long QT syndrome 1

disease

On this page

Also known as long QT syndrome type 1LQT1ventricular fibrillation with prolonged QT interval

Summary

long QT syndrome 1 (MONDO:0100316) is a disease caused by KCNQ1 (GenCC Definitive), with 16 cohort genes and 1 clinical trial. The dominant Reactome pathway is Muscle contraction (6 cohort genes). Top therapeutic interventions include racepinephrine.

At a glance

Causal gene: KCNQ1 (GenCC Definitive)
Cohort genes: 16
ClinVar variants: 776
Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	long QT syndrome 1
Mondo ID	MONDO:0100316
OMIM	192500
DOID	DOID:0110644
NCIT	C85049
SNOMED CT	20852007
UMLS	C4551647
MedGen	1641146
GARD	0026140
MedDRA	10039211
Is cancer (heuristic)	no

Also known as: long QT syndrome 1 · long QT syndrome type 1 · LQT1 · ventricular fibrillation with prolonged QT interval

Data availability: 776 ClinVar variants · 37 ClinGen variant curations · 3 GenCC gene-disease records · 72 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › long QT syndrome › familial long QT syndrome › long QT syndrome 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

191 likely benign, 112 uncertain significance, 68 pathogenic, 63 pathogenic/likely pathogenic, 58 conflicting classifications of pathogenicity, 45 likely pathogenic, 35 benign/likely benign, 16 benign, 12 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
444879	NM_000218.2(KCNQ1):c.[1249G>A;760G>A]		Pathogenic	no assertion criteria provided
1398892	NM_001743.6(CALM2):c.388G>A (p.Asp130Asn)	CALM2	Pathogenic	criteria provided, single submitter
1456260	NM_001743.6(CALM2):c.394G>T (p.Asp132Tyr)	CALM2	Pathogenic	criteria provided, single submitter
183233	NM_001743.6(CALM2):c.287A>T (p.Asp96Val)	CALM2	Pathogenic	criteria provided, multiple submitters, no conflicts
1358003	NM_005184.4(CALM3):c.390C>G (p.Asp130Glu)	CALM3	Pathogenic	criteria provided, single submitter
2138308	NM_005184.4(CALM3):c.426T>G (p.Phe142Leu)	CALM3	Pathogenic	criteria provided, single submitter
409870	NM_005184.4(CALM3):c.286G>C (p.Asp96His)	CALM3	Pathogenic	criteria provided, multiple submitters, no conflicts
409871	NM_005184.4(CALM3):c.281A>C (p.Asp94Ala)	CALM3	Pathogenic	criteria provided, single submitter
405247	NM_004415.4(DSP):c.3337C>T (p.Arg1113Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14424	NM_000238.4(KCNH2):c.2464G>A (p.Val822Met)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1179766	NM_000218.3(KCNQ1):c.1250dup (p.Val418fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1306529	NM_000218.3(KCNQ1):c.1875dup (p.Gly626fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342708	NM_000218.3(KCNQ1):c.605-2A>G	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1384067	NM_000218.3(KCNQ1):c.921+1G>A	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
1452627	NM_000218.3(KCNQ1):c.771_775dup (p.Arg259fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1712921	NC_000011.10:g.2276821_2491742del	KCNQ1	Pathogenic	no assertion criteria provided
1723453	NM_000218.3(KCNQ1):c.968G>A (p.Trp323Ter)	KCNQ1	Pathogenic	no assertion criteria provided
200814	NM_000218.3(KCNQ1):c.521G>T (p.Arg174Leu)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200851	NM_000218.3(KCNQ1):c.1685+1G>A	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200857	NM_000218.3(KCNQ1):c.1772G>T (p.Arg591Leu)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200858	NM_000218.3(KCNQ1):c.1780C>T (p.Arg594Ter)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200872	NM_000218.3(KCNQ1):c.387-5T>A	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200891	NM_000218.3(KCNQ1):c.403del (p.Val135fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200892	NM_000218.3(KCNQ1):c.425del (p.Leu142fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200898	NM_000218.3(KCNQ1):c.805G>C (p.Gly269Arg)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200912	NM_000218.3(KCNQ1):c.603_604+9del	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200915	NM_000218.3(KCNQ1):c.364dup (p.Cys122fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207967	NM_000218.3(KCNQ1):c.557G>A (p.Gly186Asp)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207969	NM_000218.3(KCNQ1):c.443del (p.Tyr148fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
207970	NM_000218.3(KCNQ1):c.1733-1G>C	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 49 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
KCNQ1	Definitive	Autosomal dominant	long QT syndrome 1	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNQ1	Orphanet:101016	Romano-Ward syndrome
KCNQ1	Orphanet:334	Hereditary atrial fibrillation
KCNQ1	Orphanet:51083	Congenital short QT syndrome
KCNQ1	Orphanet:90647	Jervell and Lange-Nielsen syndrome
RYR2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
RYR2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
RYR2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
RYR2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect
SNRPE	Orphanet:55654	Hypotrichosis simplex
SNTA1	Orphanet:101016	Romano-Ward syndrome
CALM2	Orphanet:101016	Romano-Ward syndrome
CALM2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
CALM3	Orphanet:101016	Romano-Ward syndrome
CALM3	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
CAV3	Orphanet:101016	Romano-Ward syndrome
CAV3	Orphanet:206599	Isolated asymptomatic elevation of creatine phosphokinase
CAV3	Orphanet:488650	Distal myopathy, Tateyama type
CAV3	Orphanet:97238	Rippling muscle disease
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome
DSP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSP	Orphanet:476096	Erythrokeratodermia-cardiomyopathy syndrome
DSP	Orphanet:50942	Striate palmoplantar keratoderma
DSP	Orphanet:65282	Carvajal syndrome
AKAP9	Orphanet:101016	Romano-Ward syndrome
AKAP9	Orphanet:130	Brugada syndrome
ANK2	Orphanet:101016	Romano-Ward syndrome
KCNH2	Orphanet:101016	Romano-Ward syndrome
KCNH2	Orphanet:51083	Congenital short QT syndrome
KCNQ1OT1	Orphanet:2128	Isolated hemihyperplasia
KCNQ1OT1	Orphanet:231117	Beckwith-Wiedemann syndrome due to imprinting defect of 11p15
PKP2	Orphanet:130	Brugada syndrome
PKP2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
PKP2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
PKP2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
PKP2	Orphanet:54260	Left ventricular noncompaction

Cohort genes → proteins

16 cohort genes, 14 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	16

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	gencc,clinvar
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
SNRPE	HGNC:11161	ENSG00000182004	P62304	Small nuclear ribonucleoprotein E	clinvar
SNTA1	HGNC:11167	ENSG00000101400	Q13424	Alpha-1-syntrophin	clinvar
CALM2	HGNC:1445	ENSG00000143933	P0DP24	Calmodulin-2	clinvar
CALM3	HGNC:1449	ENSG00000160014	P0DP25	Calmodulin-3	clinvar
CAV3	HGNC:1529	ENSG00000182533	P56539	Caveolin-3	clinvar
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	clinvar
AKAP9	HGNC:379	ENSG00000127914	Q99996	A-kinase anchor protein 9	clinvar
KCNQ1-AS1	HGNC:42790	ENSG00000229414		KCNQ1 antisense RNA 1	clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	clinvar
KCNQ1OT1	HGNC:6295	ENSG00000269821		KCNQ1 opposite strand/antisense transcript 1	clinvar
PKP2	HGNC:9024	ENSG00000057294	Q99959	Plakophilin-2	clinvar
PTGIR	HGNC:9602	ENSG00000160013	P43119	Prostacyclin receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNQ1	Potassium voltage-gated channel subfamily KQT member 1	Pore-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.
RYR2	Ryanodine receptor 2	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering cardiac muscle contraction.
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SNRPE	Small nuclear ribonucleoprotein E	Plays a role in pre-mRNA splicing as a core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome.
SNTA1	Alpha-1-syntrophin	Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins.
CALM2	Calmodulin-2	Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding.
CALM3	Calmodulin-3	Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding.
CAV3	Caveolin-3	May act as a scaffolding protein within caveolar membranes.
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
AKAP9	A-kinase anchor protein 9	Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus.
ANK2	Ankyrin-2	Plays 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.
KCNH2	Voltage-gated inwardly rectifying potassium channel KCNH2	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.
PKP2	Plakophilin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
PTGIR	Prostacyclin receptor	Receptor for prostacyclin (prostaglandin I2 or PGI2).

Protein-family classification

Druggable: 5 · Difficult: 3 · Unknown: 8 · Druggable fraction: 0.31

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.

Family	Genes	Fold	FDR
Ion channel	4	27.9×	4e-05
Scaffold/PPI	3	3.2×	0.123
GPCR	1	1.5×	0.660
Other/Unknown	8	0.9×	0.765

Per-gene assignment

Symbol	Family	Druggable?	InterPro (top 3)
KCNQ1	Ion channel	yes	K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1
RYR2	Ion channel	yes	RIH_dom, B30.2/SPRY, EF_hand_dom
SCN5A	Ion channel	yes	Na_channel_asu, Ion_trans_dom, Na_channel_a5su
SNRPE	Other/Unknown	no	Sm_dom_euk/arc, LSM_dom_sf, snRNP-E
SNTA1	Scaffold/PPI	no	PDZ, PH_domain, PH-like_dom_sf
CALM2	Other/Unknown	no	EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
CALM3	Other/Unknown	no	EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
CAV3	Other/Unknown	no	Caveolin, Caveolin_CS
DSP	Scaffold/PPI	no	Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
AKAP9	Other/Unknown	no	ELK_dom, PACT_domain, AKAP9/Pericentrin
KCNQ1-AS1	Other/Unknown	no
ANK2	Scaffold/PPI	no	Death_dom, ZU5_dom, Ankyrin_rpt
KCNH2	Ion channel	yes	PAS, cNMP-bd_dom, PAS-assoc_C
KCNQ1OT1	Other/Unknown	no
PKP2	Other/Unknown	no	Armadillo, ARM-like, ARM-type_fold
PTGIR	GPCR	yes	GPCR_Rhodpsn, Prostglndn_IP_rcpt, Prostanoid_rcpt

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	16
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	4
hindlimb stylopod muscle	3
heart right ventricle	2
left ventricle myocardium	2
cortical plate	2
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
myocardium	1
cardiac ventricle	1
heart left ventricle	1
ganglionic eminence	1
ventricular zone	1
gastrocnemius	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
orbitofrontal cortex	1
left testis	1
prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNQ1	132	broad	marker	left adrenal gland cortex, left adrenal gland, right adrenal gland cortex
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
SNRPE	175	ubiquitous	marker	ganglionic eminence, ventricular zone, cortical plate
SNTA1	266	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius
CALM2	310	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex
CALM3	297	ubiquitous	marker	prefrontal cortex, right frontal lobe, left testis
CAV3	157	tissue_specific	yes	hindlimb stylopod muscle, vastus lateralis, triceps brachii
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
AKAP9	292	ubiquitous	marker	jejunal mucosa, bronchial epithelial cell, cortical plate
KCNQ1-AS1	87		yes	right ovary, hindlimb stylopod muscle, leukocyte
ANK2	281	ubiquitous	marker	substantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
KCNH2	211	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
KCNQ1OT1	194	ubiquitous	marker	tibia, cardiac muscle of right atrium, kidney epithelium
PKP2	237	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
PTGIR	170	broad	marker	ascending aorta, thoracic aorta, descending thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 13.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK2	6,423
AKAP9	3,537
KCNQ1	3,235
DSP	2,897
RYR2	2,653
CAV3	2,369
SCN5A	2,090
KCNH2	1,932
PKP2	1,861
SNTA1	1,499

Intra-cohort edges

A	B	Sources
AKAP9	KCNH2	string_interaction
AKAP9	KCNQ1	biogrid_interaction, intact, string_interaction
AKAP9	SNTA1	string_interaction
CAV3	SCN5A	string_interaction
CAV3	SNTA1	string_interaction
DSP	PKP2	string_interaction
KCNH2	KCNQ1	string_interaction
KCNH2	SCN5A	string_interaction
KCNQ1	SCN5A	string_interaction
PKP2	RYR2	string_interaction
PKP2	SCN5A	string_interaction
RYR2	SNTA1	intact
SCN5A	SNTA1	biogrid_interaction, string_interaction

Structural data

PDB: 11 · AlphaFold-only: 3 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SNRPE	P62304	84
KCNQ1	P51787	28
RYR2	Q92736	26
CALM3	P0DP25	26
KCNH2	Q12809	24
CALM2	P0DP24	21
SCN5A	Q14524	16
ANK2	Q01484	11
DSP	P15924	4
PTGIR	P43119	2
PKP2	Q99959	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CAV3	P56539	88.54
SNTA1	Q13424	80.00
AKAP9	Q99996

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 82. Enrichment computed across 16 evidence-associated genes (14 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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Muscle contraction	6	33.1×	1e-06	KCNQ1, RYR2, SCN5A, CAV3, AKAP9, KCNH2
Cardiac conduction	5	38.8×	5e-06	KCNQ1, RYR2, SCN5A, AKAP9, KCNH2
Phase 3 - rapid repolarisation	3	244.7×	5e-06	KCNQ1, AKAP9, KCNH2
CASP4 inflammasome assembly	2	181.3×	0.001	CALM2, CALM3
Enterobacterial factors antagonize host defense	2	116.5×	0.002	CALM2, CALM3
Phase 2 - plateau phase	2	108.8×	0.002	KCNQ1, AKAP9
Interaction between L1 and Ankyrins	2	52.6×	0.007	SCN5A, ANK2
Voltage gated Potassium channels	2	34.7×	0.015	KCNQ1, KCNH2
Potassium Channels	2	19.2×	0.043	KCNQ1, KCNH2
L1CAM interactions	2	17.2×	0.048	SCN5A, ANK2
Prostanoid ligand receptors	1	90.6×	0.069	PTGIR
SLBP independent Processing of Histone Pre-mRNAs	1	81.6×	0.069	SNRPE
Apoptotic cleavage of cell adhesion proteins	1	74.2×	0.069	DSP
Processing of Capped Intronless Pre-mRNA	1	74.2×	0.069	SNRPE
SLBP Dependent Processing of Replication-Dependent Histone Pre-mRNAs	1	74.2×	0.069	SNRPE
Formation of the cornified envelope	2	12.6×	0.069	DSP, PKP2
Metabolism of non-coding RNA	1	45.3×	0.105	SNRPE
Prostacyclin signalling through prostacyclin receptor	1	42.9×	0.105	PTGIR
Keratinization	2	8.0×	0.109	DSP, PKP2
Phase 0 - rapid depolarisation	1	24.7×	0.146	SCN5A
Axon guidance	2	6.5×	0.146	SCN5A, ANK2
Neuronal System	2	6.3×	0.146	KCNQ1, KCNH2
Nervous system development	2	6.1×	0.146	SCN5A, ANK2
Formation of the dystrophin-glycoprotein complex (DGC)	1	22.1×	0.152	SNTA1
Smooth Muscle Contraction	1	19.0×	0.155	CAV3
RND1 GTPase cycle	1	19.0×	0.155	DSP
RND3 GTPase cycle	1	18.5×	0.155	DSP
Centrosome maturation	1	18.1×	0.155	AKAP9
Oncogenic MAPK signaling	1	17.7×	0.155	AKAP9
mRNA Splicing - Minor Pathway	1	16.0×	0.159	SNRPE

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ventricular cardiac muscle cell action potential	8	566.5×	1e-19	KCNQ1, RYR2, SCN5A, SNTA1, CAV3, ANK2, KCNH2, PKP2
regulation of ventricular cardiac muscle cell membrane repolarization	7	421.3×	4e-16	KCNQ1, SCN5A, SNTA1, CAV3, AKAP9, ANK2, KCNH2
regulation of heart rate	7	234.1×	3e-14	RYR2, SCN5A, SNTA1, CALM2, CALM3, CAV3, ANK2
regulation of heart rate by cardiac conduction	7	187.2×	1e-13	KCNQ1, SCN5A, DSP, AKAP9, ANK2, KCNH2, PKP2
regulation of cardiac muscle contraction	5	316.8×	1e-10	RYR2, CALM2, CALM3, CAV3, ANK2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	4	192.6×	2e-07	RYR2, CALM2, CALM3, ANK2
cardiac muscle contraction	4	114.6×	1e-06	KCNQ1, RYR2, SCN5A, KCNH2
atrial cardiac muscle cell action potential	3	361.1×	2e-06	KCNQ1, SCN5A, ANK2
regulation of ventricular cardiac muscle cell action potential	3	300.9×	3e-06	RYR2, DSP, PKP2
regulation of membrane repolarization	3	277.8×	3e-06	KCNQ1, AKAP9, KCNH2
detection of calcium ion	3	240.7×	5e-06	RYR2, CALM2, CALM3
regulation of sodium ion transmembrane transport	3	225.7×	5e-06	SCN5A, SNTA1, CAV3
regulation of atrial cardiac muscle cell action potential	2	802.5×	4e-05	RYR2, ANK2
negative regulation of calcium ion export across plasma membrane	2	601.9×	7e-05	CALM2, CALM3
sarcoplasmic reticulum calcium ion transport	2	481.5×	9e-05	RYR2, ANK2
membrane depolarization during SA node cell action potential	2	481.5×	9e-05	SCN5A, ANK2
presynaptic endocytosis	2	481.5×	9e-05	CALM2, CALM3
T-tubule organization	2	401.2×	1e-04	CAV3, ANK2
regulation of ventricular cardiac muscle cell membrane depolarization	2	401.2×	1e-04	SCN5A, CAV3
SA node cell action potential	2	401.2×	1e-04	SCN5A, ANK2
regulation of SA node cell action potential	2	401.2×	1e-04	RYR2, ANK2
regulation of atrial cardiac muscle cell membrane repolarization	2	343.9×	1e-04	KCNQ1, SCN5A
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	2	343.9×	1e-04	DSP, PKP2
desmosome organization	2	300.9×	2e-04	DSP, PKP2
regulation of cardiac muscle cell action potential involved in regulation of contraction	2	267.5×	2e-04	CAV3, AKAP9
regulation of cell communication by electrical coupling involved in cardiac conduction	2	267.5×	2e-04	CALM2, CALM3
cardiac muscle hypertrophy	2	240.7×	2e-04	RYR2, CAV3
membrane depolarization during action potential	2	240.7×	2e-04	SCN5A, KCNH2
membrane repolarization during action potential	2	240.7×	2e-04	KCNQ1, KCNH2
membrane repolarization during cardiac muscle cell action potential	2	240.7×	2e-04	KCNQ1, KCNH2

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 11

Druggability breadth: 8 of 16 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.

Symbol	Example approved molecule
KCNQ1	AMBRISENTAN
SCN5A	BEPRIDIL
KCNH2	CETIRIZINE
PTGIR	TREPROSTINIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH2	706	4
SCN5A	108	4
KCNQ1	15	4
PTGIR	10	4
RYR2	1	2
SNRPE	0	0
SNTA1	0	0
CALM2	0	0
CALM3	0	0
CAV3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	KCNQ1
DULOXETINE	4	KCNH2, KCNQ1, SCN5A
PALONOSETRON	4	KCNH2, KCNQ1, SCN5A
DARUNAVIR	4	KCNH2, KCNQ1, SCN5A
DARIFENACIN	4	KCNH2, KCNQ1, SCN5A
TOLTERODINE	4	KCNH2, KCNQ1, SCN5A
SOLIFENACIN	4	KCNH2, KCNQ1, SCN5A
EVEROLIMUS	4	KCNQ1
RALTEGRAVIR	4	KCNQ1
MARAVIROC	4	KCNH2, KCNQ1
ALVIMOPAN	4	KCNQ1
NEBIVOLOL	4	KCNH2, KCNQ1, SCN5A
SUNITINIB	4	KCNH2, KCNQ1, SCN5A
NELFINAVIR	4	KCNH2, KCNQ1, SCN5A
BEPRIDIL	4	KCNH2, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	KCNH2, SCN5A
IMIPRAMINE	4	KCNH2, SCN5A
DROPERIDOL	4	KCNH2, SCN5A
PONATINIB	4	KCNH2, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	KCNH2, SCN5A
FEDRATINIB	4	KCNH2, SCN5A
QUINIDINE	4	KCNH2, SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNH2	4,851	Binding:3558, Toxicity:1071, Functional:169, ADMET:53
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5
PTGIR	156	Binding:124, Functional:31, ADMET:1
RYR2	15	Binding:15
SNRPE	7	Binding:7
DSP	2	Binding:2
CALM2	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KCNQ1	179
SCN5A	594
KCNH2	4,851
PTGIR	156

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; 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.

Compound	Max phase	Cohort target (bioactivity)
AMBRISENTAN	4	KCNQ1
DULOXETINE	4	KCNH2, KCNQ1, SCN5A
PALONOSETRON	4	KCNH2, KCNQ1, SCN5A
DARUNAVIR	4	KCNH2, KCNQ1, SCN5A
DARIFENACIN	4	KCNH2, KCNQ1, SCN5A
TOLTERODINE	4	KCNH2, KCNQ1, SCN5A
SOLIFENACIN	4	KCNH2, KCNQ1, SCN5A
EVEROLIMUS	4	KCNQ1
RALTEGRAVIR	4	KCNQ1
MARAVIROC	4	KCNH2, KCNQ1
ALVIMOPAN	4	KCNQ1
NEBIVOLOL	4	KCNH2, KCNQ1, SCN5A
SUNITINIB	4	KCNH2, KCNQ1, SCN5A
NELFINAVIR	4	KCNH2, KCNQ1, SCN5A
BEPRIDIL	4	KCNH2, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	KCNH2, SCN5A
IMIPRAMINE	4	KCNH2, SCN5A
DROPERIDOL	4	KCNH2, SCN5A
PONATINIB	4	KCNH2, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	KCNH2, SCN5A
FEDRATINIB	4	KCNH2, SCN5A
QUINIDINE	4	KCNH2, SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	KCNQ1, SCN5A, KCNH2, PTGIR
B	Phased (≥1) drug, not yet approved	1	RYR2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	11	SNRPE, SNTA1, CALM2, CALM3, CAV3, DSP, AKAP9, KCNQ1-AS1, ANK2, KCNQ1OT1 (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SNTA1	0	SCN5A
AKAP9	0	KCNQ1
PKP2	0	SCN5A
SNRPE	7	—
CALM2	1	—
CALM3	0	—
CAV3	0	—
DSP	2	—
KCNQ1-AS1	0	—
ANK2	0	—
KCNQ1OT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01745666	Not specified	UNKNOWN	Comparison Between Epinephrine and Exercise Test in QT Long Syndrome Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RACEPINEPHRINE	2	1

Cohort genes: KCNQ1, RYR2, SCN5A, SNRPE, SNTA1, CALM2, CALM3, CAV3, DSP, AKAP9, KCNQ1-AS1, ANK2, KCNH2, KCNQ1OT1, PKP2, PTGIR