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Torsades de pointes

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Summary

Torsades de pointes (MONDO:0005478) is a disease with 8 cohort genes (1 GWAS associations across 1 studies) and 5 clinical trials. Top therapeutic interventions include dextrose.

At a glance

  • Cohort genes: 8
  • GWAS associations: 1
  • ClinVar variants: 5
  • Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical nametorsades de pointes
Mondo IDMONDO:0005478
EFOEFO:0005307
MeSHD016171
SNOMED CT31722008
UMLSC0040479
MedGen21214
Is cancer (heuristic)no

Data availability: 5 ClinVar variants · 1 GWAS association (1 study) · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease › ventricular tachycardia › torsades de pointes

Related subtypes (2): ventricular tachycardia, familial, polymorphic ventricular tachycardia

Genetics & variants

GWAS landscape

1 GWAS associations across 1 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
rs22763144e-07C18orf21?2

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST002269Behr ER20132160Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding1
Tier 2: splice/UTR0
Tier 3: regulatory0
Tier 4: intronic/intergenic0

MAF distribution

BucketVariants
common (>=0.05)1
low_freq (0.01-0.05)0
rare (<0.01)0
unknown0

Functional consequences

ConsequenceCount
missense_variant1

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
rs22763141835977503A>G,T0.19missense_variantC18orf214e-07Tier 1: coding

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 conflicting classifications of pathogenicity, 1 not provided

ClinVarVariant (HGVS)GeneClassificationReview
36429NM_000238.4(KCNH2):c.3140G>T (p.Arg1047Leu)KCNH2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
67604NM_001148.6(ANK2):c.1423G>A (p.Gly475Arg)ANK2Uncertain significancecriteria provided, multiple submitters, no conflicts
67095NM_000218.3(KCNQ1):c.652A>G (p.Lys218Glu)KCNQ1Uncertain significancecriteria provided, multiple submitters, no conflicts
68051NM_000335.5(SCN5A):c.871A>C (p.Asn291His)SCN5AUncertain significancecriteria provided, multiple submitters, no conflicts
67605NM_001148.6(ANK2):c.2122G>A (p.Val708Met)ANK2not providedno classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
SCN5AOrphanet:101016Romano-Ward syndrome
SCN5AOrphanet:130Brugada syndrome
SCN5AOrphanet:1344Isolated atrial standstill
SCN5AOrphanet:154Familial isolated dilated cardiomyopathy
SCN5AOrphanet:166282Hereditary sick sinus syndrome
SCN5AOrphanet:228140Idiopathic ventricular fibrillation
SCN5AOrphanet:334Hereditary atrial fibrillation
SCN5AOrphanet:871Hereditary progressive cardiac conduction defect
ANK2Orphanet:101016Romano-Ward syndrome
KCNH2Orphanet:101016Romano-Ward syndrome
KCNH2Orphanet:51083Congenital short QT syndrome
KCNQ1Orphanet:101016Romano-Ward syndrome
KCNQ1Orphanet:334Hereditary atrial fibrillation
KCNQ1Orphanet:51083Congenital short QT syndrome
KCNQ1Orphanet:90647Jervell and Lange-Nielsen syndrome

Cohort genes → proteins

8 cohort genes, 6 distinct canonical proteins.

Evidence partition

SubsetGenes
gwas_only4
multi_evidence4

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
SCN5AHGNC:10593ENSG00000183873Q14524Sodium channel protein type 5 subunit alphaclinvar
RPRD1AHGNC:25560ENSG00000141425Q96P16Regulation of nuclear pre-mRNA domain-containing protein 1Agwas
MIR187HGNC:31558ENSG00000207797microRNA 187gwas
GALNT1HGNC:4123ENSG00000141429Q10472Polypeptide N-acetylgalactosaminyltransferase 1gwas
ANK2HGNC:493ENSG00000145362Q01484Ankyrin-2clinvar
RMP24P1HGNC:57042ENSG00000251647RMP24 pseudogene 1gwas
KCNH2HGNC:6251ENSG00000055118Q12809Voltage-gated inwardly rectifying potassium channel KCNH2clinvar
KCNQ1HGNC:6294ENSG00000053918P51787Potassium voltage-gated channel subfamily KQT member 1clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
SCN5ASodium channel protein type 5 subunit alphaPore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
RPRD1ARegulation of nuclear pre-mRNA domain-containing protein 1AInteracts with phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit POLR2A, and participates in dephosphorylation of the CTD by RPAP2.
GALNT1Polypeptide N-acetylgalactosaminyltransferase 1Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor.
ANK2Ankyrin-2Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells.
KCNH2Voltage-gated inwardly rectifying potassium channel KCNH2Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.
KCNQ1Potassium voltage-gated channel subfamily KQT member 1Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

FamilyGenesFoldFDR
Ion channel341.8×2e-04
Scaffold/PPI12.2×0.669
Enzyme (other)11.5×0.669
Other/Unknown30.7×0.919

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
SCN5AIon channelyesNa_channel_asu, Ion_trans_dom, Na_channel_a5su
RPRD1AOther/UnknownnoCID_dom, ENTH_VHS, RPRD1A/B_C
MIR187Other/Unknownno
GALNT1Enzyme (other)yes2.4.1.41Ricin_B_lectin, Glyco_trans_2-like, Nucleotide-diphossugar_trans
ANK2Scaffold/PPInoDeath_dom, ZU5_dom, Ankyrin_rpt
RMP24P1Other/Unknownno
KCNH2Ion channelyesPAS, cNMP-bd_dom, PAS-assoc_C
KCNQ1Ion channelyesK_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)1
broad (>20)7
unknown0

Top tissues across cohort

TissueCohort genes
apex of heart2
heart left ventricle2
cardiac ventricle1
Brodmann (1909) area 231
adrenal tissue1
endothelial cell1
body of stomach1
olfactory segment of nasal mucosa1
buccal mucosa cell1
esophagus squamous epithelium1
pharyngeal mucosa1
lateral nuclear group of thalamus1
substantia nigra pars compacta1
substantia nigra pars reticulata1
colonic epithelium1
hindlimb stylopod muscle1
skeletal muscle tissue1
cardiac atrium1
right atrium auricular region1
left adrenal gland1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
SCN5A161broadyesapex of heart, heart left ventricle, cardiac ventricle
RPRD1A282ubiquitousmarkerBrodmann (1909) area 23, endothelial cell, adrenal tissue
MIR18733yesolfactory segment of nasal mucosa, body of stomach, heart left ventricle
GALNT1299ubiquitousmarkerbuccal mucosa cell, esophagus squamous epithelium, pharyngeal mucosa
ANK2281ubiquitousmarkersubstantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
RMP24P18yeshindlimb stylopod muscle, skeletal muscle tissue, colonic epithelium
KCNH2211broadmarkerapex of heart, right atrium auricular region, cardiac atrium
KCNQ1132broadmarkerleft adrenal gland cortex, left adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

SymbolInteractor count
ANK26,423
KCNQ13,235
SCN5A2,090
KCNH21,932
RPRD1A1,722
GALNT11,009
MIR1870
RMP24P10

Intra-cohort edges

ABSources
GALNT1RPRD1Astring_interaction
KCNH2KCNQ1string_interaction
KCNH2SCN5Astring_interaction
KCNQ1SCN5Astring_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 2

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
KCNQ1P5178728
KCNH2Q1280924
SCN5AQ1452416
ANK2Q0148411
RPRD1AQ96P162

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
GALNT1Q1047291.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 8 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Phase 3 - rapid repolarisation2380.7×2e-04KCNH2, KCNQ1
Cardiac conduction354.4×2e-04SCN5A, KCNH2, KCNQ1
Muscle contraction338.6×4e-04SCN5A, KCNH2, KCNQ1
Interaction between L1 and Ankyrins2122.8×7e-04SCN5A, ANK2
Voltage gated Potassium channels281.0×0.001KCNH2, KCNQ1
Potassium Channels244.8×0.004KCNH2, KCNQ1
L1CAM interactions240.1×0.004SCN5A, ANK2
Maturation of protein 3a1211.5×0.015GALNT1
Phase 2 - plateau phase1126.9×0.017KCNQ1
Axon guidance215.1×0.017SCN5A, ANK2
Neuronal System214.8×0.017KCNH2, KCNQ1
Nervous system development214.3×0.017SCN5A, ANK2
Phase 0 - rapid depolarisation157.7×0.034SCN5A
COPI-independent Golgi-to-ER retrograde traffic134.6×0.053GALNT1
O-linked glycosylation of mucins130.7×0.056GALNT1
RNA polymerase II transcribes snRNA genes125.7×0.063RPRD1A
ER to Golgi Anterograde Transport122.1×0.069ANK2
COPI-mediated anterograde transport118.3×0.079ANK2
Transport to the Golgi and subsequent modification117.1×0.079ANK2
Developmental Biology24.8×0.079SCN5A, ANK2
Asparagine N-linked glycosylation110.0×0.122ANK2
Membrane Trafficking16.2×0.184ANK2
Vesicle-mediated transport15.8×0.187ANK2
RNA Polymerase II Transcription13.8×0.267RPRD1A
Post-translational protein modification13.2×0.296ANK2
Gene expression (Transcription)13.0×0.303RPRD1A
Metabolism of proteins12.1×0.397ANK2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
ventricular cardiac muscle cell action potential4660.9×1e-09SCN5A, ANK2, KCNH2, KCNQ1
regulation of ventricular cardiac muscle cell membrane repolarization4561.7×1e-09SCN5A, ANK2, KCNH2, KCNQ1
regulation of heart rate by cardiac conduction4249.7×3e-08SCN5A, ANK2, KCNH2, KCNQ1
atrial cardiac muscle cell action potential3842.6×9e-08SCN5A, ANK2, KCNQ1
cardiac muscle contraction3200.6×7e-06SCN5A, KCNH2, KCNQ1
membrane depolarization during SA node cell action potential21123.5×2e-05SCN5A, ANK2
SA node cell action potential2936.2×3e-05SCN5A, ANK2
regulation of atrial cardiac muscle cell membrane repolarization2802.5×3e-05SCN5A, KCNQ1
membrane depolarization during action potential2561.7×5e-05SCN5A, KCNH2
membrane repolarization during action potential2561.7×5e-05KCNH2, KCNQ1
membrane repolarization during cardiac muscle cell action potential2561.7×5e-05KCNH2, KCNQ1
membrane repolarization during ventricular cardiac muscle cell action potential2561.7×5e-05KCNH2, KCNQ1
regulation of membrane repolarization2432.1×8e-05KCNH2, KCNQ1
regulation of cardiac muscle cell contraction2374.5×1e-04SCN5A, ANK2
potassium ion export across plasma membrane2351.1×1e-04KCNH2, KCNQ1
positive regulation of potassium ion transmembrane transport2330.4×1e-04KCNH2, KCNQ1
potassium ion homeostasis2255.3×2e-04KCNH2, KCNQ1
regulation of heart rate2156.0×4e-04SCN5A, ANK2
potassium ion import across plasma membrane2122.1×7e-04KCNH2, KCNQ1
cellular response to xenobiotic stimulus280.2×0.002KCNH2, KCNQ1
regulation of membrane potential277.0×0.002KCNH2, KCNQ1
gastrin-induced gastric acid secretion12808.7×0.002KCNQ1
protein localization to T-tubule12808.7×0.002ANK2
atrial cardiac muscle cell to AV node cell communication12808.7×0.002ANK2
SA node cell to atrial cardiac muscle cell communication12808.7×0.002ANK2
negative regulation of voltage-gated potassium channel activity12808.7×0.002KCNQ1
regulation of heart rate by hormone11404.3×0.003KCNH2
rhythmic behavior11404.3×0.003KCNQ1
corticosterone secretion11404.3×0.003KCNQ1
protein localization to M-band11404.3×0.003ANK2

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 4 of 8 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
SCN5ABEPRIDIL
KCNH2CETIRIZINE
KCNQ1AMBRISENTAN

Top cohort targets by molecule count

SymbolMoleculesMax phase
KCNH27064
SCN5A1084
KCNQ1154
RPRD1A00
MIR18700
GALNT100
ANK200
RMP24P100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
BEPRIDIL4KCNH2, SCN5A
CANDESARTAN CILEXETIL4SCN5A
TELMISARTAN4SCN5A
CARBAMAZEPINE4SCN5A
DIBUCAINE4KCNH2, SCN5A
IMIPRAMINE4KCNH2, SCN5A
DROPERIDOL4KCNH2, SCN5A
PONATINIB4KCNH2, SCN5A
DULOXETINE4KCNH2, KCNQ1, SCN5A
PALONOSETRON4KCNH2, KCNQ1, SCN5A
VILANTEROL4SCN5A
MEXILETINE HYDROCHLORIDE4SCN5A
UNOPROSTONE ISOPROPYL4SCN5A
LURASIDONE4KCNH2, SCN5A
LETERMOVIR4SCN5A
SERTINDOLE4KCNH2, SCN5A
FEDRATINIB4KCNH2, SCN5A
QUINIDINE4KCNH2, SCN5A
DARUNAVIR4KCNH2, KCNQ1, SCN5A
DARIFENACIN4KCNH2, KCNQ1, SCN5A
BENZONATATE4SCN5A
TOLTERODINE4KCNH2, KCNQ1, SCN5A
RANOLAZINE4KCNH2, SCN5A
PIMOZIDE4KCNH2, SCN5A
NIMODIPINE4SCN5A
FELODIPINE4SCN5A
NICARDIPINE4KCNH2, SCN5A
AMLODIPINE4KCNH2, SCN5A
PHENYTOIN4KCNH2, SCN5A
PALIPERIDONE4KCNH2, SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

SymbolAssaysType breakdown
KCNH24,851Binding:3558, Toxicity:1071, Functional:169, ADMET:53
SCN5A594Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
KCNQ1179Binding:96, Functional:64, ADMET:14, Toxicity:5
GALNT11Binding:1

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
GALNT12.4.1.41polypeptide N-acetylgalactosaminyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
SCN5A594
KCNH24,851
KCNQ1179

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

CompoundMax phaseCohort target (bioactivity)
BEPRIDIL4KCNH2, SCN5A
CANDESARTAN CILEXETIL4SCN5A
TELMISARTAN4SCN5A
CARBAMAZEPINE4SCN5A
DIBUCAINE4KCNH2, SCN5A
IMIPRAMINE4KCNH2, SCN5A
DROPERIDOL4KCNH2, SCN5A
PONATINIB4KCNH2, SCN5A
DULOXETINE4KCNH2, KCNQ1, SCN5A
PALONOSETRON4KCNH2, KCNQ1, SCN5A
VILANTEROL4SCN5A
MEXILETINE HYDROCHLORIDE4SCN5A
UNOPROSTONE ISOPROPYL4SCN5A
LURASIDONE4KCNH2, SCN5A
LETERMOVIR4SCN5A
SERTINDOLE4KCNH2, SCN5A
FEDRATINIB4KCNH2, SCN5A
QUINIDINE4KCNH2, SCN5A
DARUNAVIR4KCNH2, KCNQ1, SCN5A
DARIFENACIN4KCNH2, KCNQ1, SCN5A
BENZONATATE4SCN5A
TOLTERODINE4KCNH2, KCNQ1, SCN5A
RANOLAZINE4KCNH2, SCN5A
PIMOZIDE4KCNH2, SCN5A
NIMODIPINE4SCN5A
FELODIPINE4SCN5A
NICARDIPINE4KCNH2, SCN5A
AMLODIPINE4KCNH2, SCN5A
PHENYTOIN4KCNH2, SCN5A
PALIPERIDONE4KCNH2, SCN5A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)3SCN5A, KCNH2, KCNQ1
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug1GALNT1
EDifficult family or no structure, no drug4RPRD1A, MIR187, ANK2, RMP24P1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

SymbolChEMBL assaysDrugged partners (top 3)
RPRD1A0—
MIR1870—
GALNT11—
ANK20—
RMP24P10—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified4
PHASE11

Top trials by phase / activity

NCTPhaseStatusTitle
NCT00839891PHASE1COMPLETEDA Study to Evaluate How VI-0521 Affect Cardiac Repolarization in Healthy Male and Female Volunteers
NCT05521451Not specifiedRECRUITINGClinical Cohort Study - TRUST
NCT07014735Not specifiedRECRUITINGEffect of Hyperglycaemia and Moxifloxacin on QTc Interval in T2DM
NCT07374263Not specifiedRECRUITINGDo QT-Prolonging Drugs Cause Major Adverse Cardiac Events in Hospitalized Adults?
NCT04000542Not specifiedCOMPLETEDPharmacist Use of ECG to Inform Drug Therapy Decisions for Patients Receiving QT Prolonging Medications

Drugs tested across these trials (top 30)

MoleculeMax phaseTrials referencing
DEXTROSE41

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
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Sources 69

This page pulls from 69 datasets indexed by BioBTree:

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