Familial Long QT Syndrome

Genetic MONDO:0019171 Pathograph 15 Cardiac Arrhythmia Channelopathy

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.

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1
Mappings
0
Definitions
1
Inheritance
6
Pathophysiology
0
Histopathology
8
Phenotypes
15
Pathograph
11
Genes
4
Treatments
16
Subtypes
2
Differentials
1
Datasets
2
Trials
0
Models
15
References
2
Deep Research
🏷

Classifications

Channelopathy
cardiac channelopathy
🔗

Mappings

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

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.
◆

Subtypes

16
Long QT Syndrome 1 MONDO:0100316
KCNQ1-related form driven by reduced IKs-mediated repolarization reserve.
Long QT Syndrome 2 MONDO:0013367
KCNH2-related form driven by reduced IKr-mediated repolarization reserve.
Long QT Syndrome 3 MONDO:0011377
SCN5A-related form driven by persistent late sodium current and especially relevant to mexiletine precision therapy.
Long QT Syndrome 4 MONDO:0800323
Historical ANK2-related LQT4 designation; detailed ankyrin-B syndrome curation remains in the separate ANK2-focused entry.
Long QT Syndrome 5 MONDO:0013372
KCNE1-related familial LQTS subtype.
Long QT Syndrome 6 MONDO:0013370
KCNE2-related familial LQTS subtype.
Long QT Syndrome 8 MONDO:0032756
CACNA1C-related LQTS subtype, with syndromic Timothy syndrome overlap curated separately.
Long QT Syndrome 9 MONDO:0012736
CAV3-related familial LQTS subtype.
Long QT Syndrome 10 MONDO:0012737
SCN4B-related familial LQTS subtype.
Long QT Syndrome 11 MONDO:0012738
AKAP9-related familial LQTS subtype.
Long QT Syndrome 12 MONDO:0013062
SNTA1-related familial LQTS subtype.
Long QT Syndrome 13 MONDO:0013279
KCNJ5-related familial LQTS subtype.
Long QT Syndrome 14 MONDO:0014548
CALM1-related familial LQTS subtype.
Long QT Syndrome 15 MONDO:0014550
CALM2-related familial LQTS subtype.
Long QT Syndrome 16 MONDO:0032915
TRDN-related familial LQTS subtype with catecholaminergic ventricular tachycardia overlap.
Other rare-gene familial LQTS
Other inherited ion-channel or regulatory-gene forms retained at the disease root unless they define a separately curated clinically distinct syndrome.
⚙

Pathophysiology

6
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 link
KCNQ1 link KCNH2 link
potassium ion transmembrane transport link ↓ DECREASED membrane repolarization during cardiac muscle cell action potential link ↕ DYSREGULATED
heart link
Downstream
Prolonged Ventricular Action Potential Duration Reduced repolarization reserve prolongs the ventricular action potential and creates an arrhythmogenic substrate.
Show evidence (1 reference)
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.
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 link
SCN5A link
sodium ion transmembrane transport link ⚠ ABNORMAL membrane repolarization during cardiac muscle cell action potential link ↕ DYSREGULATED
heart link
Downstream
Prolonged Ventricular Action Potential Duration Persistent inward sodium current prolongs ventricular repolarization and feeds the common arrhythmogenic substrate.
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.
Prolonged Ventricular Action Potential Duration
Reduced repolarization reserve and persistent inward sodium current prolong ventricular action potential duration and delay ventricular repolarization.
cardiomyocyte link
membrane repolarization during cardiac muscle cell action potential link ↕ DYSREGULATED
heart link
Downstream
Early Afterdepolarizations Prolonged ventricular action potential duration permits early afterdepolarizations to emerge from the plateau.
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 link
cardiac muscle cell action potential link ⚠ ABNORMAL
heart link
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.
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.
Downstream
Syncope Torsades de pointes commonly presents as transient loss of consciousness from arrhythmic cerebral hypoperfusion.
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.
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.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Long QT Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Cardiovascular 4
Prolonged QTc Interval OBLIGATE Prolonged QTc interval (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 Syncope (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 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.
Sudden Cardiac Death OCCASIONAL Sudden cardiac death (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.
Nervous System 1
Seizure OCCASIONAL Seizure (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.
Other 3
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.
Sinus Bradycardia FREQUENT Sinus bradycardia (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 Abnormal T-wave (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.
🧬

Genetic Associations

11
KCNQ1 (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
"KCNQ1 | HGNC:6294 | long QT syndrome | MONDO:0002442 | AD | Definitive"
ClinGen classifies the KCNQ1-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
KCNH2 (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
"KCNH2 | HGNC:6251 | long QT syndrome | MONDO:0002442 | AD | Definitive"
ClinGen classifies the KCNH2-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
SCN5A (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)
Show evidence (1 reference)
CGGV:assertion_6499e6e2-af96-4868-bfd5-18ab35f61847-2026-01-15T010000.000Z SUPPORT Other
"ALG10B | HGNC:31088 | long QT syndrome | MONDO:0002442 | AD | Limited"
ClinGen classifies the ALG10B-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.
CACNA1C (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_c496551d-c7a7-4e49-ad41-8cfd49840dc1-2020-04-24T040000.000Z SUPPORT Other
"CACNA1C | HGNC:1390 | long QT syndrome | MONDO:0002442 | AD | Moderate"
ClinGen classifies the CACNA1C-long QT syndrome gene-disease relationship as moderate with autosomal dominant inheritance.
CALM1 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_4a150cd9-e16b-4992-8cc7-5ccec44b4d6b-2018-09-25T160000.000Z SUPPORT Other
"CALM1 | HGNC:1442 | long QT syndrome | MONDO:0002442 | AD | Definitive"
ClinGen classifies the CALM1-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
CALM2 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_86e4b783-3b60-4a1d-ab34-e61d27751ca6-2018-09-25T160000.000Z SUPPORT Other
"CALM2 | HGNC:1445 | long QT syndrome | MONDO:0002442 | AD | Definitive"
ClinGen classifies the CALM2-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
CALM3 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_3cc2a1ae-5f3d-445c-b124-f3d38fdd070a-2018-09-25T160000.000Z SUPPORT Other
"CALM3 | HGNC:1449 | long QT syndrome | MONDO:0002442 | AD | Definitive"
ClinGen classifies the CALM3-long QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
CAV3 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_74aabddc-3402-46de-ba1e-f66aa273cd9c-2020-12-15T002855.870Z SUPPORT Other
"CAV3 | HGNC:1529 | long QT syndrome | MONDO:0002442 | AD | Limited"
ClinGen classifies the CAV3-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.
KCNJ2 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_5dc2acbc-8dbe-4142-8f71-89f1576dde08-2020-12-15T002535.799Z SUPPORT Other
"KCNJ2 | HGNC:6263 | long QT syndrome | MONDO:0002442 | AD | Limited"
ClinGen classifies the KCNJ2-long QT syndrome gene-disease relationship as limited with autosomal dominant inheritance.
TRDN (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_1278bd6a-6ac7-4556-87ea-f860027b2da5-2020-04-24T040000.000Z SUPPORT Other
"TRDN | HGNC:12261 | long QT syndrome | MONDO:0002442 | AR | Strong"
ClinGen classifies the TRDN-long QT syndrome gene-disease relationship as strong with autosomal recessive inheritance.
💊

Treatments

4
Beta-Blocker Therapy
Action: beta-blocker therapy Ontology label: beta-adrenergic antagonist therapy MAXO:0000187
Agent: beta-adrenergic antagonist ↗
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 MAXO:0000476
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 MAXO:0000058
Agent: mexiletine ↗
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.
🔀

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
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 ↗
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 ↗
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.
{ }

Source YAML

click to show 
name: Familial Long QT Syndrome
creation_date: '2026-04-14T05:37:14Z'
updated_date: '2026-05-09T11:04:37Z'
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.
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 (Orphanet structured-database record)"
    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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  description: TRDN-related familial LQTS subtype with catecholaminergic ventricular tachycardia overlap.
- name: Other rare-gene familial LQTS
  description: >-
    Other inherited ion-channel or regulatory-gene forms retained at the
    disease root unless they define a separately curated clinically distinct
    syndrome.
prevalence:
- population: Live births
  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.
pathophysiology:
- name: Reduced Repolarizing Potassium Current
  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
  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.
  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
  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
  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.
- name: Prolonged Ventricular Action Potential Duration
  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.
- name: Early Afterdepolarizations
  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
  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: Torsades de Pointes
  description: >-
    Torsades de pointes is the characteristic malignant ventricular
    tachyarrhythmia of inherited LQTS, arising from prolonged repolarization,
    early afterdepolarizations, and permissive trigger conditions.
  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: 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.
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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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.
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: MAXO:0000187
      label: beta-adrenergic antagonist therapy
    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: MAXO:0000476
      label: left cardiac sympathetic denervation
  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: MAXO:0000058
      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.
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: MAXO:0000487
      label: clinical assessment
  notes: >-
    MAXO 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: MAXO:0000487
      label: clinical assessment
  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: MAXO:0000533
      label: molecular genetic testing
  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
    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
    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
    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.
references:
- 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: []
📚

References & Deep Research

References

15
PMID:10348966
The inherited long QT syndrome: from ion channel to bedside.
No top-level findings curated for this source.
PMID:10377081
Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel.
No top-level findings curated for this source.
PMID:10673253
Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome.
No top-level findings curated for this source.
PMID:11136691
Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.
No top-level findings curated for this source.
PMID:15191637
Congenital and acquired long QT syndrome. Current concepts and management.
No top-level findings curated for this source.
PMID:16001794
[The genetic disorders responsible for sudden cardiac death].
No top-level findings curated for this source.
PMID:18451998
The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.
No top-level findings curated for this source.
PMID:18606002
Congenital long QT syndrome.
No top-level findings curated for this source.
PMID:26940925
Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3.
No top-level findings curated for this source.
PMID:28670758
Congenital Long QT syndrome and torsade de pointes.
No top-level findings curated for this source.
ORPHA:101016
Romano-Ward syndrome
No top-level findings curated for this source.
PMID:9272508
Clinical management of patients with the long QT syndrome: drugs, devices, and gene-specific therapy.
No top-level findings curated for this source.
clinicaltrials:NCT01648205
Efficacy of Ranolazine in LQT3 Patients
No top-level findings curated for this source.
clinicaltrials:NCT05906732
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
No top-level findings curated for this source.
GEO:GSE288082
Modeling long QT syndrome using gene-edited pigs
No top-level findings curated for this source.

Deep Research

2
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Long QT Syndrome. Core disease mechanisms, molecular and cellular pathways...
Asta Scientific Corpus Retrieval 18 citations 2026-04-21T17:03:30.310440

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Long QT Syndrome. Core disease mechanisms, molecular and cellular pathways...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Joint effects of CD8A and ICOS in Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS)

  • Authors: Ling-bing Meng, Yongchao Li, Tingting Lv, Changhua Lv, Lianfeng Liu et al.
  • Year: 2024
  • Venue: Journal of Cardiothoracic Surgery
  • URL: https://www.semanticscholar.org/paper/5a96336f0cee51c440d5c99c8c28b51bb987a8a5
  • DOI: 10.1186/s13019-024-02804-w
  • PMID: 38845009
  • PMCID: 11155187
  • Summary: The identification of shared key genes between LQTS and BWS provides insights into common molecular mechanisms underlying these disorders, potentially facilitating the development of targeted therapeutic strategies.
  • Evidence snippets:
  • Snippet 1 (score: 0.495) > Furthermore, recent research has highlighted the intricate interplay between ion channels and growth-related pathways in cellular physiology.For instance, ion channels play crucial roles not only in cardiac electrophysiology but also in cellular proliferation, migration, and differentiation [10].Conversely, dysregulation of growthrelated pathways can influence ion channel expression and function, thereby impacting cardiac excitability and arrhythmia susceptibility [11].These findings underscore the potential convergence of molecular pathways implicated in LQTS and BWS pathogenesis.Common themes such as genetic factors, chromosomal anomalies, and gene dysregulation may underlie the clinical heterogeneity observed in these syndromes.However, further research is warranted to elucidate the precise molecular mechanisms linking LQTS and BWS and to explore potential therapeutic targets shared between these conditions. > Bioinformatics is an interdisciplinary field that combines computer science with biology, playing a pivotal role in biological research.Significant progress has also been made in protein mass spectrometry analysis, structure prediction, and functional annotation, aiding researchers in understanding protein structure and function [12].With the ongoing technological developments, the role of bioinformatics in fields such as biology, medicine, and drug development will continue to expand [13]. > Recent studies have utilized bioinformatics to explore CD8A as an immune cell infiltration and effective diagnostic biomarker in rheumatoid arthritis [14].Li [15] analyzed ICOS + Tregs as a functional subset of Tregs in immune diseases.Furthermore, recent investigations have begun to explore Long QT Syndrome and Beckwith-Wiedemann Syndrome using bioinformatics techniques [16], including artificial intelligence.Variations in genes and molecular mechanisms exist across different diseases, and the relationship between CD8A, ICOS, Long QT Syndrome, and Beckwith-Wiedemann Syndrome remains elusive. > This study seeks to utilize bioinformatics methods to identify key genes shared among Long QT Syndrome, Beckwith-Wiedemann Syndrome, and normal samples.The research will involve conducting enrichment and pathway analyses.

[2] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

  • Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
  • DOI: 10.3390/ijms22083930
  • PMID: 33920294
  • PMCID: 8069124
  • Citations: 6
  • Influential citations: 1
  • Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
  • Evidence snippets:
  • Snippet 1 (score: 0.483) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[3] Transcriptome and open chromatin analysis reveals the process of myocardial cell development and key pathogenic target proteins in Long QT syndrome type 7

  • Authors: Peipei Chen, J. Long, Tianrui Hua, Zhifa Zheng, Ying Xiao et al.
  • Year: 2024
  • Venue: Journal of Translational Medicine
  • URL: https://www.semanticscholar.org/paper/0aca10800c23f1c939942b4f6bf992317eb1be09
  • DOI: 10.1186/s12967-024-05125-7
  • PMID: 38528561
  • PMCID: 10964537
  • Citations: 1
  • Summary: TFs and target proteins related to electrophysiology and developmental pathogenicity in ATS myocardial cells are uncovered, obtaining novel targets for potential therapeutic candidate development that does not rely on gene editing.
  • Evidence snippets:
  • Snippet 1 (score: 0.465) > Long QT syndrome type 7 (Andersen–Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p < 0.05) by used single sample Gene Set Enrichment Analysis to evaluate the overall regulation of potassium-related pathways enriched in the transcriptome and proteome of late mature CMs. Among them, the three pathways (GO: 0008076, GO: 1990573 and GO: 0030007) containing the mutated gene KCNJ2 is involved that are related to the whole process by which a potassium ion enters the cell via the inward rectifier potassium channel to exert its effect were inhibited. The other four pathways are related to regulation of the potassium transmembrane pathway and sodium:potassium exchange ATPase (p < 0.05). ZNF528 small interfering (

[4] Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

  • Authors: C. Terrenoire, Kai Wang, Kelvin W Chan Tung, W. Chung, R. Pass et al.
  • Year: 2013
  • Venue: The Journal of General Physiology
  • URL: https://www.semanticscholar.org/paper/b6d8c7da3c94667fa268fc40848996fa93121757
  • DOI: 10.1085/jgp.201210899
  • PMID: 23277474
  • PMCID: 3536519
  • Citations: 205
  • Influential citations: 15
  • Summary: Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was fou...
  • Evidence snippets:
  • Snippet 1 (score: 0.447) > promise of personalized disease management (Schwartz et al., 1995;An et al., 1996;Moss and Kass, 2005). However, particularly in the case of LQTS, patients with multiple mutations have more severe clinical phenotypes and may respond uniquely to pharmacologic therapies (Westenskow et al., 2004;Itoh et al., 2010;Zhang et al., 2012). In addition, there can be significant clinical variability between individuals with the same LQT mutation, possibly as a result of genetic modifiers. Patient-specific iPSC-CMs represent a platform with potential for investigating the molecular pharmacology of ion channel mutations expressed in these complex genetic backgrounds (Tiscornia et al., 2011;Gnecchi and Schwartz, 2012;Zhang et al., 2012) and may provide unique insight into therapeutic approaches for disease management. > In this study, we report generation of iPSC-CMs from each member of an LQTS-3 (LQT-3) family and the investigation of the molecular pharmacology of key ion channels. The proband had been found to have a Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na + channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism.

[5] The channelopathies: an overview

  • Authors: J. M. Blanckenberg
  • Year: 2002
  • Venue: Southern African Journal of Anaesthesia and Analgesia
  • URL: https://www.semanticscholar.org/paper/b92e98fe413d2274a3c2688ddeb01efb297b1087
  • DOI: 10.1080/22201173.2002.10872953
  • Citations: 1
  • Summary: Because each of these diseases is caused by a discrete abnormality of an ion channel protein, this diverse variety of clinical manifestations is grouped together and described as the channelopathies.
  • Evidence snippets:
  • Snippet 1 (score: 0.445) > What at first glance appears to be a random selection of widely differing clinical presentations and syndromes, has recently been found to have as their common underlying factor an inherited abnormality of the mechanism in the cell wall, the ion channel, which is responsible for the transmembrane passage of various ions. Included in this diverse array of diseases are malignant hyperthermia, long QT syndrome, myotonia congenita, Eaton Lambert syndrome, certain forms of migraine and epilepsy, as well as cystic fibrosis.1 The common pathophysiology in all these diseases is an inherited abnormality of the amino acid sequence of the complex protein structure from which the ion channel is composed. These ion channels are ubiquitous in the body, their expression is not restricted only to excitable cells such as neurons or myocytes, and they may be found in the external membrane as well as internal organelles of cells such as pancreatic and renal cells. Because each of these diseases is caused by a discrete abnormality of an ion channel protein, this diverse variety of clinical manifestations is grouped together and described as the channelopathies.2 In order to better understand the pathophysiology involved in each of the channelopathies, it is necessary to review the normal physiology of the individual ion channels themselves.

[6] Precision medicine for long QT syndrome: patient-specific iPSCs take the lead

  • Authors: Yang Yu, I. Deschênes, Ming-Tao Zhao
  • Year: 2023
  • Venue: Expert Reviews in Molecular Medicine
  • URL: https://www.semanticscholar.org/paper/fa8b7b7f08fdd6c61e5185d1db5559fd0117c060
  • DOI: 10.1017/erm.2022.43
  • PMID: 36597672
  • PMCID: 10302164
  • Citations: 19
  • Summary: The roles of various ion channels in orchestrating APs and molecular aetiologies of various types of Long QT syndrome are described and the usage of patient-specific induced pluripotent stem cell (iPSC) models are highlighted in characterising fundamental mechanisms associated with LQTS.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > Long QT syndrome (LQTS) is an inherited or acquired arrhythmia syndrome that may co-occur with malignant sudden cardiac death. It is characterised by the prolongation of QT interval and an enhanced threat of ventricular arrhythmia (Refs 1, 2). LQTS is primarily divided into congenital and acquired types. Congenital LQTS is mainly attributed to mutations in ion channels and their accessory proteins. Acquired LQTS is primarily caused by various pharmacological agents (e.g., antibiotics, antidepressants, antihistamines, antineoplastics). > Seventeen genes have been reported to be associated with congenital LQTS. Mutations in three common genes (KCNQ1, KCNH2 and SCN5A) account for more than 75% of clinically validated congenital LQTS cases, whereas less than 5% have been attributed to mutations in other genes (Ref. 3). Genetic aetiologies for the remaining approximately 20% of hereditary LQTS are unknown. Intriguingly, a clinical study revealed that the identical LQTS-relevant mutations are not necessarily linked to the same disease phenotype (Ref. 4). Currently, effective treatment options for LQTS are beta-blockers (propranolol, nadolol, etc.), sodium channel blockers (e.g., mexiletine, flecainide, etc.), and surgical interventions that include left cardiac sympathetic denervation (LCSD) and implantable cardioverter-defibrillator (ICD) (Ref. 5). > In this review, we introduce the clinical manifestations and diagnosis of LQTS. We discuss the molecular basis of ion channels underlying congenital LQTS and explore the potential of modelling LQTS using patient-specific induced pluripotent stem cell (iPSCs). We then summarise the current treatment strategies for LQTS and speculate on the future of precision medicine in LQTS through utilising patient-specific iPSCs and whole-genome sequencing.
  • Snippet 2 (score: 0.439) > Abstract Long QT syndrome (LQTS) is a detrimental arrhythmia syndrome mainly caused by dysregulated expression or aberrant function of ion channels. The major clinical symptoms of ventricular arrhythmia, palpitations and syncope vary among LQTS subtypes. Susceptibility to malignant arrhythmia is a result of delayed repolarisation of the cardiomyocyte action potential (AP). There are 17 distinct subtypes of LQTS linked to 15 autosomal dominant genes with monogenic mutations. However, due to the presence of modifier genes, the identical mutation may result in completely different clinical manifestations in different carriers. In this review, we describe the roles of various ion channels in orchestrating APs and discuss molecular aetiologies of various types of LQTS. We highlight the usage of patient-specific induced pluripotent stem cell (iPSC) models in characterising fundamental mechanisms associated with LQTS. To mitigate the outcomes of LQTS, treatment strategies are initially focused on small molecules targeting ion channel activities. Next-generation treatments will reap the benefits from development of LQTS patient-specific iPSC platform, which is bolstered by the state-of-the-art technologies including whole-genome sequencing, CRISPR genome editing and machine learning. Deep phenotyping and high-throughput drug testing using LQTS patient-specific cardiomyocytes herald the upcoming precision medicine in LQTS.

[7] Long QT syndrome: from genetic basis to treatment

  • Authors: L. Crotti, F. Dagradi, P. Schwartz
  • Year: 2011
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/febdb2efe1958c9d3813665112a3661f30dc4ddf
  • DOI: 10.4081/CARDIOGENETICS.2011.S1.E2
  • Citations: 1
  • Summary: The congenital long QT syndrome is a monogenic disorder, not as rare as it was originally estimated to be, mainly caused by mutations in genes encoding for ion channels, and the availability of diagnostic criteria is very useful to support the diagnostic process.
  • Evidence snippets:
  • Snippet 1 (score: 0.439) > Clinical heterogeneity and variable penetrance among patients with the long QT syndrome sharing the same disease-causing mutation is usually attributed to the coexistence of additional genetic and epigenetic factors that could have a role in modifying the clinical manifestation of the disease. The search for these modifier factors is object of an intense research activity, as they could provide from one side new clinical tools useful for the risk stratification of these patients and from another side they could unveil new mechanisms/pathways involved in arrhythmogenesis, useful for development of novel therapeutic approaches. Some common genetic variants [single nucleotide polymorphisms (SNPs)] in cardiac ion channel genes represented the first good candidates as modifiers of the clinical severity of patients with a disease-causing mutation in these same genes. This hypothesis was proved in 2005, when we investigated a highly symptomatic LQTS proband with a mutation in KCNH2 (A1116V) and her relatives that despite carrying the same mutation were phenotypically mildly affected. 40 The clue of their difference was the coexistence in the proband, but not in the family members, of the common polymorphism KCNH2-K897T (present in 30% of caucasians) in trans with the mutation. 40 eterologous expression studies demonstrated that co-expression of A1116V with K897T exaggerated the I Kr reduction caused by the A1116V mutation, supporting the role of this common polymorphism as a major modifier of the clinical severity in this family. 40 Very recently, in another LQT2 family, the modifying role of K897T was further supported; 41 however, we still do not know whether the effect of the K897T is limited to some KCNH2 mutations or to all LQT2/LQTS patients. > Ideal populations to study the contribution of the so called modifier genes are populations of patients carrying the same disease-causing mutation (i.e. founder populations). 42,43

[8] Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies

  • Authors: Pi-Yin Hsiao, Hui-Chun Tien, C. Lo, J. Juang, Yihua Wang et al.
  • Year: 2013
  • Venue: The Application of Clinical Genetics
  • URL: https://www.semanticscholar.org/paper/3f16f43ee4137d38eb9d160f7ccbf33870c4d0b6
  • DOI: 10.2147/TACG.S29676
  • PMID: 23837003
  • PMCID: 3699290
  • Citations: 34
  • Influential citations: 1
  • Summary: This review has summarized the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, and the technology of induced pluripotent stem cells is a promising diagnostic and research tool.
  • Evidence snippets:
  • Snippet 1 (score: 0.433) > Over the past 15 years, molecular genetic studies have linked gene mutations to many inherited arrhythmogenic disorders, in particular, “ion channelopathies”, in which mutations in genes encode functional units of ion channels and/or their transporter-associated proteins in patients without primary cardiac structural abnormalities. These disorders are exemplified by congenital long QT syndrome (LQTS), short QT syndrome, Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Functional and pathophysiological studies have led to better understanding of the clinical spectrum, ion channel structures and cellular electrophysiology involving dynamics of intracellular calcium cycling in many subtypes of these disorders and more importantly, development of potentially more effective pharmacological agents and even curative gene therapy. In this review, we have summarized (1) the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, (2) the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, (3) mutations with channel function modulated by protein Kinase A-dependent phosphorylation can be the culprit of CPVT mimicry in Andersen-Tawil syndrome (LQT7), (4) ablation of the ion channel anchoring protein may prevent arrhythmogenesis in Timothy syndrome (LQT8), (5) altered intracellular Ca2+ cycling can be the basis of effective targeted pharmacotherapy in CPVT, and (6) the technology of induced pluripotent stem cells is a promising diagnostic and research tool as it has become a new paradigm for pathophysiological study of patient- and disease-specific cells aimed at screening new drugs and eventual clinical application of gene therapy. Lastly, we have discussed (7) genotype-phenotype correlation in relation to risk stratification of patients with congenital LQTS in clinical practice.

[9] The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy

  • Authors: Nesrin Gariballa, Fedah E. Mohamed, Sally Badawi, Bassam R. Ali
  • Year: 2024
  • Venue: Journal of Biomedical Science
  • URL: https://www.semanticscholar.org/paper/fd94e849860c8fa64b14cdbd8be13351948ff6f4
  • DOI: 10.1186/s12929-024-01054-1
  • PMID: 38937821
  • PMCID: 11210014
  • Citations: 7
  • Summary: The importance of this area of research is emphasized, offering substantial potential for understanding the factors influencing phenotypic variability associated with genetic variants, and current and prospective therapeutic approaches targeted at ameliorating the effects of mutations exhibiting dominant-negative effects are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.432) > It is crucial to highlight that the majority of TGFβ signaling pathways involve dimeric proteins, whether secretory or membrane-bound.As illustrated in a prior review, through an extensive literature search, we have shown that these proteins are implicated in around 25 monogenic human diseases [109].However, the disease mechanisms of these conditions remain underexplored in terms of possible implication of ERQC mechanism and also the potential existence of dominant-negative effects.Further investigation into these aspects is warranted to enhance our understanding of the pathogenesis associated with TGFβ signaling-related monogenic diseases. > Long QT syndromes (LQTS) are a group of autosomal inherited arrhythmogenic disorders characterized by abnormal cardiac activity presented by prolonged QT intervals, leading to a type of arrhythmia known as torsades de pointes [176].Irregularities in the heartbeat have the potential to result in fainting, seizures, or sudden cardiac arrest.LQTS is classified into three primary types based on the causative genes: LQTS1, MIM # 192500, LQST2, MIM # 613688, and LQTS3, MIM # 603830 encoded by the genes (KCNQ1), (KCNH2) and (SCN5A), respectively.These genes encode ion channels essential for cardiac repolarization [177].Nonetheless, each type has distinct triggers, clinical manifestations, severity and penetrance profile, suggesting variable molecular mechanisms involved, in addition to environmental factors, age and gender [178].LQTS2 is associated with KCNH2, a gene that encodes the voltage-gated K + channel α-subunit (Kv11.1),which function as tetrameric complex that consists of four Kv11.1 α-subunit [179]. > Ficker and colleagues reported through immunoprecipitation analysis that Kv11.1 disease-causing variants R752W and G601S show defective trafficking, evidenced by their strong association with molecular chaperones Hsp90 and Hsp70 in the ER.Defective trafficking results in ER-retention of misfolded Kv11.1variants, followed by premature degradation through the ERAD mechanism.

[10] Molecular Mechanisms of Inherited Arrhythmias

  • Authors: C. Wolf, C. Berul
  • Year: 2008
  • Venue: Current Genomics
  • URL: https://www.semanticscholar.org/paper/8dc574fc997d6e863ac851b4a75d122de6d9aa61
  • DOI: 10.2174/138920208784340768
  • PMID: 19440513
  • PMCID: 2679644
  • Citations: 26
  • Influential citations: 3
  • Summary: The molecular basis of inherited arrhythmias in structurally normal and altered hearts is summarized, which helps explain the molecular and functional mechanisms of long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and other electrical myopathies.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Inherited arrhythmias can be life threatening, and are major cause of mortality and morbidity in developed nations. Identification of molecular pathways that increase susceptibility to arrhythmia is necessary to prevent disease occurrence, to improve current therapies and to target new drug development. In recent years, the discovery of pathogenic mutations in inherited arrhythmia syndromes has provided novel insights for the understanding and treatment of diseases predisposing to sudden cardiac death. In patients with the long QT syndromes (LQTS), genotype-phenotype relation studies [1] and genetic testing have influenced patient risk stratification [2] and refined treatment strategies [3]. > Arrhythmia mechanisms include abnormal automaticity, triggered activity, and re-entrant excitation. Each of these mechanisms can occur in any type of myocardial disease or in inherited cardiac arrhythmias. The current article focuses on molecular mechanisms of arrhythmias in the structurally abnormal and normal heart. Hypertrophic and dilated cardiomyopathies, as well as arrhythmogenic right ventricular dysplasia/cardiomyopathy are common substrates of inherited arrhythmias in the structurally abnormal heart. Genetic diseases causing arrhythmias in the structural normal heart, also called electrical myopathies, include the long QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and non-defined familiar idiopathic ventricular fibrillation. Most, but not all of these disorders are caused by mutations in genes encoding cardiac ion-channel proteins. Among family members carrying an identical mutation in a single gene, remarkable phenotypic variability and expressivity may be observed, suggesting both environmental [4] and genetic modifiers [5].

[11] Application of Human Induced Pluripotent Stem Cells for Tissue Engineered Cardiomyocyte Modelling

  • Authors: P. Katili, Amira P. Karima, Winda Azwani, R. Antarianto, M. Djer
  • Year: 2023
  • Venue: Regenerative Engineering and Translational Medicine
  • URL: https://www.semanticscholar.org/paper/230ce81f53920be5341915add9ac3de36432f6f2
  • DOI: 10.1007/s40883-023-00294-1
  • Citations: 5
  • Summary: The cardiac patch is currently the most effective delivery system, proving safety and improvements in animal models, which are suggested to be the role of the paracrine mechanism.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Disease models of cardiac diseases had been reported for long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), Friedreich's ataxia and Barth syndrome, and syndromic diagnosis associated with cardiomyopathy (LEOPARD syndrome, Pompe disease, laminopathies) [52][53][54][55]. These diagnoses comprise largely of genetic mutations; however, direct causality between genetic and environmental factors that affect disease phenotypes is still largely unknown, and until recently, there has been no reliable, human-sourced model to reenact disease progression outside the human body. hiPSCs allow the collection of diseased cell types to be investigated as cardiomyocytes develop in vitro, enabling the investigation of molecular and cellular mechanisms that contribute to pathological changes in an individual context. > Current studies focus on identifying new genetic mutations and reproducing their phenotypes in vitro using cell lines from diagnosed patients and their families. Disease models of hypertrophic cardiomyopathy (HCM) showed hypertrophy of cardiomyocytes, irregular sarcomere, and interstitial fibrosis in a hiPSC-CMs model. In the study by Lan et al., genetic analysis was carried out on ten patients in 2nd-and 3rd-generation families where one family member had been diagnosed with HCM. A missense mutation confirmed genetic aetiology in the myosin heavy chain (MYH7 gene) in 5 family members, but only one family member showed clinical manifestation [56]. Arrhythmias and irregular calcium handling were also found in the cellular level analysis. Genetic mutations without clinical phenotypes are an exciting area of research, and mechanisms regarding environmental influence on the genetic background are yet to be discovered. To confirm this hypothesis, Tanaka et al. analysed the influence of multiple hypertrophy-promoting factors in the hiPSC-CMs disease model from 3 known HCM patients, in which two of them were negative for known sarcomeric mutations. hiPSC-CMs HCM model treated with endothelin-1 (ET-1) showed disorganised cell hypertrophy and myofibrils compared to negative controls.

[12] Which came first: validity or clinical testing? The example of long QT genes

  • Authors: Lacey J. Boshe, A. K. Foreman, J. Goldstein, Natasha T. Strande, J. Berg et al.
  • Year: 2018
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/3d4e26b266983915b6da5664ffa1d69e8660b724
  • DOI: 10.20517/JTGG.2018.18
  • Summary: Inclusion of the gene on gene-disease associations may help laboratories to determine gene panel content and the ultimate impact of such information on the composition of clinical gene tests as well as their utilization by clinicians and coverage by health insurance policies remains to be seen.
  • Evidence snippets:
  • Snippet 1 (score: 0.422) > OMIM was queried to identify the genes associated with hereditary LQTS and references supporting the association between each gene and LQTS. A comprehensive PubMed query was conducted to identify relevant information for the curation of each gene as described below. PubMed search syntax included the gene symbol and disease name (e.g., LQTS1, "KCNQ1 AND Long QT Syndrome"). > The gene evidence curated from the literature search included: (1) the year each gene was first asserted to be associated with LQTS; (2) the number of clinical cases associated with each gene; (3) the size and number of affected families that exhibit segregation of the phenotype with the genotype; and (4) the robustness of the associated functional data [Table 1]. Cases were included in the total count if the patient had a variant plus either a prolonged QTc on an EKG or clinical symptoms. Segregation data was considered strong if a gene variant was found in the majority of symptomatic or EKG positive members of at least one large family (3 or more generations) without being found in asymptomatic or EKG negative members. Segregation data was considered moderate if the same criteria were met in small families (1 or 2 generations). The robustness of functional data was determined based on the presence of multiple lines of supportive experiments that demonstrated the role for that particular gene in the LQTS disease phenotype. Examples of functional data considered to be supportive of a gene-disease correlation include gene expression analysis that demonstrates the gene is expressed in the target tissue, ion channel protein expression and functional assays, gene knock-out and rescue, animal models and, to a lesser degree, in silico predictions. Genes with numerous and multiple types of functional data were given the highest level of functional evidence. Comparatively, genes with fewer papers/experiments describing functional data from a narrower range of categories were given moderate or minimal levels of functional evidence. Animal models were weighted heavier than the other types of functional data. Gene evidence curation was done initially in November 2014 and last updated in January 2018.

[13] Modelling Human Channelopathies Using Induced Pluripotent Stem Cells: A Comprehensive Review

  • Authors: Martin Müller, T. Seufferlein, A. Illing, J. Homann
  • Year: 2013
  • Venue: Stem Cells International
  • URL: https://www.semanticscholar.org/paper/90202711981d47f844f834f08a2cb7e1d5038224
  • DOI: 10.1155/2013/496501
  • PMID: 23766769
  • PMCID: 3666272
  • Citations: 16
  • Summary: This review summarizes the efforts of reprogramming various types of long QT syndrome and discusses the potential underlying mechanisms and their application.
  • Evidence snippets:
  • Snippet 1 (score: 0.419) > Mutations in long QT syndromes are consistently resulting in a relative increase of depolarizing currents against repolarizing ones (Figure 1). This results in two arrhythmiapromoting situations: (i) channels that remain depolarized for extended periods lead to increased refractory period, thus leading to areas of functional blocking which act as a reentry spot for ectopic excitation; (ii) as the elongation of action potential differs between epicardial (outer) and more endocardial (inner) cardiomyocytes, this may also promote the generation of functional reentry circles [2]. To date, 13 types of long QT syndromes are distinguished. Long QT syndromes are inherited either autosomal dominant or recessive with the recessive ones mostly having a more severe phenotype. Nonetheless, the penetrance in most long QT syndromes differs; as a consequence, there are individuals with mutations without any clinical appearance [4]. > Upon expression of a defined set of transcription factors in somatic cells, iPS cells can be generated from virtually every type of tissue. The first human iPSCs were generated independently in 2007 by the Yamanaka [5] and the Thomson Laboratory [6]. Their unique features of unlimited selfrenewal and nonrestricted differentiation power define a landmark in the context of understanding human development and disease [7][8][9]. More precisely, in case of applying this tool to patients who are classified into a disease group, it enables the generation of disease-specific iPS cells. iPS cells have proven a significant tool to elucidate pathophysiological mechanisms in various diseases such as diabetes, blood disorders, defined neurological disorders, and genetic liver disease [10][11][12]. iPS cells enable the dissection of monogenic human disease [13] mechanisms as well as mechanisms of genetically complex human disorders such as schizophrenia [14]. This opens promising perspectives both for the screening of innovative "druggable" targets [15] and ex vivo gene targeting therapies [13].

[14] Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

  • Authors: Jeonghyeon Park, K. Noh, H. Lee, M. Lim, S. Seong et al.
  • Year: 2013
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/5230cdd6879c504b17a881b1f292af647e522ccc
  • DOI: 10.1371/journal.pone.0060556
  • PMID: 23593245
  • PMCID: 3617128
  • Citations: 7
  • Influential citations: 1
  • Summary: Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs and would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.
  • Evidence snippets:
  • Snippet 1 (score: 0.416) > Endogenous metabolites in the human body may change due to many factors, such as dietary habits, the environment, heredity, disease and medicines. We developed a pharmacometabolomic approach to discover metabolic phenotypes that could predict changes in biochemical metabolites directly related to physiological or pathological functions and that can also predict drug toxicity in the guinea pig. Metabolic phenotypes can be applied to understand pharmacological roles related to pharmacodynamics, as well as to pre-clinical or clinical settings. Cardiovascular risk factors are strongly related to abdominal obesity, increased blood pressure, impaired fasting glucose and dyslipidemia, and also increased incidence and lethality of ischemic heart disease and stroke [73,74,75]. Although it is known that such factors increase cardiovascular risk [76,77,78,79], little is known about the relationship with asymptomatic risk factors, such as long QT syndrome on an electrocardiogram. QTc interval prolongation is considered a prognostic factor for arrhythmia although its mechanism has not been completely known, since it is a phenomenon accompanying delayed ventricular repolrarisation [80,81,82,83]. QT interval prolongation is a side effect of sparfloxacin, and has been reported to have I Kr -blocking ability [22,23,24] and to be related to TdP [14]. hERG, one of the genes [84] that can cause long QT syndrome, controls an important repolarising current called I Kr . Guinea pigs have hERG channels and thus are suitable for measuring the proarrhythmic effect [85,86,87]. This integrative approach was applied to predict druginduced QT prolongation of sparfloxacin. Significant prolongation of the QT interval was observed when sparfloxacin was administered at doses of 33.3, 100, and 300 mg/kg [44], and these doses were used in our experiments. We analyzed plasma samples using LC-MS, and detected 1,178 metabolic features.

[15] Modeling Short QT Syndrome Using Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes

  • Authors: I. El-Battrawy, H. Lan, Lukas Cyganek, Zhihan Zhao, Xin Li et al.
  • Year: 2018
  • Venue: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
  • URL: https://www.semanticscholar.org/paper/e917e7f7389eb98708e26a55f784f13735995f9c
  • DOI: 10.1161/JAHA.117.007394
  • PMID: 29574456
  • PMCID: 5907581
  • Citations: 102
  • Influential citations: 6
  • Summary: Patient‐specific hiPSC‐CMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.415) > Background Short QT syndrome (SQTS), a disorder associated with characteristic ECG QT‐segment abbreviation, predisposes affected patients to sudden cardiac death. Despite some progress in assessing the organ‐level pathophysiology and genetic changes of the disorder, the understanding of the human cellular phenotype and discovering of an optimal therapy has lagged because of a lack of appropriate human cellular models of the disorder. The objective of this study was to establish a cellular model of SQTS using human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs). Methods and Results This study recruited 1 patient with short QT syndrome type 1 carrying a mutation (N588K) in KCNH2 as well as 2 healthy control subjects. We generated hiPSCs from their skin fibroblasts, and differentiated hiPSCs into cardiomyocytes (hiPSC‐CMs) for physiological and pharmacological studies. The hiPSC‐CMs from the patient showed increased rapidly activating delayed rectifier potassium channel current (IK r) density and shortened action potential duration compared with healthy control hiPSC‐CMs. Furthermore, they demonstrated abnormal calcium transients and rhythmic activities. Carbachol increased the arrhythmic events in SQTS but not in control cells. Gene and protein expression profiling showed increased KCNH2 expression in SQTS cells. Quinidine but not sotalol or metoprolol prolonged the action potential duration and abolished arrhythmic activity induced by carbachol. Conclusions Patient‐specific hiPSC‐CMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.

[16] MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes

  • Authors: Y. Lee, Luca Sala, M. Mura, M. Rocchetti, M. Pedrazzini et al.
  • Year: 2020
  • Venue: Cardiovascular Research
  • URL: https://www.semanticscholar.org/paper/ea0d921c83677ac82cac1ea791c6c3af20f4a804
  • DOI: 10.1093/cvr/cvaa019
  • PMID: 32173736
  • PMCID: 7898949
  • Citations: 38
  • Summary: This finding represents the first demonstration of the cellular mechanism of action of a protective modifier gene in LQTS and provides new clues for advanced risk stratification and paves the way for the design of new therapies targeting this specific molecular pathway.
  • Evidence snippets:
  • Snippet 1 (score: 0.411) > One of the most puzzling questions in arrhythmic disorders of genetic origin concerns why the clinical manifestations in two siblings carrying the same disease-causing mutations may vary from benign to highly malignant. Genetic variants acting as 'modifier genes' are the commonly accepted explanation. 1 The congenital long QT syndrome (LQTS) is caused by mutations of the genes encoding ion channels or excitationcontraction coupling proteins, 2 has a prevalence of 1 in 2000, 3 is associated with life-threatening arrhythmias, 4 shows a good genotype-phenotype correlation, 5 and is regarded as a paradigm for sudden cardiac death. 6 QT1, the most common type of LQTS, is caused by loss-of-function mutations on the KCNQ1 gene encoding for the repolarizing current I Ks. 2,5 As I Ks mutations impair QT shortening during heart rate increase, most arrhythmic events among LQT1 patients are triggered by sympathetic activation during exercise and emotions. 5 ere, we performed cellular electrophysiology in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) 7,8 and whole-exome sequencing to identify potential mechanisms by which modifier genes may exert their action in LQTS. We focused on the common mutation KCNQ1-Y111C (henceforth, Y111C) characterized by a generally benign phenotype. 9,10 Y111C is associated with channel trafficking defects 11 and accelerated degradation by the proteasome. 12 By studying a family whose members carry the same Y111C mutation but have distinct clinical severity of LQTS, we discovered two protective single-nucleotide variants (SNVs) on the same gene present in the asymptomatic (AS) Y111C carriers and unravelled their mechanism of action.
  • Snippet 2 (score: 0.406) > Abstract Aims In long QT syndrome (LQTS) patients, modifier genes modulate the arrhythmic risk associated with a disease-causing mutation. Their recognition can improve risk stratification and clinical management, but their discovery represents a challenge. We tested whether a cellular-driven approach could help to identify new modifier genes and especially their mechanism of action. Methods and results We generated human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) from two patients carrying the same KCNQ1-Y111C mutation, but presenting opposite clinical phenotypes. We showed that the phenotype of the iPSC-CMs derived from the symptomatic patient is due to impaired trafficking and increased degradation of the mutant KCNQ1 and wild-type human ether-a-go-go-related gene. In the iPSC-CMs of the asymptomatic (AS) patient, the activity of an E3 ubiquitin-protein ligase (Nedd4L) involved in channel protein degradation was reduced and resulted in a decreased arrhythmogenic substrate. Two single-nucleotide variants (SNVs) on the Myotubularin-related protein 4 (MTMR4) gene, an interactor of Nedd4L, were identified by whole-exome sequencing as potential contributors to decreased Nedd4L activity. Correction of these SNVs by CRISPR/Cas9 unmasked the LQTS phenotype in AS cells. Importantly, the same MTMR4 variants were present in 77% of AS Y111C mutation carriers of a separate cohort. Thus, genetically mediated interference with Nedd4L activation seems associated with protective effects. Conclusion Our finding represents the first demonstration of the cellular mechanism of action of a protective modifier gene in LQTS. It provides new clues for advanced risk stratification and paves the way for the design of new therapies targeting this specific molecular pathway.

[17] An overview on cardiac involvement in Inborn Errors of Metabolism: from clinical clues to nutritional management strategies

  • Authors: C. Montanari, V. Tagi, Martina Tosi, Eliana Stucchi, Eleonora Pisano et al.
  • Year: 2025
  • Venue: Frontiers in Cardiovascular Medicine
  • URL: https://www.semanticscholar.org/paper/53edcd65284033a78e81633fbeb8012f21599561
  • DOI: 10.3389/fcvm.2025.1648010
  • PMID: 41425985
  • PMCID: 12711851
  • Summary: This review examines nutritional strategies for managing patients affected by IEMs with cardiac involvement, providing clinicians with research-backed guidance to support cardiological care, since specific nutritional strategies have shown promise in reversing or improving cardiac function in specific IEMs.
  • Evidence snippets:
  • Snippet 1 (score: 0.408) > Approximately 10% to 30% of the known causes of cardiomyopathy in childhood are attributable to IEMs (10, 130,131). In IEMs, cardiac manifestations can be indicative symptoms discovered during regular multisystem screening. While in disorders like MPS, heart manifestations may dominate the clinical presentation, in others, such as PD, they represent the sole clinical manifestation. Four fundamental mechanisms underlie the pathophysiology of cardiac involvement. First, cardiac symptoms can be linked to a reduction in energy production resulting from genetic mutations in proteins involved in energy homeostasis, molecular transport, or cellular organelles. Second, the intracellular accumulation of intermediates or storage substrates within cardiac myocytes can lead to structural and functional damage of the cardiac tissue. Third, the accumulation of intermediate metabolites may exert toxic effects on cardiac and surrounding tissues, for example, by triggering apoptosis in cardiac myocytes. Fourth, altered cellular functions such as signal transduction, depolarization, and cell adhesion, caused by the absence or alteration of glyconjugates, can compromise tissue integrity and cardiac function. It is important to note that pathogenetic mechanisms, summarized in Figure 3, may often overlap, particularly in later stages of the illness progression (33). In this review, we offered a comprehensive description of the cardiovascular diseases primarily associated with various types of IEMs, to guide cardiologists in the differential diagnosis (Figure 4). Moreover, the diagnosis of an underlying metabolic disorder should rely on the recognition of associated signs and symptoms characteristic of each specific disease. > IEMs have a wide phenotypic spectrum and may be characterized by a late onset or mild organ involvement, remaining misdiagnosed. Following the diagnosis of heart complications, the cardiologist should first conduct a detailed investigation of the patient's and family's medical history, including an assessment of consanguinity and/or the presence of rare inherited disorders. The patient's history should include age of onset of each clinically relevant symptom, the presence of associated pathological conditions and/or symptoms (hypoglycemia, myalgia, neurological issues or liver problems) and the result of neonatal screening.

[18] The continuum of personalized cardiovascular medicine: a position paper of the European Society of Cardiology

  • Authors: P. Kirchhof, K. Sipido, M. Cowie, T. Eschenhagen, K. Fox et al.
  • Year: 2014
  • Venue: European Heart Journal
  • URL: https://www.semanticscholar.org/paper/32d5f1334d80db7bf778e662a62b68c7e8d2fdea
  • DOI: 10.1093/eurheartj/ehu312
  • PMID: 25148837
  • PMCID: 4258224
  • Citations: 87
  • Influential citations: 4
  • Summary: Clinical information obtained from history and physical examination, functional and imaging studies, biochemical biomarkers, genetic/epigenetic data, and pathophysiological insights into disease-driving processes need to be integrated into a new taxonomy of CVDs to allow personalized disease management.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > Several familial, monogenic heart diseases such as hypertrophic cardiomyopathy or the long QT syndromes have been well characterized. The genetic defects have been reported, and disease mechanisms have been described in suitable models. The clinical impact of the underpinning molecular defects on diagnosis, risk stratification, and management remains rather heterogeneous. 55 Despite this progress, mechanism-based or genotype-specific prevention of sudden death has yet to become clinical reality: 56 The long QT syndromes are the only example where the genetic defect can inform prognosis and hence management at present. 56 Only recently some studies have approached the field with a more integrated 'omics' view to investigate the consequences on the phenotype of polymorphisms in the coding regions of causative genes and in other regulatory gene structures as well as the role of gene -gene interaction to regulate protein expression. There is expectation that these investigations will provide insights in the identification of patients at a higher risk of life-threatening arrhythmias. > Pharmacogenomics, i.e. the use of genetic markers to identify patients at risk for adverse reactions to pharmacotherapy, has been proposed for several cardiovascular therapeutics including antithrombotic agents, antiarrhythmic drugs, 2,57 or rhabdomyolysis on statin therapy. 58 Even though the evidence for genetically conferred differences in the response, e.g., to oral anticoagulants is good, controlled trials of genotype-informed dosing did not improve therapy. 59,60 The interaction of ambient and inherited factors that often results in unexpected reactions to therapy may be easier assessed using integrated functional biomarkers, e.g., clinical profiles (as done in warfarin dosing schemes) or ECG changes, 30,61 on therapy.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.
OpenAI ▸
Deep Research Notes: Long QT Syndrome
gpt-5

Deep Research Notes: Long QT Syndrome

Scope Decision

  • Curate the disease root at MONDO:0002442 (long QT syndrome) rather than splitting the canonical subtype series into separate disorder files.
  • Keep the narrative explicitly inherited/familial so the entry does not absorb acquired QT prolongation.
  • Exclude already distinct syndromic or gene-specific entities from this root: Jervell and Lange-Nielsen syndrome and ANK2 ankyrin-B syndrome (historical LQT4).

Key PMID-Backed Quotes Used for Curation

  • PMID:18606002
  • "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."
  • "Disease prevalence is estimated at close to 1 in 2,500 live births."
  • "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."
  • "Treatment should always begin with beta-blockers, unless there are valid contraindications."

  • "If the patient has one more syncope despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation and implantable cardioverter defibrillator (ICD) therapy should be considered"

  • PMID:24093767

  • "Congenital long QT syndrome (LQTS) is a genetically heterogeneous group of heritable disorders of myocardial repolarization linked by the shared clinical phenotype of QT prolongation on electrocardiogram and an increased risk of potentially life-threatening cardiac arrhythmias."

  • PMID:10348966

  • "The majority of cases are inherited by autosomal dominant transmission."
  • "The primary electrophysiologic disturbance is delayed recovery of the action potential, because of diverse physiologic perturbations dependent upon the specific ion channel and mutation."
  • "The delayed recovery predisposes individuals to the development of early afterdepolarizations and initiation of torsade de pointes arrhythmias."
  • "The torsade produces the syncope and sudden death."

  • "The principal treatment is beta-blocker therapy."

  • PMID:28670758

  • "A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD)."

  • "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."

  • PMID:11136691

  • "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%)."

  • PMID:10673253

  • "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"

  • PMID:10377081

  • "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."

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

  • PMID:26940925

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

  • PMID:9272508

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

Mechanistic Model Selected for YAML

  1. Reduced repolarizing potassium current
  2. Root node for the common KCNQ1/KCNH2-dominant branches.

  3. Ontology terms:

    • GO:0071805 potassium ion transmembrane transport
    • GO:0086013 membrane repolarization during cardiac muscle cell action potential
    • CL:0000746 cardiac muscle cell
    • UBERON:0000948 heart

  4. Persistent late sodium current in LQT3

  5. Explicit subtype-aware branch retained because it has a clean precision-therapy hook to mexiletine.

  6. Ontology terms:

    • GO:0035725 sodium ion transmembrane transport
    • GO:0086013 membrane repolarization during cardiac muscle cell action potential

  7. Prolonged ventricular repolarization and early afterdepolarizations

  8. Common convergent substrate downstream of potassium-current loss or late sodium current gain.

  9. Ontology terms:

    • GO:0086001 cardiac muscle cell action potential
    • GO:0086013 membrane repolarization during cardiac muscle cell action potential

  10. Adrenergic trigger susceptibility

  11. Retained to justify beta-blockers and LCSD at the disease root while still preserving subtype-specific trigger heterogeneity.

  12. Torsades de pointes and sudden cardiac death

  13. Final mechanistic-output node connecting the repolarization substrate to the defining clinical risks.

Subtype and Lumping Rationale

  • Keep Type 1, Type 2, and Type 3 as has_subtypes because they are the canonical clinically meaningful series directly referenced in LQTS practice.
  • Do not create separate disorder files here for the subtype series; keep them nested under the root because this issue asked for a disease-level inherited LQTS entry and the repo’s prioritizer tests explicitly treat long QT syndrome as a broad parent that should absorb subtype rows.
  • Do not pull Jervell and Lange-Nielsen syndrome into this root because it is a recessive syndromic deafness-associated entity with a distinct MONDO term and clinical framing.
  • Do not pull ANK2/historical LQT4 into this root because the repo already has a curated ANK2_Ankyrin_B_Syndrome.yaml entry documenting why it is not classic long QT syndrome.

Treatment Choices Kept in Scope

  • Beta-Blocker Therapy: first-line disease-root treatment.
  • Left Cardiac Sympathetic Denervation: escalation for recurrent syncope on full-dose beta-blockade.
  • Implantable Cardioverter-Defibrillator Placement: high-risk rescue/device therapy.
  • Mexiletine: kept as a subtype-targeted treatment because the root entry still needs one precision-therapy example tied to the LQT3 mechanism.