Inherited Arrhythmia Syndromes (Cardiac Channelopathies)

name: Inherited Arrhythmia Syndromes
display_name: Inherited Arrhythmia Syndromes (Cardiac Channelopathies)
creation_date: "2026-06-12T00:00:00Z"
description: >-
  The inherited arrhythmia syndromes (cardiac channelopathies) are a group of
  Mendelian disorders of cardiac electrical function occurring in a
  structurally normal heart. Each is caused by variants in genes encoding
  cardiac ion channels or calcium-handling proteins, producing an
  arrhythmogenic substrate (altered repolarization or triggered activity) that
  predisposes to syncope and sudden cardiac death. They are distinguished from
  the structural cardiomyopathies, whose arrhythmias arise from myocardial
  remodeling rather than a primary electrical defect.
grouping_basis:
- SHARED_MECHANISM
- SHARED_GENE_FAMILY
grouping_rationale: >-
  Grouped on a shared electrophysiological mechanism: each member conforms to
  the cardiac_ion_channel_repolarization module (ion-channel/Ca-handling variant
  -> arrhythmogenic substrate -> ventricular tachyarrhythmia -> sudden death) in
  a structurally normal heart. Members are kept as separate Disease entries
  because they differ in the causal channel gene, the direction of the
  repolarization defect (QT prolongation vs shortening), and the arrhythmia
  trigger (adrenergic, rest/sleep, fever). The defining criterion is
  NECESSARY_AND_SUFFICIENT: conforming to the channelopathy module in the
  absence of a primary cardiomyopathy both characterizes every member and
  identifies candidate members not yet listed.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:1010180
      label: cardiogenetic rhythm disorder
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      narrowMatch: this grouping is the cardiac channelopathy subset of the
      broader MONDO cardiogenetic rhythm disorder class. MONDO:1010180 covers
      any monogenic cardiac rhythm disorder and explicitly includes entities
      beyond the DisMech channelopathy/module-defined scope, such as familial
      atrial fibrillation, progressive cardiac conduction disease, and other
      inherited rhythm disorders. (Note: inherited paroxysmal ventricular
      fibrillation is itself a primary channelopathy and is curated as a member
      of this grouping; only acquired/structural ventricular fibrillation is
      out of scope.)
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        MONDO currently lacks a precise cardiac-channelopathy grouping term.
        MONDO:1010180 is useful as a broader alignment target, but its descendant
        set should not be treated as exhaustive DisMech curation gaps for this
        grouping.
membership_criteria:
- description: >-
    A disorder is an inherited arrhythmia syndrome if and only if it conforms to
    the cardiac ion-channel repolarization module (an arrhythmogenic substrate
    driven by an ion-channel or calcium-handling variant) AND does not arise
    from a primary structural cardiomyopathy.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    operator: AND
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity
      description: >-
        Conforms to the cardiac ion-channel repolarization module
        (arrhythmogenic substrate and triggered activity).
    - criterion_predicate: CONFORMS_TO_MODULE
      module: cardiomyopathy_maladaptive_remodeling
      negated: true
      description: >-
        Structurally normal heart — does NOT conform to the maladaptive
        cardiomyopathy remodeling module.
members:
- member: Familial Long QT Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss-of-function of repolarizing potassium currents (e.g., KCNQ1/IKs in
      LQT1) prolongs the action potential and QT interval, predisposing to
      torsades de pointes; adrenergically triggered in LQT1.
    gene:
      preferred_term: KCNQ1
      term:
        id: hgnc:6294
        label: KCNQ1
- member: Jervell and Lange-Nielsen Syndrome 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The biallelic, recessive counterpart of LQT1 at the same locus: whereas a
      single heterozygous KCNQ1 variant produces dominant LQT1 (curated within
      Familial Long QT Syndrome), homozygous or compound-heterozygous
      loss-of-function abolishes IKs almost completely, giving markedly longer
      QTc and childhood-onset events. The same channel lesion is expressed in a
      second tissue — the stria vascularis marginal cells, whose KCNQ1-KCNE1 K+
      secretion generates the endocochlear potential — so the entry is
      distinguished from every other member by congenital profound bilateral
      sensorineural deafness accompanying the arrhythmia. Accounts for ~90% of
      Jervell and Lange-Nielsen syndrome.
    gene:
      preferred_term: KCNQ1
      term:
        id: hgnc:6294
        label: KCNQ1
    module: cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity
- member: Jervell and Lange-Nielsen Syndrome 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The rarer (~10%) allelic sibling of JLNS1: biallelic loss of KCNE1/MinK,
      the single-transmembrane beta subunit that assembles with the KCNQ1 alpha
      subunit, abolishes the same IKs current from the accessory rather than the
      pore-forming side. It is therefore distinguished from JLNS1 only by which
      subunit of one channel complex is lost, and from KCNE1-related dominant
      LQT5 by allele dosage — a single KCNE1 variant gives at best a
      low-penetrance QT-prolongation phenotype, while biallelic loss produces the
      severe cardioauditory syndrome.
    gene:
      preferred_term: KCNE1
      term:
        id: hgnc:6240
        label: KCNE1
    module: cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling
- member: Short QT Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Gain-of-function of repolarizing potassium currents (e.g., KCNH2/IKr)
      abbreviates the action potential and QT interval — the mirror image of
      long QT — shortening refractoriness and favoring reentry.
    gene:
      preferred_term: KCNH2
      term:
        id: hgnc:6251
        label: KCNH2
- member: Brugada syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss-of-function of the cardiac sodium channel (SCN5A/INa) produces
      right-precordial ST elevation and phase-2 reentry; arrhythmias are
      classically triggered at rest, during sleep, or with fever.
    gene:
      preferred_term: SCN5A
      term:
        id: hgnc:10593
        label: SCN5A
- member: RYR2 CPVT
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Gain-of-function of the ryanodine receptor (RYR2) causes diastolic
      sarcoplasmic-reticulum calcium leak and delayed afterdepolarizations;
      bidirectional VT is provoked by catecholamines (exercise/emotion) with a
      normal resting ECG.
    gene:
      preferred_term: RYR2
      term:
        id: hgnc:10484
        label: RYR2
- member: CASQ2 CPVT
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The other half of the CPVT pair. RYR2 CPVT places the lesion in the
      calcium-release channel itself; here it is in calsequestrin-2, the
      high-capacity luminal calcium buffer of the junctional sarcoplasmic
      reticulum that sets how much calcium is stored and how RyR2 gates against
      it — so the same delayed-afterdepolarization endpoint is reached by
      destabilising the store rather than the release channel. It is also the
      recessive form: classically biallelic (the Bedouin founder p.D307H
      missense), although certain heterozygous missense alleles that disrupt
      calsequestrin filament assembly act dominant-negatively.
    gene:
      preferred_term: CASQ2
      term:
        id: hgnc:1513
        label: CASQ2
    module: cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity
- member: Andersen-Tawil Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss-of-function of the strong inward rectifier (KCNJ2/Kir2.1, IK1)
      destabilizes the resting potential and terminal repolarization, producing
      frequent ectopy at rest, a prolonged QU interval with prominent U waves
      (often with a normal QTc, despite the historical LQT7 label), and
      bidirectional ventricular tachycardia. It is distinguished from its
      closest arrhythmic mimic, RYR2 CPVT, by resting rather than
      adrenergically provoked ectopy, and from the other members by two
      extracardiac manifestations of the same channel lesion: episodic
      potassium-sensitive periodic paralysis in skeletal muscle, and
      craniofacial and skeletal dysmorphism arising from disrupted bioelectric
      patterning in development.
    gene:
      preferred_term: KCNJ2
      term:
        id: hgnc:6263
        label: KCNJ2
- member: Timothy Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Gain-of-function of the L-type calcium channel (CACNA1C) impairs
      voltage-dependent inactivation, markedly prolonging the action potential
      and producing a multisystem syndrome (QT prolongation, syndactyly,
      autism) beyond the isolated arrhythmia.
    gene:
      preferred_term: CACNA1C
      term:
        id: hgnc:1390
        label: CACNA1C
- member: Familial Sick Sinus Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Variants in the pacemaker current (HCN4/If) or SCN5A impair sinoatrial
      automaticity, producing bradyarrhythmia and sinus-node dysfunction — the
      automaticity-failure branch of the module rather than ventricular
      tachyarrhythmia.
    gene:
      preferred_term: HCN4
      term:
        id: hgnc:16882
        label: HCN4
    module: cardiac_ion_channel_repolarization#Sinoatrial Node Pacemaker Dysfunction
- member: Sick Sinus Syndrome 2, Autosomal Dominant
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The HCN4-specific, autosomal dominant member of the familial sick sinus
      syndrome set: heterozygous loss-of-function variants in the pacemaker
      channel reduce the funny current (I_f) that drives diastolic
      depolarization, and truncating alleles additionally uncouple the current
      from cAMP, adding chronotropic incompetence to the resting bradycardia.
      Like Familial Sick Sinus Syndrome it sits on the automaticity-failure
      branch of the module rather than the ventricular-tachyarrhythmia branch,
      but it is distinguished from that gene-heterogeneous umbrella (and from
      the recessive SCN5A form) by the funny-current mechanism and by a high
      burden of atrial fibrillation. Membership caveat: a substantial minority
      of HCN4 carriers also have left ventricular noncompaction, so the
      "structurally normal heart" criterion holds only in the sense that the
      entry does not conform to cardiomyopathy_maladaptive_remodeling — the
      noncompaction is a developmental co-segregating malformation of the same
      channel lesion, not arrhythmia-driven remodeling.
    gene:
      preferred_term: HCN4
      term:
        id: hgnc:16882
        label: HCN4
    module: cardiac_ion_channel_repolarization#Sinoatrial Node Pacemaker Dysfunction
- member: Sinoatrial Node Dysfunction and Deafness
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The third member on the automaticity-failure branch, and the only one
      whose pacemaker lesion is a calcium rather than a sodium or funny current:
      biallelic loss of CACNA1D yields non-conducting Cav1.3 channels, removing
      the low-threshold, slowly inactivating L-type calcium current that
      contributes to sinoatrial diastolic depolarization, so it presents as
      resting bradycardia with increased heart-rate variability and exertional
      syncope rather than as tachyarrhythmia. It is distinguished from Familial
      Sick Sinus Syndrome and from the dominant HCN4 form by being recessive
      (heterozygous carriers are unaffected) and by a second organ: Cav1.3 also
      supplies the calcium influx that triggers glutamate release at the
      cochlear inner-hair-cell ribbon synapse, so the same lesion produces
      congenital severe-to-profound sensorineural deafness with intact
      vestibular function. It shares that cardioauditory shape with the Jervell
      and Lange-Nielsen members while sitting on the opposite (bradyarrhythmic)
      branch of the module.
    gene:
      preferred_term: CACNA1D
      term:
        id: hgnc:1391
        label: CACNA1D
    module: cardiac_ion_channel_repolarization#Sinoatrial Node Pacemaker Dysfunction
- member: Paroxysmal Familial Ventricular Fibrillation
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Ventricular fibrillation in a structurally normal heart without a long
      QT, short QT, or Brugada ECG signature. The type 2 form is driven by
      cardiac DPP6 overexpression that selectively enhances Purkinje-fiber
      transient outward current (Ito) and accelerates Purkinje repolarization,
      producing a Purkinje early-repolarization substrate with rest-triggered
      VF; the type 1 form is SCN5A-associated and overlaps the sodium
      channelopathy spectrum.
    gene:
      preferred_term: DPP6
      term:
        id: hgnc:3010
        label: DPP6
- member: Torsade de Pointes Syndrome With Short Coupling Interval
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Short-coupled torsade de pointes / short-coupled idiopathic ventricular
      fibrillation in a structurally normal heart, defined by a very short
      coupling interval of the initiating premature ventricular complex and a
      normal-to-short QT (distinguishing it from long QT syndrome). It is
      genetically heterogeneous with case-based susceptibility rather than a
      single monogenic cause; rare RYR2 variants implicate diastolic
      sarcoplasmic-reticulum calcium leak as a candidate trigger substrate.
      Unlike RYR2 CPVT — its sibling ryanodinopathy, in which catecholamines
      provoke bidirectional VT — short-coupled TdP arrhythmias arise largely at
      rest and are not adrenergically dependent.
    gene:
      preferred_term: RYR2
      term:
        id: hgnc:10484
        label: RYR2
notes: >-
  Worked example demonstrating NECESSARY_AND_SUFFICIENT criteria with a NOT
  (negated) leaf. Because the members declare conforms_to edges to the cardiac
  module, `just check-groupings` reports them as SATISFIED and flags any other
  conforming disorder (e.g., a short-coupled torsade/VF entry) as a candidate
  member.


  TWO CANDIDATES DELIBERATELY NOT ADMITTED (see issue #4242). `check-groupings`
  reports both as satisfying the sufficient criterion; both are held out
  pending a maintainer decision rather than silently added or silently ignored.

  (1) FAMILIAL ATRIAL FIBRILLATION. `Familial_Atrial_Fibrillation.yaml`
  declares conformance at three module nodes including the defining one, so the
  N&S logic classifies it in, while the mapping_justification prose above names
  familial atrial fibrillation as out of scope. That prose predates the FAF
  entry, so this is a live contradiction between the grouping's logic and its
  own note, not merely a deferred call. Deciding it either way is a nosology
  judgement (is an atrial-substrate channelopathy an inherited arrhythmia
  syndrome, or the seed of a sibling grouping alongside progressive cardiac
  conduction disease?) and is issue #4242 decision A.

  (2) TANGO2 DEFICIENCY DISORDER. A false positive of the criterion as written,
  and the more interesting of the two. Its arrhythmia node chain does conform to
  this module, but the proximal lesion is `Cardiomyocyte ATP Depletion and
  Repolarization Instability` during catabolic-stress metabolic crises — TANGO2
  is not a gene encoding a cardiac ion channel or calcium-handling protein, so
  the entry fails this grouping's own `description` while satisfying its formal
  criterion. The NOT leaf does not exclude it either: ~70% of TANGO2 patients in
  the reported cardiac-crisis cohort develop cardiomyopathy, but the entry does
  not declare `cardiomyopathy_maladaptive_remodeling` conformance, and absence of
  a declared conformance is not absence of the disease feature. Admitting it
  would make "inherited arrhythmia syndrome" mean "any Mendelian disease with an
  arrhythmia", which is what the structurally-normal-heart clause exists to
  prevent. Tightening the criterion (e.g. adding a HAS_GENE-style channel/
  calcium-handling conjunct, or a NOT against
  metabolic_intoxication_decompensation) is the fix, and is a schema/criteria
  change rather than a membership edit.


  TOOLING CAVEAT worth knowing before reading the audit output. The criterion
  leaf carries a `#Arrhythmogenic Substrate and Triggered Activity` node anchor,
  but `evaluate_grouping` in `src/dismech/groupings.py` splits the anchor off and
  matches the module STEM only (`_evaluate_leaf`, and `extract_disease_facts`
  which stores `module_stems`). The anchor is therefore decorative here, and the
  criterion behaves as plain module-level conformance. That is in fact what this
  grouping means — Familial Sick Sinus Syndrome, Sick Sinus Syndrome 2 and
  Sinoatrial Node Dysfunction and Deafness all sit on the
  `#Sinoatrial Node Pacemaker Dysfunction` branch, and Jervell and Lange-Nielsen
  Syndrome 2 runs variant -> altered action potential -> ventricular
  tachyarrhythmia without the intervening node, so four of the fourteen members
  never declare the anchored node — but the criterion text overstates the
  requirement, and if the evaluator is ever made anchor-aware those four members
  flip to NOT_SATISFIED and are reported as contradictions. Every member that
  attaches somewhere other than the anchored node now carries a `module:` slot on
  its differentiating_mechanisms naming the node it actually attaches at, so the
  distinction survives in the data either way; members without that slot are on
  the anchored node.