Short QT Syndrome

◆

Subtypes

7

SQTS1 (KCNH2 / IKr gain-of-function) MONDO:0012312

KCNH2 hgnc:6251

Potassium-channel subtype caused by gain-of-function KCNH2 variants (canonical N588K), the first-described and best-characterized form; attenuated IKr rectification abbreviates ventricular repolarization.

SQTS2 (KCNQ1 / IKs gain-of-function) MONDO:0012313

KCNQ1 hgnc:6294

Potassium-channel subtype caused by gain-of-function KCNQ1 variants (canonical V307L), producing an IKs gain of function that shortens repolarization.

SQTS3 (KCNJ2 / IK1 gain-of-function) MONDO:0012314

KCNJ2 hgnc:6263

Potassium-channel subtype caused by gain-of-function KCNJ2 variants (canonical D172N), increasing inward-rectifier IK1 current and accelerating the terminal phase of repolarization; the original family showed a distinctive tall, peaked, asymmetric T-wave ECG signature.

SQTS4 (CACNA1C loss-of-function)

CACNA1C hgnc:1390

Calcium-channel subtype caused by loss-of-function CACNA1C variants, reducing inward L-type calcium current.

SQTS5 (CACNB2 loss-of-function)

CACNB2 hgnc:1402

Calcium-channel subtype caused by loss-of-function CACNB2 variants, reducing inward L-type calcium current.

SQTS6 (CACNA2D1 loss-of-function)

CACNA2D1 hgnc:1399

Calcium-channel subtype caused by loss-of-function CACNA2D1 variants, reducing inward L-type calcium current.

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Pathophysiology

5

Ion-channel gain- and loss-of-function variants

The upstream trigger of SQTS is a pathogenic germline variant that alters a cardiac ion channel. Gain-of-function variants in the potassium channels KCNH2 (IKr), KCNQ1 (IKs), and KCNJ2 (IK1) increase repolarizing current, while loss-of-function variants in the L-type calcium channel subunits CACNA1C, CACNB2, and CACNA2D1 reduce inward calcium current. Either route shifts the net balance of currents toward accelerated repolarization in structurally normal myocardium.

cardiomyocyte CL:0000746

KCNH2 hgnc:6251 KCNQ1 hgnc:6294 KCNJ2 hgnc:6263 CACNA1C hgnc:1390 CACNB2 hgnc:1402 CACNA2D1 hgnc:1399

monoatomic ion channel activity GO:0005216 ⚠ ABNORMAL

heart UBERON:0000948

Downstream

Accelerated myocardial repolarization The gain-of-function potassium or loss-of-function calcium variant shifts the net current balance toward repolarization, abbreviating the action potential and refractory period in working myocardium.

Show evidence (2 references)

PMID:14676148 SUPPORT Human Clinical

"In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2)."

Identifies the gain-of-function KCNH2 (HERG) variant that is the upstream ion-channel trigger of SQTS.

PMID:16039272 SUPPORT In Vitro

"Physiologically the N588K mutation abolishes rectification of HERG currents and specifically increases I(Kr) in the ventricle with minimal effects on the Purkinje fiber action potential duration."

Mechanistic electrophysiology showing how the channel variant alters channel function to increase ventricular repolarizing current, the variant-to-current step of the trigger node.

Accelerated myocardial repolarization

The core electrophysiologic lesion in SQTS is accelerated repolarization, typically due to increased repolarizing potassium current in ventricular myocardium. This abbreviates action potential duration and refractory periods, producing the characteristic shortened QT interval and reducing the margin against re-entry.

cardiomyocyte CL:0000746

membrane repolarization during cardiac muscle cell action potential GO:0086013 ↕ DYSREGULATED ventricular cardiac muscle cell action potential GO:0086005 ↕ DYSREGULATED cardiac muscle cell action potential GO:0086001 ↕ DYSREGULATED

heart UBERON:0000948

Downstream

Shortened QT Interval Accelerated myocardial repolarization shortens the surface ECG QT interval, the diagnostic electrophysiologic phenotype of SQTS.

Re-entry-prone arrhythmia substrate Shortened refractory periods and impaired adaptation of repolarization favor rotor stabilization and re-entry in atrial and ventricular tissue.

Show evidence (3 references)

PMID:14676148 SUPPORT Human Clinical

"The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers."

Establishes the canonical SQTS mechanism of increased repolarizing current with abbreviated action potentials and refractory periods.

PMID:29574456 SUPPORT In Vitro

"The hiPSC-CMs from the patient showed increased rapidly activating delayed rectifier potassium channel current (IKr) density and shortened action potential duration compared with healthy control hiPSC-CMs."

Patient-specific hiPSC-cardiomyocytes recapitulate the increased IKr and shortened action potential phenotype at the cellular level.

PMID:16039272 SUPPORT In Vitro

"Physiologically the N588K mutation abolishes rectification of HERG currents and specifically increases I(Kr) in the ventricle with minimal effects on the Purkinje fiber action potential duration."

Provides mechanistic electrophysiology showing how a canonical KCNH2 SQTS mutation selectively increases ventricular repolarizing current.

Re-entry-prone arrhythmia substrate

Abbreviated refractory periods and impaired rate adaptation create a myocardial substrate that is vulnerable to atrial and ventricular fibrillation. At the tissue level this is expressed as shortened excitation wavelength, enhanced inducibility of sustained spiral waves, and increased ventricular vulnerability to fibrillation.

cardiomyocyte CL:0000746

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

Downstream

Atrial and ventricular fibrillation susceptibility The re-entry-prone substrate manifests clinically as atrial fibrillation, ventricular fibrillation, syncope, and sudden cardiac death.

Show evidence (2 references)

PMID:12925462 SUPPORT Human Clinical

"During electrophysiological study, short atrial and ventricular refractory periods were documented in all and increased ventricular vulnerability to fibrillation in 3 of 4 patients."

Human electrophysiology directly demonstrates the shortened refractory periods and ventricular fibrillation vulnerability that define the SQTS substrate.

PMID:31072576 SUPPORT In Vitro

"Optical mapping of the SQTS-hiPSC-CCSs revealed shortened APD, impaired APD-rate adaptation, abbreviated wavelength of excitation, and increased inducibility of sustained spiral waves."

Tissue-scale hiPSC cardiac sheet modeling links abbreviated repolarization to re-entry and sustained arrhythmia induction.

Atrial and ventricular fibrillation susceptibility

SQTS clinically presents with malignant atrial and ventricular arrhythmias. Atrial fibrillation is common and may be the presenting feature, whereas ventricular fibrillation underlies aborted cardiac arrest and sudden cardiac death.

cardiomyocyte CL:0000746

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

Downstream

Atrial Fibrillation The atrial component of the arrhythmogenic substrate manifests clinically as atrial fibrillation or atrial flutter in affected SQTS families.

Ventricular Fibrillation The ventricular component of the substrate creates vulnerability to ventricular fibrillation.

Palpitations Atrial or ventricular tachyarrhythmias can be perceived as palpitations.

Syncope and Sudden Cardiac Death Sustained ventricular fibrillation abolishes effective cardiac output, producing syncope and, if not terminated, sudden cardiac death.

Show evidence (2 references)

PMID:30571592 SUPPORT Human Clinical

"Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or atrial flutter."

Long-term family follow-up shows that atrial arrhythmia and syncope are common manifestations of clinically diagnosed SQTS.

PMID:12925462 SUPPORT Human Clinical

"The short QT syndrome is characterized by familial sudden death, short refractory periods, and inducible ventricular fibrillation."

Directly connects the SQTS clinical syndrome to ventricular fibrillation and sudden death risk.

Syncope and Sudden Cardiac Death

Loss of effective cardiac output from sustained ventricular fibrillation (or self-terminating tachyarrhythmia) causes transient cerebral hypoperfusion and syncope and, when the rhythm does not terminate, sudden cardiac death. These are the shared clinical endpoints of SQTS and are frequently the sentinel manifestation, occurring in infants, children, and young adults with structurally normal hearts.

Downstream

Syncope Self-terminating or sustained tachyarrhythmia can transiently abolish effective cerebral perfusion, producing syncope.

Sudden Cardiac Death Sustained malignant ventricular arrhythmia can culminate in sudden cardiac death.

Show evidence (2 references)

PMID:30571592 SUPPORT Human Clinical

"Short QT syndrome ( SQTS ) is a rare inheritable disease associated with sudden cardiac death."

Human clinical evidence tying SQTS to sudden cardiac death as the terminal outcome of the cascade.

PMID:12925462 SUPPORT Human Clinical

"The short QT syndrome is characterized by familial sudden death, short refractory periods, and inducible ventricular fibrillation."

Connects the SQTS substrate to familial sudden death as the clinical endpoint.

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Pathograph

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Phenotypes

7

Cardiovascular 5

Atrial Fibrillation HP:0005110

Show evidence (1 reference)

PMID:30571592 SUPPORT Human Clinical

"Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or atrial flutter."

Supports atrial fibrillation as a common clinical manifestation in SQTS families.

Ventricular Fibrillation HP:0001663

Show evidence (1 reference)

PMID:12925462 SUPPORT Human Clinical

"The short QT syndrome is characterized by familial sudden death, short refractory periods, and inducible ventricular fibrillation."

Establishes ventricular fibrillation as a central malignant arrhythmia in SQTS.

Syncope HP:0001279

Show evidence (1 reference)

PMID:30571592 SUPPORT Human Clinical

"Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or atrial flutter."

Direct long-term cohort evidence that syncope is part of the SQTS phenotype spectrum.

Palpitations HP:0001962

Show evidence (1 reference)

PMID:12925462 SUPPORT Human Clinical

"Several members of 2 different families were referred for syncope, palpitations, and resuscitated cardiac arrest in the presence of a positive family history for sudden cardiac death."

Shows palpitations among the presenting manifestations in the original SQTS family series.

Sudden Cardiac Death HP:0001645

Show evidence (1 reference)

PMID:14676148 SUPPORT Human Clinical

"We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2."

Confirms sudden cardiac death as a defining high-severity clinical outcome of SQTS.

Other 2

Shortened QT Interval HP:0012232

Show evidence (2 references)

PMID:12925462 SUPPORT Human Clinical

"At baseline ECG, all patients exhibited a QT interval <or=280 ms (QTc <or=300 ms)."

Documents the hallmark ECG phenotype that defines SQTS in the original familial cohort.

ORPHA:51083 SUPPORT Other

"HP:0012232 | Shortened QT interval | Obligate (100%)"

Orphadata lists shortened QT interval as an obligate SQTS phenotype.

Asymmetric T Waves Abnormal T-wave HP:0005135

Show evidence (1 reference)

PMID:15761194 SUPPORT Human Clinical

"Here we identify a new variant, "SQT3", which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel."

Documents the asymmetric-T-wave ECG phenotype that distinguishes the SQTS3 (KCNJ2/IK1) subtype from the other short QT subtypes.

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Genetic Associations

7

KCNH2 gain-of-function variants (Causative)

Gene: KCNH2 hgnc:6251

Autosomal dominant

Show evidence (2 references)

PMID:14676148 SUPPORT Human Clinical

"In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2)."

Establishes KCNH2 as a causative SQTS gene in the best-characterized potassium-channel subtype.

CGGV:assertion_6b033c3f-04de-4806-a9f3-0b318082b32e-2020-08-03T160000.000Z SUPPORT Other

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

KCNQ1 gain-of-function variants (Causative)

Gene: KCNQ1 hgnc:6294

Autosomal dominant

Show evidence (3 references)

PMID:15159330 SUPPORT Human Clinical

"Functional and computational studies of the KCNQ1 V307L mutation identified in a patient with this disorder favor the association of short QT with mutation in KCNQ1."

Abstract-based human genetic evidence supporting KCNQ1 as a causative SQTS gene.

PMID:15159330 SUPPORT In Vitro

"Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with the wild-type channel, in the presence of IsK) revealed a pronounced shift of the half-activation potential and an acceleration of the activation kinetics leading to a gain of function in I(Ks)."

Heterologous-expression electrophysiology defines the IKs gain-of-function mechanism of the canonical SQTS2 KCNQ1 V307L variant.

CGGV:assertion_5000dde0-156c-45b0-87db-35a935c69cb7-2020-10-27T160000.000Z SUPPORT Other

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

KCNJ2 gain-of-function variants (Causative)

Gene: KCNJ2 hgnc:6263

Autosomal dominant

Show evidence (3 references)

PMID:15761194 SUPPORT Human Clinical

"The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N)."

Abstract-based family evidence supporting KCNJ2 as the causative gene in SQTS3.

PMID:15761194 SUPPORT In Vitro

"Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I(K1) than the wild-type (P<0.05) at potentials between -75 mV and -45 mV"

Patch-clamp electrophysiology defines the IK1 (Kir2.1) gain-of-function mechanism of the canonical SQTS3 KCNJ2 D172N variant.

CGGV:assertion_9111653a-7d9c-4d0e-94d9-daaa208a0b05-2020-10-27T160000.000Z SUPPORT Other

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

CACNA1C loss-of-function variants (Causative)

Gene: CACNA1C hgnc:1390

Autosomal dominant

Show evidence (1 reference)

PMID:30571592 SUPPORT Human Clinical

"An SQTS -related gene was found in 76% of the patients as follows: KCNH 2 ( SQTS 1) in 4, CACNA 1C ( SQTS 4) in 3, and CACN b2 ( SQTS 5) in 6."

Abstract-based cohort evidence identifying CACNA1C as the calcium-channel gene underlying SQTS4 in this series.

CACNB2 loss-of-function variants (Causative)

Gene: CACNB2 hgnc:1402

Autosomal dominant

Show evidence (1 reference)

PMID:30571592 SUPPORT Human Clinical

"An SQTS -related gene was found in 76% of the patients as follows: KCNH 2 ( SQTS 1) in 4, CACNA 1C ( SQTS 4) in 3, and CACN b2 ( SQTS 5) in 6."

Abstract-based cohort evidence identifying CACNB2 as the calcium-channel gene underlying SQTS5 in this series.

CACNA2D1 loss-of-function variants (Causative)

Gene: CACNA2D1 hgnc:1399

Autosomal dominant

Show evidence (1 reference)

PMID:21383000 SUPPORT Human Clinical

"In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS."

Abstract-based evidence that pathogenic CACNA2D1 variation causes SQTS6.

SLC4A3 (Pathogenic Variants)

Gene: SLC4A3 hgnc:11029

Show evidence (1 reference)

CGGV:assertion_b5f6fcca-f8a9-47c2-bae9-a72df92f3bd1-2020-08-03T160000.000Z SUPPORT Other

ClinGen classifies the SLC4A3-short QT syndrome gene-disease relationship as moderate with autosomal dominant inheritance.

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Medical Actions

2

Quinidine/Hydroquinidine Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: quinidine CHEBI:28593

Hydroquinidine is the best-supported pharmacologic therapy for SQTS. It prolongs the QT interval and ventricular refractory period and can suppress inducible or recurrent ventricular arrhythmias.

Show evidence (2 references)

PMID:15093889 SUPPORT Human Clinical

"Only hydroquinidine administration caused a QT prolongation, which increased from 263 +/- 12 ms to 362 +/- 25 ms (calculated QT from 290 +/- 13 ms to 405 +/- 26 ms)."

Demonstrates that hydroquinidine, unlike the other tested agents, meaningfully prolongs the abbreviated QT interval in SQTS.

PMID:31427960 SUPPORT Human Clinical

"HQ increases the corrected QT interval and prevents VAs in the majority of the patients in this cohort."

Supports hydroquinidine as the most consistently effective long-term antiarrhythmic drug reported for SQTS.

Implantable Cardioverter-Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Surgical Procedure NCIT:C15329

ICD implantation is used for secondary prevention or in high-risk patients, especially after aborted cardiac arrest or when malignant ventricular arrhythmia risk remains high.

Show evidence (1 reference)

PMID:30571592 SUPPORT Human Clinical

"Five patients (29%) received an implantable cardioverter-defibrillator and 5 patients received long-term prophylaxis with hydroquinidine."

Long-term cohort follow-up shows ICD use as a standard individualized management strategy in SQTS.

📊

Prevalence

1

Global

Unknown Rare

Show evidence (1 reference)

PMID:30571592 SUPPORT Human Clinical

"Short QT syndrome ( SQTS ) is a rare inheritable disease associated with sudden cardiac death."

Supports classifying SQTS as a rare inherited arrhythmia syndrome without asserting a numeric prevalence estimate not stated in the abstract.

📊

Related Datasets

1

Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome ega:EGAS00001002632

Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain less than 25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Short QT Syndrome"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

{ }

Source YAML

click to show

name: Short QT Syndrome
creation_date: '2026-04-12T22:34:01Z'
description: >-
  Short QT syndrome (SQTS) is a rare inherited cardiac channelopathy defined by
  marked abbreviation of the QT interval, shortened atrial and ventricular
  refractory periods, and high susceptibility to atrial and ventricular
  tachyarrhythmias in structurally normal hearts. The shared disease mechanism
  is accelerated myocardial repolarization, most definitively linked to
  gain-of-function potassium-channel defects and, in some families,
  loss-of-function calcium-channel defects. This abbreviated repolarization
  creates a re-entry-prone substrate that manifests clinically as palpitations,
  syncope, atrial fibrillation, ventricular fibrillation, and sudden cardiac
  death.
synonyms:
- SQTS
- short-QT syndrome
- familial short QT syndrome
category: Genetic
disease_term:
  preferred_term: short QT syndrome
  term:
    id: MONDO:0000453
    label: short QT syndrome
parents:
- Cardiac Arrhythmia
- Channelopathy
prevalence:
- population: Global
  measure_type: UNKNOWN
  prevalence_class: RARE
  evidence:
  - reference: PMID:30571592
    reference_title: >-
      Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
      and Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short QT syndrome ( SQTS ) is a rare inheritable disease associated with
      sudden cardiac death.
    explanation: >-
      Supports classifying SQTS as a rare inherited arrhythmia syndrome without
      asserting a numeric prevalence estimate not stated in the abstract.
has_subtypes:
- name: SQTS1
  display_name: SQTS1 (KCNH2 / IKr gain-of-function)
  subtype_term:
    preferred_term: short QT syndrome type 1
    term:
      id: MONDO:0012312
      label: short QT syndrome type 1
  description: >-
    Potassium-channel subtype caused by gain-of-function KCNH2 variants
    (canonical N588K), the first-described and best-characterized form;
    attenuated IKr rectification abbreviates ventricular repolarization.
  genes:
  - preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
- name: SQTS2
  display_name: SQTS2 (KCNQ1 / IKs gain-of-function)
  subtype_term:
    preferred_term: short QT syndrome type 2
    term:
      id: MONDO:0012313
      label: short QT syndrome type 2
  description: >-
    Potassium-channel subtype caused by gain-of-function KCNQ1 variants
    (canonical V307L), producing an IKs gain of function that shortens
    repolarization.
  genes:
  - preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
- name: SQTS3
  display_name: SQTS3 (KCNJ2 / IK1 gain-of-function)
  subtype_term:
    preferred_term: short QT syndrome type 3
    term:
      id: MONDO:0012314
      label: short QT syndrome type 3
  description: >-
    Potassium-channel subtype caused by gain-of-function KCNJ2 variants
    (canonical D172N), increasing inward-rectifier IK1 current and accelerating
    the terminal phase of repolarization; the original family showed a
    distinctive tall, peaked, asymmetric T-wave ECG signature.
  genes:
  - preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
- name: SQTS4
  display_name: SQTS4 (CACNA1C loss-of-function)
  description: >-
    Calcium-channel subtype caused by loss-of-function CACNA1C variants,
    reducing inward L-type calcium current.
  genes:
  - preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
- name: SQTS5
  display_name: SQTS5 (CACNB2 loss-of-function)
  description: >-
    Calcium-channel subtype caused by loss-of-function CACNB2 variants,
    reducing inward L-type calcium current.
  genes:
  - preferred_term: CACNB2
    term:
      id: hgnc:1402
      label: CACNB2
- name: SQTS6
  display_name: SQTS6 (CACNA2D1 loss-of-function)
  description: >-
    Calcium-channel subtype caused by loss-of-function CACNA2D1 variants,
    reducing inward L-type calcium current.
  genes:
  - preferred_term: CACNA2D1
    term:
      id: hgnc:1399
      label: CACNA2D1
- name: SLC4A3-Related
  display_name: SLC4A3-related short QT syndrome
  subtype_term:
    preferred_term: SLC4A3-related short QT syndrome
    term:
      id: MONDO:0859368
      label: short QT syndrome 7
  description: >-
    Anion-exchanger form caused by SLC4A3 (AE3) variants (ClinGen Moderate
    gene-disease validity). The `name` is kept gene-based rather than numbered
    because the SQT6/SQT7 numbering for SLC4A3 versus CACNA2D1 is not consistent
    across sources; the `subtype_term` grounds the disease concept in
    MONDO:0859368 (short QT syndrome 7, OMIM:620231), whose SLC4A3 gene
    association is unambiguous even though its MONDO label carries a number.
  genes:
  - preferred_term: SLC4A3
    term:
      id: hgnc:11029
      label: SLC4A3
genetic:
- name: KCNH2 gain-of-function variants
  subtype: SQTS1
  association: Causative
  features: >-
    Gain-of-function KCNH2 variants cause SQTS1, the first-described and
    best-characterized short QT subtype. The canonical N588K substitution in
    the S5-P (pore) loop attenuates the rapid inactivation (rectification) of
    the IKr (HERG/Kv11.1) channel, so IKr flows abnormally throughout the
    action potential plateau and abbreviates ventricular action potential
    duration and refractoriness.
  gene_term:
    preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:14676148
    reference_title: >-
      Sudden death associated with short-QT syndrome linked to mutations in
      HERG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 2 of them, we identified 2 different missense mutations resulting in
      the same amino acid change (N588K) in the S5-P loop region of the cardiac
      IKr channel HERG (KCNH2).
    explanation: >-
      Establishes KCNH2 as a causative SQTS gene in the best-characterized
      potassium-channel subtype.
  - reference: CGGV:assertion_6b033c3f-04de-4806-a9f3-0b318082b32e-2020-08-03T160000.000Z
    reference_title: "KCNH2 / short QT syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNH2 | HGNC:6251 | short QT syndrome | MONDO:0000453 | AD | Definitive"
    explanation: ClinGen classifies the KCNH2-short QT syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: KCNQ1 gain-of-function variants
  subtype: SQTS2
  association: Causative
  features: >-
    Gain-of-function KCNQ1 variants cause SQTS2. The canonical V307L
    substitution in KvLQT1 shifts the half-activation potential and accelerates
    activation kinetics, producing a gain of function in the slow delayed
    rectifier current IKs that shortens repolarization.
  gene_term:
    preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:15159330
    reference_title: >-
      Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional and computational studies of the KCNQ1 V307L mutation
      identified in a patient with this disorder favor the association of short
      QT with mutation in KCNQ1.
    explanation: >-
      Abstract-based human genetic evidence supporting KCNQ1 as a causative
      SQTS gene.
  - reference: PMID:15159330
    reference_title: >-
      Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with
      the wild-type channel, in the presence of IsK) revealed a pronounced shift
      of the half-activation potential and an acceleration of the activation
      kinetics leading to a gain of function in I(Ks).
    explanation: >-
      Heterologous-expression electrophysiology defines the IKs gain-of-function
      mechanism of the canonical SQTS2 KCNQ1 V307L variant.
  - reference: CGGV:assertion_5000dde0-156c-45b0-87db-35a935c69cb7-2020-10-27T160000.000Z
    reference_title: "KCNQ1 / short QT syndrome (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNQ1 | HGNC:6294 | short QT syndrome | MONDO:0000453 | AD | Strong"
    explanation: ClinGen classifies the KCNQ1-short QT syndrome gene-disease relationship as strong with autosomal dominant inheritance.
- name: KCNJ2 gain-of-function variants
  subtype: SQTS3
  association: Causative
  features: >-
    Gain-of-function KCNJ2 variants cause SQTS3. The canonical D172N
    substitution increases outward current through the inwardly rectifying
    Kir2.1 (IK1) channel, accelerating the terminal phase of repolarization.
    The originally reported SQTS3 family showed a distinctive ECG signature of
    tall, peaked, asymmetric T waves, proposed to distinguish it from the other
    potassium-channel subtypes; the feature derives from a single family and
    awaits broader confirmation.
  gene_term:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:15761194
    reference_title: >-
      A novel form of short QT syndrome (SQT3) is caused by a mutation in the
      KCNJ2 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected members of a single family had a G514A substitution in the
      KCNJ2 gene that resulted in a change from aspartic acid to asparagine at
      position 172 (D172N).
    explanation: >-
      Abstract-based family evidence supporting KCNJ2 as the causative gene in
      SQTS3.
  - reference: PMID:15761194
    reference_title: >-
      A novel form of short QT syndrome (SQT3) is caused by a mutation in the
      KCNJ2 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Whole-cell patch-clamp studies of the heterologously expressed human
      D172N channel demonstrated a larger outward I(K1) than the wild-type
      (P<0.05) at potentials between -75 mV and -45 mV
    explanation: >-
      Patch-clamp electrophysiology defines the IK1 (Kir2.1) gain-of-function
      mechanism of the canonical SQTS3 KCNJ2 D172N variant.
  - reference: CGGV:assertion_9111653a-7d9c-4d0e-94d9-daaa208a0b05-2020-10-27T160000.000Z
    reference_title: "KCNJ2 / short QT syndrome (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNJ2 | HGNC:6263 | short QT syndrome | MONDO:0000453 | AD | Moderate"
    explanation: ClinGen classifies the KCNJ2-short QT syndrome gene-disease relationship as moderate with autosomal dominant inheritance.
- name: CACNA1C loss-of-function variants
  subtype: SQTS4
  association: Causative
  features: >-
    Loss-of-function CACNA1C variants cause SQTS4 within the calcium-channel
    subgroup of autosomal dominant SQTS.
  gene_term:
    preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:30571592
    reference_title: >-
      Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
      and Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An SQTS -related gene was found in 76% of the patients as follows: KCNH 2
      ( SQTS 1) in 4, CACNA 1C ( SQTS 4) in 3, and CACN b2 ( SQTS 5) in 6.
    explanation: >-
      Abstract-based cohort evidence identifying CACNA1C as the calcium-channel
      gene underlying SQTS4 in this series.
- name: CACNB2 loss-of-function variants
  subtype: SQTS5
  association: Causative
  features: >-
    Loss-of-function CACNB2 variants cause SQTS5 within the calcium-channel
    subgroup of autosomal dominant SQTS.
  gene_term:
    preferred_term: CACNB2
    term:
      id: hgnc:1402
      label: CACNB2
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:30571592
    reference_title: >-
      Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
      and Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An SQTS -related gene was found in 76% of the patients as follows: KCNH 2
      ( SQTS 1) in 4, CACNA 1C ( SQTS 4) in 3, and CACN b2 ( SQTS 5) in 6.
    explanation: >-
      Abstract-based cohort evidence identifying CACNB2 as the calcium-channel
      gene underlying SQTS5 in this series.
- name: CACNA2D1 loss-of-function variants
  subtype: SQTS6
  association: Causative
  features: >-
    Loss-of-function CACNA2D1 variants cause SQTS6 within the calcium-channel
    subgroup of autosomal dominant SQTS.
  gene_term:
    preferred_term: CACNA2D1
    term:
      id: hgnc:1399
      label: CACNA2D1
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:21383000
    reference_title: >-
      Identification of a novel loss-of-function calcium channel gene mutation
      in short QT syndrome (SQTS6).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report the first pathogenic mutation in the
      CACNA2D1 gene in humans, which causes a new variant of SQTS.
    explanation: >-
      Abstract-based evidence that pathogenic CACNA2D1 variation causes SQTS6.
- name: SLC4A3
  subtype: SLC4A3-Related
  gene_term:
    preferred_term: SLC4A3
    term:
      id: hgnc:11029
      label: SLC4A3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_b5f6fcca-f8a9-47c2-bae9-a72df92f3bd1-2020-08-03T160000.000Z
    reference_title: "SLC4A3 / short QT syndrome (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC4A3 | HGNC:11029 | short QT syndrome | MONDO:0000453 | AD | Moderate"
    explanation: ClinGen classifies the SLC4A3-short QT syndrome gene-disease relationship as moderate with autosomal dominant inheritance.
pathophysiology:
- name: Ion-channel gain- and loss-of-function variants
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  description: >-
    The upstream trigger of SQTS is a pathogenic germline variant that alters a
    cardiac ion channel. Gain-of-function variants in the potassium channels
    KCNH2 (IKr), KCNQ1 (IKs), and KCNJ2 (IK1) increase repolarizing current,
    while loss-of-function variants in the L-type calcium channel subunits
    CACNA1C, CACNB2, and CACNA2D1 reduce inward calcium current. Either route
    shifts the net balance of currents toward accelerated repolarization in
    structurally normal myocardium.
  genes:
  - preferred_term: KCNH2
    term:
      id: hgnc:6251
      label: KCNH2
  - preferred_term: KCNQ1
    term:
      id: hgnc:6294
      label: KCNQ1
  - preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  - preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  - preferred_term: CACNB2
    term:
      id: hgnc:1402
      label: CACNB2
  - preferred_term: CACNA2D1
    term:
      id: hgnc:1399
      label: CACNA2D1
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: monoatomic ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
    modifier: ABNORMAL
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:14676148
    reference_title: >-
      Sudden death associated with short-QT syndrome linked to mutations in
      HERG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 2 of them, we identified 2 different missense mutations resulting in
      the same amino acid change (N588K) in the S5-P loop region of the cardiac
      IKr channel HERG (KCNH2).
    explanation: >-
      Identifies the gain-of-function KCNH2 (HERG) variant that is the upstream
      ion-channel trigger of SQTS.
  - reference: PMID:16039272
    reference_title: >-
      Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to
      arrhythmogenesis in short QT syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Physiologically the N588K mutation abolishes rectification of HERG
      currents and specifically increases I(Kr) in the ventricle with minimal
      effects on the Purkinje fiber action potential duration.
    explanation: >-
      Mechanistic electrophysiology showing how the channel variant alters
      channel function to increase ventricular repolarizing current, the
      variant-to-current step of the trigger node.
  downstream:
  - target: Accelerated myocardial repolarization
    description: >-
      The gain-of-function potassium or loss-of-function calcium variant shifts
      the net current balance toward repolarization, abbreviating the action
      potential and refractory period in working myocardium.
- name: Accelerated myocardial repolarization
  role: central_effector
  conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
  description: >-
    The core electrophysiologic lesion in SQTS is accelerated repolarization,
    typically due to increased repolarizing potassium current in ventricular
    myocardium. This abbreviates action potential duration and refractory
    periods, producing the characteristic shortened QT interval and reducing the
    margin against re-entry.
  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
  - preferred_term: ventricular cardiac muscle cell action potential
    term:
      id: GO:0086005
      label: ventricular cardiac muscle cell action potential
    modifier: DYSREGULATED
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: DYSREGULATED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:14676148
    reference_title: >-
      Sudden death associated with short-QT syndrome linked to mutations in
      HERG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutations dramatically increase IKr, leading to heterogeneous
      abbreviation of action potential duration and refractoriness, and reduce
      the affinity of the channels to IKr blockers.
    explanation: >-
      Establishes the canonical SQTS mechanism of increased repolarizing
      current with abbreviated action potentials and refractory periods.
  - reference: PMID:29574456
    reference_title: >-
      Modeling Short QT Syndrome Using Human-Induced Pluripotent Stem
      Cell-Derived Cardiomyocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The hiPSC-CMs from the patient showed increased rapidly activating
      delayed rectifier potassium channel current (IKr) density and shortened
      action potential duration compared with healthy control hiPSC-CMs.
    explanation: >-
      Patient-specific hiPSC-cardiomyocytes recapitulate the increased IKr and
      shortened action potential phenotype at the cellular level.
  - reference: PMID:16039272
    reference_title: >-
      Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to
      arrhythmogenesis in short QT syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Physiologically the N588K mutation abolishes rectification of HERG
      currents and specifically increases I(Kr) in the ventricle with minimal
      effects on the Purkinje fiber action potential duration.
    explanation: >-
      Provides mechanistic electrophysiology showing how a canonical KCNH2 SQTS
      mutation selectively increases ventricular repolarizing current.
  downstream:
  - target: Shortened QT Interval
    causal_link_type: DIRECT
    description: >-
      Accelerated myocardial repolarization shortens the surface ECG QT
      interval, the diagnostic electrophysiologic phenotype of SQTS.
    evidence:
    - reference: PMID:12925462
      reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At baseline ECG, all patients exhibited a QT interval <or=280 ms (QTc
        <or=300 ms).
      explanation: >-
        The original family series documents the shortened QT interval
        resulting from the repolarization-abbreviation mechanism.
  - target: Re-entry-prone arrhythmia substrate
    description: >-
      Shortened refractory periods and impaired adaptation of repolarization
      favor rotor stabilization and re-entry in atrial and ventricular tissue.
- name: Re-entry-prone arrhythmia substrate
  role: amplifier
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  description: >-
    Abbreviated refractory periods and impaired rate adaptation create a
    myocardial substrate that is vulnerable to atrial and ventricular
    fibrillation. At the tissue level this is expressed as shortened
    excitation wavelength, enhanced inducibility of sustained spiral waves, and
    increased ventricular vulnerability to fibrillation.
  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: DYSREGULATED
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:12925462
    reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During electrophysiological study, short atrial and ventricular
      refractory periods were documented in all and increased ventricular
      vulnerability to fibrillation in 3 of 4 patients.
    explanation: >-
      Human electrophysiology directly demonstrates the shortened refractory
      periods and ventricular fibrillation vulnerability that define the SQTS
      substrate.
  - reference: PMID:31072576
    reference_title: >-
      Modeling Reentry in the Short QT Syndrome With Human-Induced Pluripotent
      Stem Cell-Derived Cardiac Cell Sheets.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Optical mapping of the SQTS-hiPSC-CCSs revealed shortened APD, impaired
      APD-rate adaptation, abbreviated wavelength of excitation, and increased
      inducibility of sustained spiral waves.
    explanation: >-
      Tissue-scale hiPSC cardiac sheet modeling links abbreviated repolarization
      to re-entry and sustained arrhythmia induction.
  downstream:
  - target: Atrial and ventricular fibrillation susceptibility
    description: >-
      The re-entry-prone substrate manifests clinically as atrial fibrillation,
      ventricular fibrillation, syncope, and sudden cardiac death.
- name: Atrial and ventricular fibrillation susceptibility
  role: effector
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  description: >-
    SQTS clinically presents with malignant atrial and ventricular arrhythmias.
    Atrial fibrillation is common and may be the presenting feature, whereas
    ventricular fibrillation underlies aborted cardiac arrest and sudden cardiac
    death.
  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: DYSREGULATED
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30571592
    reference_title: >-
      Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
      and Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or
      atrial flutter.
    explanation: >-
      Long-term family follow-up shows that atrial arrhythmia and syncope are
      common manifestations of clinically diagnosed SQTS.
  - reference: PMID:12925462
    reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The short QT syndrome is characterized by familial sudden death, short
      refractory periods, and inducible ventricular fibrillation.
    explanation: >-
      Directly connects the SQTS clinical syndrome to ventricular fibrillation
      and sudden death risk.
  downstream:
  - target: Atrial Fibrillation
    causal_link_type: DIRECT
    description: >-
      The atrial component of the arrhythmogenic substrate manifests clinically
      as atrial fibrillation or atrial flutter in affected SQTS families.
    evidence:
    - reference: PMID:30571592
      reference_title: >-
        Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
        and Outcome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or
        atrial flutter.
      explanation: >-
        Long-term family follow-up links the SQTS arrhythmia substrate to
        atrial fibrillation.
  - target: Ventricular Fibrillation
    causal_link_type: DIRECT
    description: >-
      The ventricular component of the substrate creates vulnerability to
      ventricular fibrillation.
    evidence:
    - reference: PMID:12925462
      reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The short QT syndrome is characterized by familial sudden death, short
        refractory periods, and inducible ventricular fibrillation.
      explanation: >-
        The original SQTS family series directly links short refractory periods
        to ventricular fibrillation.
  - target: Palpitations
    causal_link_type: DIRECT
    description: >-
      Atrial or ventricular tachyarrhythmias can be perceived as palpitations.
    evidence:
    - reference: PMID:12925462
      reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Several members of 2 different families were referred for syncope,
        palpitations, and resuscitated cardiac arrest in the presence of a
        positive family history for sudden cardiac death.
      explanation: >-
        Palpitations were among the presenting symptoms in SQTS families with
        the arrhythmic substrate.
  - target: Syncope and Sudden Cardiac Death
    description: >-
      Sustained ventricular fibrillation abolishes effective cardiac output,
      producing syncope and, if not terminated, sudden cardiac death.
- name: Syncope and Sudden Cardiac Death
  role: outcome
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  description: >-
    Loss of effective cardiac output from sustained ventricular fibrillation (or
    self-terminating tachyarrhythmia) causes transient cerebral hypoperfusion
    and syncope and, when the rhythm does not terminate, sudden cardiac death.
    These are the shared clinical endpoints of SQTS and are frequently the
    sentinel manifestation, occurring in infants, children, and young adults
    with structurally normal hearts.
  downstream:
  - target: Syncope
    causal_link_type: DIRECT
    description: >-
      Self-terminating or sustained tachyarrhythmia can transiently abolish
      effective cerebral perfusion, producing syncope.
    evidence:
    - reference: PMID:30571592
      reference_title: >-
        Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
        and Outcome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or
        atrial flutter.
      explanation: >-
        Syncope is a clinical endpoint observed in SQTS families.
  - target: Sudden Cardiac Death
    causal_link_type: DIRECT
    description: >-
      Sustained malignant ventricular arrhythmia can culminate in sudden
      cardiac death.
    evidence:
    - reference: PMID:14676148
      reference_title: >-
        Sudden death associated with short-QT syndrome linked to mutations in
        HERG.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We demonstrate a novel genetic and biophysical mechanism responsible for
        sudden death in infants, children, and young adults caused by mutations
        in KCNH2.
      explanation: >-
        KCNH2-mediated SQTS provides human genetic evidence linking the
        mechanism to sudden death.
  evidence:
  - reference: PMID:30571592
    reference_title: >-
      Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
      and Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short QT syndrome ( SQTS ) is a rare inheritable disease associated with
      sudden cardiac death.
    explanation: >-
      Human clinical evidence tying SQTS to sudden cardiac death as the terminal
      outcome of the cascade.
  - reference: PMID:12925462
    reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The short QT syndrome is characterized by familial sudden death, short
      refractory periods, and inducible ventricular fibrillation.
    explanation: >-
      Connects the SQTS substrate to familial sudden death as the clinical
      endpoint.
phenotypes:
- category: Cardiovascular
  name: Shortened QT Interval
  diagnostic: true
  description: >-
    Marked QT abbreviation on surface ECG is the defining diagnostic
    electrophysiologic feature of SQTS.
  phenotype_term:
    preferred_term: Shortened QT interval
    term:
      id: HP:0012232
      label: Shortened QT interval
  evidence:
  - reference: PMID:12925462
    reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At baseline ECG, all patients exhibited a QT interval <or=280 ms (QTc
      <or=300 ms).
    explanation: >-
      Documents the hallmark ECG phenotype that defines SQTS in the original
      familial cohort.
  - reference: ORPHA:51083
    reference_title: "Congenital short QT syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012232 | Shortened QT interval | Obligate (100%)"
    explanation: Orphadata lists shortened QT interval as an obligate SQTS phenotype.
- category: Cardiovascular
  name: Asymmetric T Waves
  subtype: SQTS3
  description: >-
    A distinctive ECG signature of tall, peaked, asymmetric T waves was
    reported in the original KCNJ2 (IK1) subtype SQTS3 family, reflecting the
    accelerated terminal phase of repolarization, and was proposed to help
    distinguish it from the other potassium-channel short QT subtypes. The
    signature derives from a single family and awaits broader confirmation.
  phenotype_term:
    preferred_term: Tall, peaked, asymmetric T waves
    term:
      id: HP:0005135
      label: Abnormal T-wave
  evidence:
  - reference: PMID:15761194
    reference_title: >-
      A novel form of short QT syndrome (SQT3) is caused by a mutation in the
      KCNJ2 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we identify a new variant, "SQT3", which has a unique ECG phenotype
      characterized by asymmetrical T waves, and a defect in the gene coding for
      the inwardly rectifying Kir2.1 (I(K1)) channel.
    explanation: >-
      Documents the asymmetric-T-wave ECG phenotype that distinguishes the
      SQTS3 (KCNJ2/IK1) subtype from the other short QT subtypes.
- category: Cardiovascular
  name: Atrial Fibrillation
  description: >-
    Atrial fibrillation is a common presenting arrhythmia and may precede more
    severe ventricular events.
  phenotype_term:
    preferred_term: atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:30571592
    reference_title: >-
      Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
      and Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or
      atrial flutter.
    explanation: >-
      Supports atrial fibrillation as a common clinical manifestation in SQTS
      families.
- category: Cardiovascular
  name: Ventricular Fibrillation
  description: >-
    Ventricular fibrillation reflects the malignant ventricular re-entry
    phenotype responsible for aborted cardiac arrest and sudden death in SQTS.
  phenotype_term:
    preferred_term: ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:12925462
    reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The short QT syndrome is characterized by familial sudden death, short
      refractory periods, and inducible ventricular fibrillation.
    explanation: >-
      Establishes ventricular fibrillation as a central malignant arrhythmia in
      SQTS.
- category: Cardiovascular
  name: Syncope
  description: >-
    Transient loss of consciousness can result from brief self-terminating or
    sustained tachyarrhythmia in SQTS.
  phenotype_term:
    preferred_term: syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:30571592
    reference_title: >-
      Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
      and Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or
      atrial flutter.
    explanation: >-
      Direct long-term cohort evidence that syncope is part of the SQTS
      phenotype spectrum.
- category: Cardiovascular
  name: Palpitations
  description: >-
    Palpitations are a common symptom of atrial or ventricular tachyarrhythmia
    in affected individuals.
  phenotype_term:
    preferred_term: palpitations
    term:
      id: HP:0001962
      label: Palpitations
  evidence:
  - reference: PMID:12925462
    reference_title: 'Short QT Syndrome: a familial cause of sudden death.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several members of 2 different families were referred for syncope,
      palpitations, and resuscitated cardiac arrest in the presence of a
      positive family history for sudden cardiac death.
    explanation: >-
      Shows palpitations among the presenting manifestations in the original
      SQTS family series.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden cardiac death is the most severe outcome of SQTS and may occur in
    infants, children, or young adults with structurally normal hearts.
  phenotype_term:
    preferred_term: sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:14676148
    reference_title: >-
      Sudden death associated with short-QT syndrome linked to mutations in
      HERG.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate a novel genetic and biophysical mechanism responsible for
      sudden death in infants, children, and young adults caused by mutations
      in KCNH2.
    explanation: >-
      Confirms sudden cardiac death as a defining high-severity clinical outcome
      of SQTS.
treatments:
- name: Quinidine/Hydroquinidine Therapy
  description: >-
    Hydroquinidine is the best-supported pharmacologic therapy for SQTS. It
    prolongs the QT interval and ventricular refractory period and can suppress
    inducible or recurrent ventricular arrhythmias.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: quinidine
      term:
        id: CHEBI:28593
        label: quinidine
  evidence:
  - reference: PMID:15093889
    reference_title: 'Short QT syndrome: pharmacological treatment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only hydroquinidine administration caused a QT prolongation, which
      increased from 263 +/- 12 ms to 362 +/- 25 ms (calculated QT from 290 +/-
      13 ms to 405 +/- 26 ms).
    explanation: >-
      Demonstrates that hydroquinidine, unlike the other tested agents,
      meaningfully prolongs the abbreviated QT interval in SQTS.
  - reference: PMID:31427960
    reference_title: Impact of Antiarrhythmic Drugs on the Outcome of Short QT Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HQ increases the corrected QT interval and prevents VAs in the majority
      of the patients in this cohort.
    explanation: >-
      Supports hydroquinidine as the most consistently effective long-term
      antiarrhythmic drug reported for SQTS.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    ICD implantation is used for secondary prevention or in high-risk patients,
    especially after aborted cardiac arrest or when malignant ventricular
    arrhythmia risk remains high.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:30571592
    reference_title: >-
      Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile
      and Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients (29%) received an implantable cardioverter-defibrillator
      and 5 patients received long-term prophylaxis with hydroquinidine.
    explanation: >-
      Long-term cohort follow-up shows ICD use as a standard individualized
      management strategy in SQTS.
notes: >-
  This entry is intentionally framed at the shared Short QT syndrome disease
  level rather than being split into individual subtype entries. The genetic
  forms are captured as within-entry `has_subtypes` (SQTS1-6 plus the
  SLC4A3-related form) rather than as separate disease files, so the shared
  mechanism stays unified while each subtype remains individually addressable
  as a `subtype:` foreign key from the per-gene `genetic` blocks and from
  subtype-specific phenotypes. The curation emphasizes the common
  repolarization-abbreviation mechanism and the clinical arrhythmia substrate
  across genetically heterogeneous SQTS families. The subtype-distinguishing
  detail is held in the per-gene `genetic` blocks: SQTS1 (KCNH2/IKr, N588K loss
  of channel inactivation), SQTS2 (KCNQ1/IKs, V307L gain-of-function), and
  SQTS3 (KCNJ2/IK1, D172N) with its characteristic tall, asymmetric T-wave ECG
  signature; and the calcium-channel subtypes SQTS4-6 (CACNA1C, CACNB2,
  CACNA2D1). Four subtypes carry a MONDO `subtype_term`: SQTS1-3 (MONDO gene
  series 1-3) and the SLC4A3-related form (MONDO:0859368, short QT syndrome 7).
  SQTS4-6 are left unbound because MONDO has no matching gene-series class for
  them and no term is preferable to a false match.
datasets:
- accession: ega:EGAS00001002632
  title: Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome
  description: Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain less than 25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Short QT Syndrome"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'

Short QT Syndrome

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