      correlate of the QT interval and the principal LQTS readout.
    unit: ms
    mappings_list:
    - preferred_term: Prolonged QTc interval
      description: >-
        APD90 is the cellular correlate of the clinical QT interval, not a direct
        QT measurement. Thresholds are illustrative, calibrated to ORd
        endocardial steady-state APD90 (about 270 ms at 1 Hz pacing), not to
        clinical QTc reference values.
      term:
        id: HP:0005184
        label: Prolonged QTc interval
      threshold: 300
      threshold_direction: above
      severity_scale:
      - threshold: 300
        name: mild
      - threshold: 400
        name: moderate
      - threshold: 500
        name: severe
    notes: >-
      severity_scale thresholds (300/400/500) are APD90 values in milliseconds,
      calibrated to ORd endocardial steady-state and illustrative rather than
      clinical QTc cutoffs.
  notes: >-
    CellML encoding in the Physiome Model Repository (exposure e/71); original
    MATLAB from the Rudy Lab. Endocardial, midmyocardial, and epicardial cell
    variants are provided. Base model for the CiPA IKr-dynamic ORd and ToR-ORd
    refinements below.
- name: CiPA IKr-Dynamic ORd Proarrhythmia Model
  description: >-
    Regulatory in-silico proarrhythmia model built on the O'Hara-Rudy ORd model
    by replacing the I_Kr formulation with a Markov model of dynamic drug-hERG
    (I_Kr) binding. Combined with multi-channel pharmacology (up to seven
    currents), it computes the net-charge metric qNet to stratify drug-induced
    torsades de pointes (TdP) risk. This is the acquired (drug-induced) long QT /
    proarrhythmia arm and is the consensus cell model of the FDA/HESI CiPA
    initiative.
  model_type: KINETIC
  repository_url: https://github.com/FDA/CiPA
  base_model: O'Hara-Rudy ORd human ventricular action potential model (PMID:21637795)
  publication: PMID:28878692
  perturbations:
  - preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  modeled_mechanisms:
  - target: Torsades de Pointes
    description: >-
      The qNet metric derived from this model classifies drug-induced torsades de
      pointes risk.
  evidence:
  - reference: PMID:28878692
    reference_title: "Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      we modified the original O'Hara Rudy ventricular cell mathematical model to
      include a Markov model of IKr to represent dynamic drug-IKr interactions
      (IKr-dynamic ORd model)
    explanation: >-
      Documents that the CiPA proarrhythmia model is the ORd model extended with a
      dynamic drug-I_Kr (hERG) Markov model, tying acquired long QT and TdP risk
      to the same repolarization-reserve mechanism as congenital LQTS.
  findings:
  - statement: The CiPA initiative uses an in-silico cell model with multi-channel pharmacology to predict drug-induced torsades de pointes risk
    evidence:
    - reference: PMID:28878692
      reference_title: "Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        The Comprehensive in vitro Proarrhythmia Assay (CiPA) was proposed to
        improve prediction of TdP risk, using in silico models and in vitro
        multi-channel pharmacology data as integral parts of this initiative.
      explanation: >-
        Establishes the regulatory purpose of the model: in-silico prediction of
        drug-induced TdP risk.
  - statement: The qNet net-charge metric classifies drug-induced TdP risk across a range of concentrations and pacing rates
    evidence:
    - reference: PMID:28878692
      reference_title: "Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        we developed an updated version of the metric that quantifies the net
        electronic charge carried by major inward and outward ionic currents
        during the steady state action potential, which could classify the level
        of drug-induced TdP risk across a wide range of concentrations and pacing
        rates
      explanation: >-
        Defines qNet as the model output used to stratify drug-induced TdP risk.
  variables:
  - name: qNet
    dataset_identifier: qNet
    description: >-
      Net electronic charge carried by the major inward and outward ionic
      currents over a steady-state action potential; lower qNet indicates higher
      drug-induced torsades de pointes risk.
    unit: microC/microF
    mappings_list:
    - preferred_term: Torsade de pointes
      description: >-
        qNet is an inverse risk metric: lower values indicate higher TdP
        liability. No clinical threshold is asserted here; CiPA uses ordinal
        high/intermediate/low risk categories rather than a single numeric cutoff.
      term:
        id: HP:0001664
        label: Torsade de pointes
      threshold_direction: below
  notes: >-
    Consensus in-silico model of the FDA/HESI Comprehensive in vitro
    Proarrhythmia Assay (CiPA); reference implementation at github.com/FDA/CiPA.
    Optimized by Dutta et al. 2017 from the IKr-dynamic ORd model.
- name: ToR-ORd Human Ventricular Myocyte Model
  description: >-
    Tomek-Rodriguez-O'Hara-Rudy refinement of the ORd model, recalibrated and
    independently validated across health, disease, and drug block, with a
    reformulated L-type Ca2+ current and a replaced hERG (I_Kr) current. It scales
    from single-cell ionic dynamics to whole-organ simulation including the
    electrocardiogram, and is a current reference human ventricular model for
    LQTS repolarization and drug-block studies.
  model_type: KINETIC
  repository_url: https://github.com/jtmff/torord
  base_model: O'Hara-Rudy ORd human ventricular action potential model (PMID:21637795)
  model_format: CellML
  publication: PMID:31868580
  perturbations:
  - preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  modeled_mechanisms:
  - target: Prolonged Ventricular Action Potential Duration
    description: >-
      Multiscale validation includes repolarization abnormalities and
      drug-induced I_Kr block relevant to LQTS.
  evidence:
  - reference: PMID:31868580
    reference_title: "Development, calibration, and validation of a novel human ventricular myocyte model in health, disease, and drug block."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      we present the design, development, calibration and independent validation
      of a human-based ventricular model (ToR-ORd) for simulations of
      electrophysiology and excitation-contraction coupling, from ionic to
      whole-organ dynamics, including the electrocardiogram
    explanation: >-
      Describes ToR-ORd as a multiscale (cell to ECG) human ventricular model
      suitable for linking LQTS ion-channel defects to the QT interval.
  findings:
  - statement: ToR-ORd is validated under healthy and key disease conditions and under drug blockade, supporting its use for LQTS and drug-induced repolarization studies
    evidence:
    - reference: PMID:31868580
      reference_title: "Development, calibration, and validation of a novel human ventricular myocyte model in health, disease, and drug block."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Validation based on substantial multiscale simulations supports the
        credibility of the ToR-ORd model under healthy and key disease
        conditions, as well as drug blockade.
      explanation: >-
        Confirms disease- and drug-block validation, the basis for applying the
        model to congenital and acquired long QT syndrome.
  variables:
  - name: Membrane potential
    dataset_identifier: v
    description: Transmembrane potential of the ventricular cardiomyocyte, the primary ODE state variable.
    unit: mV
  - name: Action potential duration at 90% repolarization (APD90)
    dataset_identifier: APD90
    description: >-
      ToR-ORd recalibrated action potential duration at 90% repolarization; the
      single-cell correlate of the QT interval and the principal LQTS readout,
      computed with the reformulated I_CaL and replaced hERG (I_Kr) formulations.
    unit: ms
    notes: >-
      severity_scale thresholds are APD90 values in milliseconds, held consistent
      with the ORd model rather than re-derived from ToR-ORd steady-state values.
    mappings_list:
    - preferred_term: Prolonged QTc interval
      description: >-
        APD90 is the cellular correlate of the clinical QT interval, not a direct
        QT measurement. Thresholds are illustrative and calibrated to the same
        scale as the ORd model, not to clinical QTc reference values.
      term:
        id: HP:0005184
        label: Prolonged QTc interval
      threshold: 300
      threshold_direction: above
      severity_scale:
      - threshold: 300
        name: mild
      - threshold: 400
        name: moderate
      - threshold: 500
        name: severe
  notes: >-
    Code (MATLAB and CellML), the validation pipeline, and human AP morphology
    data at github.com/jtmff/torord; a CellML exposure is also in the Physiome
    Model Repository.
discussions:
- discussion_id: q_lqt_drug_query_nam_confirmation
  prompt: >-
    Can New Approach Methodologies functionally confirm and risk-stratify the
    latent congenital LQTS carriers surfaced by the drug-induced-torsade EHR
    case-finding query — distinguishing true reduced-repolarization-reserve
    carriers from incidental variants — using the CiPA in-vitro/in-silico
    paradigm and patient iPSC-cardiomyocytes?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#QT-Prolonging Drug Unmasking of Reduced Repolarization Reserve
  rationale: >-
    The EHR query (see this entry's definitions) surfaces candidates but cannot
    say whether a given variant actually reduces repolarization reserve. CiPA —
    the Comprehensive in vitro Proarrhythmia Assay — is a mature regulatory NAM
    that pairs in-vitro multi-ion-channel (notably hERG/IKr) measurement with an
    in-silico human ventricular action-potential model to predict torsade risk;
    this entry already curates such an O'Hara-Rudy-derived model. Applying CiPA
    to a candidate's variant, plus a patient-iPSC-cardiomyocyte drug challenge,
    is the mechanistic complement to the population EHR arm and a route to
    resolving variants of uncertain significance.
  proposed_experiments:
  - experiment_id: exp_lqt_cipa_nam_confirmation
    name: CiPA in-vitro/in-silico and iPSC-cardiomyocyte confirmation of query hits
    description: >-
      For candidate carriers surfaced by the drug-induced-torsade query, express
      the candidate KCNH2/KCNQ1/SCN5A variant heterologously and measure IKr (and
      the CiPA multi-channel panel); challenge patient-derived (and isogenic
      control) iPSC-cardiomyocytes with a QT-prolonging drug; and integrate the
      channel data into an in-silico human ventricular action-potential model
      (O'Hara-Rudy/ToR-ORd) to predict torsade risk. Concordant loss of
      repolarizing current, drug-induced APD prolongation/EADs, and an elevated
      in-silico torsade metric would confirm reduced repolarization reserve.
    experiment_type:
      preferred_term: CiPA in-vitro/in-silico proarrhythmia assay with iPSC-cardiomyocytes
    model_systems:
    - name: Heterologous ion-channel expression (CiPA multi-channel panel)
      description: >-
        Candidate variant expressed in a mammalian cell line; IKr/hERG and the
        CiPA multi-channel panel measured by patch clamp.
      experimental_model_type: CELL_LINE
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
    - name: Patient iPSC-derived cardiomyocytes
      description: >-
        Patient-derived and isogenic-corrected iPSC-cardiomyocytes challenged with
        a QT-prolonging drug.
      experimental_model_type: IPSC_DERIVED_MODEL
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      cell_source: patient-derived and isogenic CRISPR-corrected iPSC
    - name: In-silico human ventricular action-potential model
      description: >-
        O'Hara-Rudy/ToR-ORd human ventricular model integrating the measured
        channel block to predict torsade risk (CiPA in-silico arm).
      experimental_model_type: OTHER
    perturbations:
    - name: QT-prolonging drug challenge
      target: pathophysiology#QT-Prolonging Drug Unmasking of Reduced Repolarization Reserve
      description: Apply a QT-prolonging (IKr-blocking) drug across the in-vitro and in-silico systems.
    readouts:
    - name: Repolarizing current, APD prolongation and EADs
      target: pathophysiology#Prolonged Ventricular Action Potential Duration
      description: >-
        IKr density, drug-induced APD prolongation and early afterdepolarizations
        in iPSC-cardiomyocytes, and the in-silico torsade metric.
    - name: Torsade propensity
      target: pathophysiology#Torsades de Pointes
      description: In-silico/iPSC torsade-risk classification for the candidate variant.
    decision_criterion: >-
      Concordant reduction of repolarizing current, drug-induced APD
      prolongation/EADs, and an elevated in-silico torsade metric for a candidate
      variant versus isogenic control.
    supporting_outcome:
    - >-
      The variant genuinely reduces repolarization reserve, confirming a query hit
      as a true latent congenital LQTS carrier.
    refuting_outcome:
    - >-
      No functional deficit, indicating the query hit is not explained by that
      variant (incidental finding).
references:
- reference: PMID:20301308
  title: "Long QT Syndrome Overview."
  tags:
  - GeneReviews
- reference: PMID:10348966
  title: "The inherited long QT syndrome: from ion channel to bedside."
  findings: []
- reference: PMID:10377081
  title: Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel.
  findings: []
- reference: PMID:10673253
  title: Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome.
  findings: []
- reference: PMID:11136691
  title: "Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias."
  findings: []
- reference: PMID:15191637
  title: Congenital and acquired long QT syndrome. Current concepts and management.
  findings: []
- reference: PMID:16001794
  title: "[The genetic disorders responsible for sudden cardiac death]."
  findings: []
- reference: PMID:18451998
  title: The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.
  findings: []
- reference: PMID:18606002
  title: Congenital long QT syndrome.
  findings: []
- reference: PMID:26940925
  title: Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3.
  findings: []
- reference: PMID:28670758
  title: Congenital Long QT syndrome and torsade de pointes.
  findings: []
- reference: ORPHA:101016
  title: Romano-Ward syndrome
  findings: []
- reference: PMID:9272508
  title: "Clinical management of patients with the long QT syndrome: drugs, devices, and gene-specific therapy."
  findings: []
- reference: clinicaltrials:NCT01648205
  title: Efficacy of Ranolazine in LQT3 Patients
  findings: []
- reference: clinicaltrials:NCT05906732
  title: "A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 in Patients Diagnosed With Type 2 or 3 Long QT Syndrome"
  findings: []
- reference: GEO:GSE288082
  title: Modeling long QT syndrome using gene-edited pigs
  findings: []

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References & Deep Research