familial long QT syndrome

Summary

familial long QT syndrome (MONDO:0019171) is a disease (an umbrella term covering 19 Mondo subtypes) caused by variants in CALM3 and TRDN, with 37 cohort genes (5 GWAS associations across 1 studies) and 66 clinical trials. The dominant Reactome pathway is Cardiac conduction (10 cohort genes). Top therapeutic interventions include ibutilide, progesterone, and dofetilide.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal genes: CALM3 (GenCC Definitive), TRDN (GenCC Strong)
• Umbrella term: 19 Mondo subtypes
• Cohort genes: 37
• GWAS associations: 5
• ClinVar variants: 978
• Phenotypes (HPO): 13
• Clinical trials: 66

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	40	Europe	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0005184	Prolonged QTc interval	Obligate (100%)
HP:0001279	Syncope	Frequent (30-79%)
HP:0001688	Sinus bradycardia	Frequent (30-79%)
HP:0005135	Abnormal T-wave	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001645	Sudden cardiac death	Occasional (5-29%)
HP:0001664	Torsade de pointes	Occasional (5-29%)
HP:0004308	Ventricular arrhythmia	Occasional (5-29%)
HP:0012332	Abnormal autonomic nervous system physiology	Occasional (5-29%)
HP:0500018	Abnormal cardiac exercise stress test	Occasional (5-29%)
HP:0000365	Hearing impairment	Excluded (0%)
HP:0001197	Abnormality of prenatal development or birth	Very rare (<1-4%)
HP:0002900	Hypokalemia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial long QT syndrome
Mondo ID	MONDO:0019171
OMIM	192500
Orphanet	101016, 768
ICD-11	1208831985
SNOMED CT	442917000
UMLS	C1141890
MedGen	685787
GARD	0016547
MedDRA	10057926
NORD	1675
Is cancer (heuristic)	no

Also known as: congenital long QT syndrome · familial long QT syndrome · hereditary long QT syndrome · Long QT Syndrome · LQTS · Romano-Ward long QT syndrome · Romano-Ward syndrome · Ward-Romano syndrome

Data availability: 978 ClinVar variants · 5 GWAS associations (1 study) · 2 GenCC gene-disease records · 138 cell lines.

Disease family

An umbrella term covering 19 Mondo subtypes.

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

Subtypes (19): Jervell and Lange-Nielsen syndrome, Andersen-Tawil syndrome, cardiac arrhythmia, ankyrin-B-related, Timothy syndrome, long QT syndrome 3, long QT syndrome 9, long QT syndrome 10, long QT syndrome 11, long QT syndrome 12, long QT syndrome 13, long QT syndrome 2, long QT syndrome 6, long QT syndrome 5, long QT syndrome 14, long QT syndrome 15, long QT syndrome 8, long QT syndrome 16, long QT syndrome 1, long QT syndrome 4

Genetics & variants

GWAS landscape

5 GWAS associations across 1 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12143842	1e-11	OLFML2B - NOS1AP	T	1.32
rs179405	2e-08	KCNQ1	?	1.38
rs17061696	4e-08	KLF12	?	1.25
rs1805128	5e-07	KCNE1	T	2.79
rs3934467	3e-06	NOS1AP	T	1.22

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST010651	Lahrouchi N	2020	1,238	8,219	Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	4

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	3
intergenic_variant	1
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12143842	1	162064100	C>G,T	0.05	intergenic_variant	OLFML2B - NOS1AP	1e-11	Tier 4: intronic/intergenic
rs179405	11	2504165	G>A,C	0.05	intron_variant	KCNQ1	2e-08	Tier 4: intronic/intergenic
rs17061696	13	73937854	G>A,C	0.05	intron_variant	KLF12	4e-08	Tier 4: intronic/intergenic
rs1805128	21	34449382	C>T	0.05	missense_variant	KCNE1	5e-07	Tier 1: coding
rs3934467	1	162212887	C>A,G,T	0.05	intron_variant	NOS1AP	3e-06	Tier 4: intronic/intergenic

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

131 not provided, 116 uncertain significance, 106 pathogenic/likely pathogenic, 101 pathogenic, 86 conflicting classifications of pathogenicity, 56 likely pathogenic, 1 conflicting classifications of pathogenicity; other; risk factor, 1 benign/likely benign, 1 conflicting classifications of pathogenicity; risk factor, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
17632	NM_000719.7(CACNA1C):c.1216G>A (p.Gly406Arg)	CACNA1C	Pathogenic	criteria provided, multiple submitters, no conflicts
17633	NM_000719.7(CACNA1C):c.1204G>A (p.Gly402Ser)	CACNA1C	Pathogenic	criteria provided, multiple submitters, no conflicts
132654	NM_000219.6(KCNE1):c.154G>A (p.Gly52Arg)	KCNE1	Pathogenic	criteria provided, single submitter
13476	NM_000219.6(KCNE1):c.20C>T (p.Thr7Ile)	KCNE1	Pathogenic	no assertion criteria provided
6056	NM_172201.2(KCNE2):c.178T>C (p.Phe60Leu)	KCNE2	Pathogenic	no assertion criteria provided
1076966	NM_000238.4(KCNH2):c.893del (p.Pro298fs)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14420	NM_000238.4(KCNH2):c.1682C>T (p.Ala561Val)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14421	NM_000238.4(KCNH2):c.1408A>G (p.Asn470Asp)	KCNH2	Pathogenic	no assertion criteria provided
14423	NM_000238.4(KCNH2):c.1778T>G (p.Ile593Arg)	KCNH2	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
14427	NM_000238.4(KCNH2):c.1882G>A (p.Gly628Ser)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
14428	NM_000238.4(KCNH2):c.1744C>T (p.Arg582Cys)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14429	NM_000238.4(KCNH2):c.1714G>C (p.Gly572Arg)	KCNH2	Pathogenic	no assertion criteria provided
14430	NM_000238.4(KCNH2):c.1468G>A (p.Ala490Thr)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14432	NM_000238.4(KCNH2):c.2453C>T (p.Ser818Leu)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
14434	NM_000238.4(KCNH2):c.193A>C (p.Thr65Pro)	KCNH2	Pathogenic	no assertion criteria provided
14435	NM_000238.4(KCNH2):c.2255G>A (p.Arg752Gln)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14444	NM_000238.4(KCNH2):c.1672G>C (p.Ala558Pro)	KCNH2	Pathogenic	no assertion criteria provided
1698966	NM_000238.4(KCNH2):c.1819del (p.Ile607fs)	KCNH2	Pathogenic	criteria provided, single submitter
180383	NM_000238.4(KCNH2):c.2230C>T (p.Arg744Ter)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
200518	NM_000238.4(KCNH2):c.3040C>T (p.Arg1014Ter)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
200660	NM_000238.4(KCNH2):c.2724_2728dup (p.Pro910fs)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
220208	NM_000238.4(KCNH2):c.2587C>T (p.Arg863Ter)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
29777	NM_000238.4(KCNH2):c.1841C>T (p.Ala614Val)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
29778	NM_000238.4(KCNH2):c.1831T>C (p.Tyr611His)	KCNH2	Pathogenic	no assertion criteria provided
667408	NM_000238.4(KCNH2):c.1983del (p.Ile662fs)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67174	NM_000238.4(KCNH2):c.1264G>A (p.Ala422Thr)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
67177	NM_000238.4(KCNH2):c.127T>G (p.Tyr43Asp)	KCNH2	Pathogenic	criteria provided, single submitter
67182	NM_000238.4(KCNH2):c.128A>G (p.Tyr43Cys)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
67195	NM_000238.4(KCNH2):c.140G>T (p.Gly47Val)	KCNH2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 82 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 2

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
KCNE1	KCNE1	GWAS, Orphanet
KCNQ1	KCNQ1	GWAS, Orphanet

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
CALM3	Definitive	Autosomal dominant	familial long QT syndrome	5
TRDN	Strong	Autosomal recessive	familial long QT syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CALM3	Orphanet:101016	Romano-Ward syndrome
CALM3	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
KCNE1	Orphanet:101016	Romano-Ward syndrome
KCNE1	Orphanet:334	Hereditary atrial fibrillation
KCNE1	Orphanet:90647	Jervell and Lange-Nielsen syndrome
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
TRDN	Orphanet:101016	Romano-Ward syndrome
TRDN	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
SCN10A	Orphanet:101016	Romano-Ward syndrome
SCN10A	Orphanet:130	Brugada syndrome
SCN10A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN10A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN10A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN10A	Orphanet:90026	Primary erythromelalgia
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
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
SLC2A2	Orphanet:2088	Fanconi-Bickel syndrome
SNTA1	Orphanet:101016	Romano-Ward syndrome
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy

Cohort genes → proteins

37 cohort genes, 35 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	2
gwas_and_clinvar	2
multi_evidence	33

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CALM3	HGNC:1449	ENSG00000160014	P0DP25	Calmodulin-3	gencc,clinvar
KCNE1	HGNC:6240	ENSG00000180509	P15382	Potassium voltage-gated channel subfamily E member 1	gwas,clinvar
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	gwas,clinvar
TRDN	HGNC:12261	ENSG00000186439	Q13061	Triadin	gencc
BCL9	HGNC:1008	ENSG00000116128	O00512	B-cell CLL/lymphoma 9 protein	clinvar
SCN10A	HGNC:10582	ENSG00000185313	Q9Y5Y9	Sodium channel protein type 10 subunit alpha	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
SLC2A2	HGNC:11006	ENSG00000163581	P11168	Solute carrier family 2, facilitated glucose transporter member 2	clinvar
SNTA1	HGNC:11167	ENSG00000101400	Q13424	Alpha-1-syntrophin	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
VSX1	HGNC:12723	ENSG00000100987	Q9NZR4	Visual system homeobox 1	clinvar
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar
CACNA1D	HGNC:1391	ENSG00000157388	Q01668	Voltage-dependent L-type calcium channel subunit alpha-1D	clinvar
CACNA1I	HGNC:1396	ENSG00000100346	Q9P0X4	Voltage-dependent T-type calcium channel subunit alpha-1I	clinvar
MUC16	HGNC:15582	ENSG00000181143	Q8WXI7	Mucin-16	clinvar
CCND1	HGNC:1582	ENSG00000110092	P24385	G1/S-specific cyclin-D1	clinvar
MIDN	HGNC:16298	ENSG00000167470	Q504T8	Midnolin	clinvar
NOS1AP	HGNC:16859	ENSG00000198929	O75052	Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein	gwas
UFM1	HGNC:20597	ENSG00000120686	P61960	Ubiquitin-fold modifier 1	clinvar
VPS13B	HGNC:2183	ENSG00000132549	Q7Z7G8	Intermembrane lipid transfer protein VPS13B	clinvar
MBLAC1	HGNC:22180	ENSG00000214309	A4D2B0	Metallo-beta-lactamase domain-containing protein 1	clinvar
ACKR3	HGNC:23692	ENSG00000144476	P25106	Atypical chemokine receptor 3	clinvar
VEPH1	HGNC:25735	ENSG00000197415	Q14D04	Ventricular zone-expressed PH domain-containing protein homolog 1	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
FLNC-AS1	HGNC:53474	ENSG00000242902		FLNC antisense RNA 1	clinvar
ITPR3	HGNC:6182	ENSG00000096433	Q14573	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3	clinvar
KCNA10	HGNC:6219	ENSG00000143105	Q16322	Potassium voltage-gated channel subfamily A member 10	clinvar
KCNE2	HGNC:6242	ENSG00000159197	Q9Y6J6	Potassium voltage-gated channel subfamily E member 2	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	clinvar
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	clinvar
KLF12	HGNC:6346	ENSG00000118922	Q9Y4X4	Krueppel-like factor 12	gwas
PFKFB1	HGNC:8872	ENSG00000158571	P16118	6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar
PTPN13	HGNC:9646	ENSG00000163629	Q12923	Tyrosine-protein phosphatase non-receptor type 13	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
KCNE1	Potassium voltage-gated channel subfamily E member 1	Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.
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.
TRDN	Triadin	Contributes to the regulation of lumenal Ca2+ release via the sarcoplasmic reticulum calcium release channels RYR1 and RYR2, a key step in triggering skeletal and heart muscle contraction.
BCL9	B-cell CLL/lymphoma 9 protein	Involved in signal transduction through the Wnt pathway.
SCN10A	Sodium channel protein type 10 subunit alpha	Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes.
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.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
SLC2A2	Solute carrier family 2, facilitated glucose transporter member 2	Facilitative hexose transporter that mediates the transport of glucose, fructose and galactose.
SNTA1	Alpha-1-syntrophin	Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
VSX1	Visual system homeobox 1	Binds to the 37-bp core of the locus control region (LCR) of the red/green visual pigment gene cluster.
CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
CACNA1D	Voltage-dependent L-type calcium channel subunit alpha-1D	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CACNA1I	Voltage-dependent T-type calcium channel subunit alpha-1I	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
MUC16	Mucin-16	Thought to provide a protective, lubricating barrier against particles and infectious agents at mucosal surfaces.
CCND1	G1/S-specific cyclin-D1	Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition.
MIDN	Midnolin	Facilitates the ubiquitin-independent proteasomal degradation of stimulus-induced transcription factors such as FOSB, EGR1, NR4A1, and IRF4 to the proteasome for degradation.
NOS1AP	Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein	Adapter protein involved in neuronal nitric-oxide (NO) synthesis regulation via its association with nNOS/NOS1.
UFM1	Ubiquitin-fold modifier 1	Ubiquitin-like modifier which can be covalently attached via an isopeptide bond to lysine residues of substrate proteins as a monomer or a lysine-linked polymer.
VPS13B	Intermembrane lipid transfer protein VPS13B	Mediates the transfer of lipids between membranes at organelle contact sites.
MBLAC1	Metallo-beta-lactamase domain-containing protein 1	Endoribonuclease that catalyzes the hydrolysis of histone-coding pre-mRNA 3’-end.
ACKR3	Atypical chemokine receptor 3	Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degrad…
VEPH1	Ventricular zone-expressed PH domain-containing protein homolog 1	Interacts with TGF-beta receptor type-1 (TGFBR1) and inhibits dissociation of activated SMAD2 from TGFBR1, impeding its nuclear accumulation and resulting in impaired TGF-beta signaling.
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.
ITPR3	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3	Inositol 1,4,5-trisphosphate-gated calcium channel that, upon 1D-myo-inositol 1,4,5-trisphosphate binding, transports calcium from the endoplasmic reticulum lumen to cytoplasm, thus releasing the intracellular calcium and therefore partici…
KCNA10	Potassium voltage-gated channel subfamily A member 10	Voltage-gated potassium ion channel that mediates K(+) permeability of excitable membranes.
KCNE2	Potassium voltage-gated channel subfamily E member 2	Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.
KCNH2	Voltage-gated inwardly rectifying potassium channel KCNH2	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.
KCNJ2	Inward rectifier potassium channel 2	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
KLF12	Krueppel-like factor 12	Confers strong transcriptional repression to the AP-2-alpha gene.
PFKFB1	6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1	Synthesis and degradation of fructose 2,6-bisphosphate.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.
PTPN13	Tyrosine-protein phosphatase non-receptor type 13	Tyrosine phosphatase which negatively regulates FAS-induced apoptosis and NGFR-mediated pro-apoptotic signaling.

Protein-family classification

Druggable: 19 · Difficult: 6 · Unknown: 12 · Druggable fraction: 0.51

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	12	36.2×	3e-15
Phosphatase	2	4.5×	0.323
Transporter	1	2.1×	0.698
Kinase	2	1.5×	0.698
Scaffold/PPI	3	1.4×	0.698
Transcription factor	3	0.7×	0.999
GPCR	1	0.7×	0.999
Other/Unknown	12	0.6×	0.999
Enzyme (other)	1	0.3×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CALM3	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
KCNE1	Ion channel	yes		K_chnl_KCNE, KCNE1
KCNQ1	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1
TRDN	Other/Unknown	no		Asp-B-hydro/Triadin_dom, Triadin
BCL9	Transcription factor	no		Znf_RING/FYVE/PHD, Bcl-9/Bcl-9l, BCL9_beta-catenin-bd_dom
SCN10A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
SLC2A2	Transporter	yes		Glc_transpt_2, Sugar/inositol_transpt, MFS_sugar_transport-like
SNTA1	Scaffold/PPI	no		PDZ, PH_domain, PH-like_dom_sf
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
VSX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
CACNA1D	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, LVDCC_a1dsu
CACNA1I	Ion channel	yes		VDCCAlpha1, VDCC_T_a1, Ion_trans_dom
MUC16	Other/Unknown	no		SEA_dom, MUC16, SEA_dom_sf
CCND1	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
MIDN	Other/Unknown	no		Ubiquitin-like_dom, Ubiquitin-like_domsf, Midnolin
NOS1AP	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Adapter_Engulfment-Domain
UFM1	Other/Unknown	no		UFM1, Ubiquitin-like_domsf
VPS13B	Other/Unknown	no		VPS13_VAB, VPS13_N, VPS13B
MBLAC1	Other/Unknown	no		Metallo-B-lactamas, RibonucZ/Hydroxyglut_hydro, MBLAC1
ACKR3	GPCR	yes		GPCR_Rhodpsn, ACKR3, GPCR_Rhodpsn_7TM
VEPH1	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, ARM-type_fold
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
FLNC-AS1	Other/Unknown	no
ITPR3	Ion channel	yes		InsP3_rcpt, RIH_dom, Ion_trans_dom
KCNA10	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
KCNE2	Ion channel	yes		K_chnl_KCNE, K_chnl_volt-dep_bsu_KCNE2
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N
KLF12	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
PFKFB1	Enzyme (other)	yes	2.7.1.105	PG/BPGM_mutase_AS, 6Pfruct_kin, His_Pase_superF_clade-1
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2
PTPN13	Phosphatase	yes	3.1.3.48	PTP_cat, FERM_domain, Tyr_Pase_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	36
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	5
hindlimb stylopod muscle	4
gastrocnemius	3
skeletal muscle tissue of rectus abdominis	3
buccal mucosa cell	3
prefrontal cortex	2
leukocyte	2
biceps brachii	2
cortical plate	2
ventricular zone	2
olfactory bulb	2
type B pancreatic cell	2
jejunal mucosa	2
right lobe of liver	2
upper arm skin	2
corpus epididymis	2
bronchial epithelial cell	2
tendon of biceps brachii	2
pigmented layer of retina	2
pylorus	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CALM3	297	ubiquitous	marker	prefrontal cortex, right frontal lobe, left testis
KCNE1	121	broad	marker	blood, monocyte, leukocyte
KCNQ1	132	broad	marker	left adrenal gland cortex, left adrenal gland, right adrenal gland cortex
TRDN	182	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, gastrocnemius
BCL9	198	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
SCN10A	21		marker	type B pancreatic cell, olfactory bulb, diaphragm
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
SLC2A2	80	tissue_specific	marker	right lobe of liver, liver, jejunal mucosa
SNTA1	266	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
VSX1	110	tissue_specific	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
CACNA1D	219	broad	marker	buccal mucosa cell, adrenal tissue, right lung
CACNA1I	145		yes	Brodmann (1909) area 23, primary visual cortex, middle temporal gyrus
MUC16	113	broad	marker	nasal cavity epithelium, epithelium of bronchus, bronchus
CCND1	280	ubiquitous	marker	endometrium epithelium, stromal cell of endometrium, upper arm skin
MIDN	254	ubiquitous	marker	oviduct epithelium, mucosa of stomach, left uterine tube
NOS1AP	203	ubiquitous	marker	CA1 field of hippocampus, type B pancreatic cell, olfactory bulb
UFM1	295	ubiquitous	marker	corpus epididymis, choroid plexus epithelium, caput epididymis
VPS13B	291	ubiquitous	marker	sural nerve, nipple, bronchial epithelial cell
MBLAC1	173	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, prefrontal cortex
ACKR3	278	ubiquitous	marker	synovial joint, vena cava, tendon of biceps brachii
VEPH1	178	ubiquitous	marker	pigmented layer of retina, ventricular zone, kidney epithelium
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
FLNC-AS1	114		yes	hindlimb stylopod muscle, apex of heart, muscle of leg
ITPR3	262	ubiquitous	marker	cartilage tissue, pylorus, upper arm skin
KCNA10	4		yes	buccal mucosa cell, skeletal muscle tissue of rectus abdominis, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 29.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCND1	8,328
BRAF	7,394
ANK2	6,423
PTPN11	6,009
TTN	4,237
AKAP9	3,537
KCNQ1	3,235
CACNA1C	3,145
ITPR3	3,135
SLC2A2	2,839

Intra-cohort edges

A	B	Sources
AKAP9	KCNE1	string_interaction
AKAP9	KCNE2	string_interaction
AKAP9	KCNH2	string_interaction
AKAP9	KCNQ1	biogrid_interaction, intact, string_interaction
AKAP9	SNTA1	string_interaction
ANK2	ITPR3	string_interaction
ANK2	TTN	string_interaction
CACNA1C	CACNA1I	string_interaction
CACNA1C	KCNE1	string_interaction
CACNA1C	KCNE2	biogrid_interaction, string_interaction
CACNA1C	KCNH2	string_interaction
KCNE1	KCNH2	biogrid_interaction, string_interaction
KCNE1	KCNQ1	biogrid_interaction, intact, string_interaction
KCNE1	NOS1AP	string_interaction
KCNE1	SCN5A	string_interaction
KCNE1	SNTA1	string_interaction
KCNE2	KCNH2	string_interaction
KCNE2	KCNQ1	biogrid_interaction, string_interaction
KCNE2	SCN5A	string_interaction
KCNE2	SNTA1	string_interaction
KCNH2	KCNQ1	string_interaction
KCNH2	NOS1AP	string_interaction
KCNH2	SCN5A	string_interaction
KCNQ1	NOS1AP	string_interaction
KCNQ1	SCN5A	string_interaction
MUC16	TTN	string_interaction
NOS1AP	SCN5A	string_interaction
NOS1AP	SNTA1	string_interaction
SCN5A	SNTA1	biogrid_interaction, string_interaction

Structural data

PDB: 25 · AlphaFold-only: 10 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131
PTPN11	Q06124	115
TTN	Q8WZ42	64
CACNA1C	Q13936	33
KCNQ1	P51787	28
MIDN	Q504T8	27
CALM3	P0DP25	26
ITPR3	Q14573	24
KCNH2	Q12809	24
SCN5A	Q14524	16
UFM1	P61960	14
ACKR3	P25106	14
PTPN13	Q12923	12
CCND1	P24385	11
ANK2	Q01484	11
BCL9	O00512	8
SCN10A	Q9Y5Y9	8
CACNA1D	Q01668	6
KCNE1	P15382	5
CACNA1I	Q9P0X4	4
MUC16	Q8WXI7	4
KCNJ2	P63252	3
MBLAC1	A4D2B0	1
KCNE2	Q9Y6J6	1
PFKFB1	P16118	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC2A2	P11168	86.56
SNTA1	Q13424	80.00
KCNA10	Q16322	77.53
VEPH1	Q14D04	73.24
NOS1AP	O75052	65.59
VSX1	Q9NZR4	61.61
KLF12	Q9Y4X4	51.57
TRDN	Q13061	47.65
VPS13B	Q7Z7G8
AKAP9	Q99996

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 268. Enrichment computed across 37 evidence-associated genes (27 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 27 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cardiac conduction	10	40.3×	3e-12	KCNE1, KCNQ1, SCN10A, SCN5A, CACNA1C, AKAP9, ITPR3, KCNE2 (+2 more)
Muscle contraction	11	31.4×	3e-12	KCNE1, KCNQ1, SCN10A, SCN5A, CACNA1C, CACNA1I, AKAP9, ITPR3 (+3 more)
Phase 3 - rapid repolarisation	5	211.5×	1e-09	KCNE1, KCNQ1, AKAP9, KCNE2, KCNH2
Phase 2 - plateau phase	5	141.0×	1e-08	KCNE1, KCNQ1, CACNA1C, AKAP9, KCNE2
Regulation of insulin secretion	4	32.5×	3e-04	SLC2A2, CACNA1C, CACNA1D, ITPR3
Axon guidance	6	10.0×	1e-03	SCN10A, SCN5A, CACNA1C, CACNA1D, CACNA1I, ANK2
Nervous system development	6	9.5×	0.001	SCN10A, SCN5A, CACNA1C, CACNA1D, CACNA1I, ANK2
Potassium Channels	4	19.9×	0.001	KCNQ1, KCNA10, KCNH2, KCNJ2
Interaction between L1 and Ankyrins	3	40.9×	0.002	SCN10A, SCN5A, ANK2
Phase 0 - rapid depolarisation	3	38.5×	0.002	SCN10A, SCN5A, CACNA1C
NCAM signaling for neurite out-growth	3	30.2×	0.003	CACNA1C, CACNA1D, CACNA1I
NCAM1 interactions	3	27.6×	0.004	CACNA1C, CACNA1D, CACNA1I
Voltage gated Potassium channels	3	27.0×	0.004	KCNQ1, KCNA10, KCNH2
Integration of energy metabolism	3	19.5×	0.009	CACNA1C, CACNA1D, ITPR3
Spry regulation of FGF signaling	2	52.9×	0.011	BRAF, PTPN11
Regulation of RUNX1 Expression and Activity	2	49.8×	0.012	CCND1, PTPN11
Interleukin-37 signaling	2	38.5×	0.019	PTPN11, PTPN13
L1CAM interactions	3	13.4×	0.021	SCN10A, SCN5A, ANK2
Negative regulation of FGFR3 signaling	2	32.5×	0.024	BRAF, PTPN11
Negative regulation of FGFR4 signaling	2	30.2×	0.025	BRAF, PTPN11
Developmental Biology	7	3.8×	0.025	SCN10A, SCN5A, CACNA1C, CACNA1D, CACNA1I, CCND1, ANK2
Adrenaline,noradrenaline inhibits insulin secretion	2	29.2×	0.026	CACNA1C, CACNA1D
Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS)	1	423.0×	0.026	SLC2A2
Negative regulation of FGFR1 signaling	2	27.3×	0.026	BRAF, PTPN11
Negative regulation of FGFR2 signaling	2	27.3×	0.026	BRAF, PTPN11
Sensory Perception	3	10.6×	0.028	CACNA1D, ITPR3, KCNJ2
Sensory perception of taste	2	24.9×	0.028	ITPR3, KCNJ2
Neuronal System	4	6.6×	0.028	KCNQ1, KCNA10, KCNH2, KCNJ2
Sensory perception of sour taste	1	211.5×	0.044	KCNJ2
Oncogenic MAPK signaling	2	18.4×	0.047	BRAF, AKAP9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 35 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of ventricular cardiac muscle cell membrane repolarization	9	216.7×	2e-17	KCNE1, KCNQ1, SCN5A, SNTA1, NOS1AP, AKAP9, ANK2, KCNE2 (+1 more)
regulation of heart rate by cardiac conduction	10	107.0×	2e-16	KCNE1, KCNQ1, SCN5A, CACNA1C, CACNA1D, AKAP9, ANK2, KCNE2 (+2 more)
ventricular cardiac muscle cell action potential	7	198.3×	2e-13	KCNE1, KCNQ1, SCN5A, SNTA1, ANK2, KCNE2, KCNH2
cardiac muscle cell action potential involved in contraction	7	140.4×	3e-12	KCNE1, SCN10A, SCN5A, CACNA1C, CACNA1D, KCNE2, KCNJ2
membrane repolarization during action potential	5	240.7×	6e-10	KCNE1, KCNQ1, KCNE2, KCNH2, KCNJ2
regulation of membrane repolarization	5	185.2×	2e-09	KCNQ1, AKAP9, KCNE2, KCNH2, KCNJ2
positive regulation of potassium ion transmembrane transport	5	141.6×	1e-08	KCNE1, KCNQ1, NOS1AP, KCNH2, KCNJ2
membrane repolarization during cardiac muscle cell action potential	4	192.6×	1e-07	KCNE1, KCNQ1, KCNH2, KCNJ2
membrane repolarization during ventricular cardiac muscle cell action potential	4	192.6×	1e-07	KCNE1, KCNQ1, KCNE2, KCNH2
membrane depolarization during cardiac muscle cell action potential	4	160.5×	3e-07	SCN5A, CACNA1C, CACNA1D, KCNJ2
regulation of heart rate	5	66.9×	4e-07	CALM3, SCN10A, SCN5A, SNTA1, ANK2
potassium ion export across plasma membrane	4	120.4×	9e-07	KCNE1, KCNQ1, KCNE2, KCNH2
membrane depolarization during SA node cell action potential	3	288.9×	3e-06	SCN5A, CACNA1D, ANK2
negative regulation of delayed rectifier potassium channel activity	3	240.7×	5e-06	KCNE1, KCNQ1, KCNE2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	4	77.0×	5e-06	CALM3, TRDN, CACNA1C, ANK2
potassium ion transmembrane transport	6	23.3×	5e-06	KCNE1, KCNQ1, KCNA10, KCNE2, KCNH2, KCNJ2
regulation of potassium ion transmembrane transport	4	71.3×	6e-06	KCNE1, CACNA1D, KCNE2, KCNH2
regulation of atrial cardiac muscle cell membrane repolarization	3	206.3×	6e-06	KCNQ1, SCN5A, CACNA1D
membrane depolarization during action potential	3	144.4×	2e-05	SCN10A, SCN5A, KCNH2
atrial cardiac muscle cell action potential	3	144.4×	2e-05	KCNQ1, SCN5A, ANK2
cardiac muscle contraction	4	45.9×	3e-05	KCNQ1, SCN5A, TTN, KCNH2
membrane repolarization	3	111.1×	4e-05	KCNE1, KCNE2, KCNH2
potassium ion import across plasma membrane	4	41.9×	4e-05	KCNQ1, KCNE2, KCNH2, KCNJ2
regulation of cardiac muscle cell contraction	3	96.3×	6e-05	SCN5A, ANK2, KCNJ2
bundle of His cell action potential	2	481.5×	7e-05	SCN10A, SCN5A
response to calcium ion	4	36.3×	7e-05	CALM3, TTN, CCND1, ITPR3
regulation of cardiac muscle contraction	3	76.0×	1e-04	CALM3, SCN10A, ANK2
membrane depolarization during atrial cardiac muscle cell action potential	2	321.0×	2e-04	SCN5A, CACNA1C
cellular response to xenobiotic stimulus	4	27.5×	2e-04	KCNQ1, BRAF, KCNE2, KCNH2
AV node cell action potential	2	240.7×	3e-04	SCN10A, SCN5A

Therapeutics

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 13 · Phased (≥1): 13 · Undrugged: 24

Druggability breadth: 22 of 37 evidence-associated genes (59%) 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
KCNE1	AMBRISENTAN
KCNQ1	AMBRISENTAN
SCN10A	IMIPRAMINE
SCN5A	BEPRIDIL
BRAF	VEMURAFENIB
CACNA1C	REMIFENTANIL
CACNA1D	BEPRIDIL
CACNA1I	NIMODIPINE
CCND1	PALBOCICLIB
KCNH2	CETIRIZINE
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH2	706	4
SCN5A	108	4
CACNA1C	85	4
BRAF	48	4
CACNA1D	48	4
CCND1	35	4
SCN10A	21	4
KCNQ1	15	4
KCNE1	14	4
PTPN11	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	KCNE1, KCNQ1
DULOXETINE	4	CACNA1C, CACNA1D, KCNE1, KCNH2, KCNQ1, SCN5A
PALONOSETRON	4	KCNE1, KCNH2, KCNQ1, SCN5A
DARUNAVIR	4	KCNE1, KCNH2, KCNQ1, SCN5A
DARIFENACIN	4	KCNE1, KCNH2, KCNQ1, SCN5A
TOLTERODINE	4	CACNA1C, KCNE1, KCNH2, KCNQ1, SCN5A
SOLIFENACIN	4	CACNA1C, CACNA1D, KCNE1, KCNH2, KCNQ1, SCN5A
EVEROLIMUS	4	KCNE1, KCNQ1
RALTEGRAVIR	4	KCNE1, KCNQ1
MARAVIROC	4	KCNE1, KCNH2, KCNQ1
ALVIMOPAN	4	CACNA1C, KCNE1, KCNQ1
NEBIVOLOL	4	CACNA1C, KCNE1, KCNH2, KCNQ1, SCN5A
SUNITINIB	4	CACNA1C, CACNA1D, KCNE1, KCNH2, KCNQ1, SCN5A
NELFINAVIR	4	KCNE1, KCNH2, KCNQ1, SCN5A
IMIPRAMINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
SERTINDOLE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
PIMOZIDE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
NIFEDIPINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
DILTIAZEM	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
MIBEFRADIL	4	CACNA1C, CACNA1D, CACNA1I, KCNH2, SCN10A, SCN5A
HALOPERIDOL	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
MEXILETINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
AMITRIPTYLINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
AMIODARONE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
CHLORPROMAZINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
LAMOTRIGINE	4	SCN10A, SCN5A
BEPRIDIL	4	CACNA1C, CACNA1D, KCNH2, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
CCND1	576	Binding:574, Functional:1, ADMET:1
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
CACNA1D	233	Binding:145, Functional:81, Toxicity:5, ADMET:2
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5
SCN10A	144	Binding:124, Functional:16, ADMET:4
BCL9	125	Binding:125
KCNE1	117	Functional:63, Binding:47, ADMET:6, Toxicity:1
ACKR3	102	Binding:77, Functional:24, ADMET:1
CACNA1I	56	Binding:44, Functional:9, ADMET:3
KCNJ2	31	Binding:23, ADMET:8
PTPN13	23	Binding:22, ADMET:1
KCNA10	22	Binding:20, Toxicity:1, ADMET:1
SLC2A2	12	Binding:11, Functional:1
ITPR3	11	Binding:9, Functional:2
PFKFB1	2	Binding:2
TTN	1	Binding:1
UFM1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
TTN	2.7.11.1	non-specific serine/threonine protein kinase
PFKFB1	2.7.1.105, 3.1.3.46	6-phosphofructo-2-kinase, fructose-2,6-bisphosphate 2-phosphatase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase
PTPN13	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KCNE1	117
KCNQ1	179
BCL9	125
SCN10A	144
SCN5A	594
BRAF	1,442
CACNA1C	575
CACNA1D	233
CCND1	576
ACKR3	102
KCNH2	4,851
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 35; 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	KCNE1, KCNQ1
DULOXETINE	4	CACNA1C, CACNA1D, KCNE1, KCNH2, KCNQ1, SCN5A
PALONOSETRON	4	KCNE1, KCNH2, KCNQ1, SCN5A
DARUNAVIR	4	KCNE1, KCNH2, KCNQ1, SCN5A
DARIFENACIN	4	KCNE1, KCNH2, KCNQ1, SCN5A
TOLTERODINE	4	CACNA1C, KCNE1, KCNH2, KCNQ1, SCN5A
SOLIFENACIN	4	CACNA1C, CACNA1D, KCNE1, KCNH2, KCNQ1, SCN5A
EVEROLIMUS	4	KCNE1, KCNQ1
RALTEGRAVIR	4	KCNE1, KCNQ1
MARAVIROC	4	KCNE1, KCNH2, KCNQ1
ALVIMOPAN	4	CACNA1C, KCNE1, KCNQ1
NEBIVOLOL	4	CACNA1C, KCNE1, KCNH2, KCNQ1, SCN5A
SUNITINIB	4	CACNA1C, CACNA1D, KCNE1, KCNH2, KCNQ1, SCN5A
NELFINAVIR	4	KCNE1, KCNH2, KCNQ1, SCN5A
IMIPRAMINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
SERTINDOLE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
PIMOZIDE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
NIFEDIPINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
DILTIAZEM	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
MIBEFRADIL	4	CACNA1C, CACNA1D, CACNA1I, KCNH2, SCN10A, SCN5A
HALOPERIDOL	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
MEXILETINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
AMITRIPTYLINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
AMIODARONE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
CHLORPROMAZINE	4	CACNA1C, CACNA1D, KCNH2, SCN10A, SCN5A
LAMOTRIGINE	4	SCN10A, SCN5A
BEPRIDIL	4	CACNA1C, CACNA1D, KCNH2, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	KCNE1, KCNQ1, SCN10A, SCN5A, BRAF, CACNA1C, CACNA1D, CACNA1I, CCND1, KCNH2 (+1 more)
B	Phased (≥1) drug, not yet approved	2	BCL9, SLC2A2
C	Druggable family + PDB, no drug	7	TTN, ACKR3, ITPR3, KCNE2, KCNJ2, PFKFB1, PTPN13
D	Druggable family + AlphaFold only, no drug	1	KCNA10
E	Difficult family or no structure, no drug	16	CALM3, TRDN, SNTA1, VSX1, MUC16, MIDN, NOS1AP, UFM1, VPS13B, MBLAC1 (+6 more)

Undrugged target profiles

24 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, KCNE1
KCNE2	0	KCNQ1, KCNH2, SCN5A
ACKR3	102	—
CALM3	0	—
TRDN	0	—
TTN	1	—
VSX1	0	—
MUC16	0	—
MIDN	0	—
NOS1AP	0	—
UFM1	1	—
VPS13B	0	—
MBLAC1	0	—
VEPH1	0	—
KCNQ1-AS1	0	—
ANK2	0	—
FLNC-AS1	0	—
ITPR3	11	—
KCNA10	22	—
KCNJ2	31	—
KLF12	0	—
PFKFB1	2	—
PTPN13	23	—

Clinical trials & evidence

Clinical trials

Clinical trials: 66.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	52
PHASE1	6
PHASE4	4
PHASE2	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT03775954	Not specified	RECRUITING	Fetal Electrophysiologic Abnormalities in High-Risk Pregnancies Associated With Fetal Demise
NCT04189822	Not specified	ENROLLING_BY_INVITATION	Hearts in Rhythm Organization (HiRO)National Registry and Bio Bank
NCT04336644	Not specified	RECRUITING	Continuous Versus Intermittent cARdiac Electrical moNitorinG
NCT05348564	Not specified	RECRUITING	Comparing Direct vs Indirect Methods for Cascade Screening
NCT05521451	Not specified	RECRUITING	Clinical Cohort Study - TRUST
NCT06087367	Not specified	RECRUITING	Building of a Diagnostic/Prognostic Database for Human ERG Variant Effects
NCT06546137	Not specified	RECRUITING	National Network for Cardiovascular Genomics: Advancing Cardiovascular Healthcare for Hereditary Diseases in Brazil’s Unified Health System Through a Multicenter Registry
NCT06661278	Not specified	RECRUITING	Evaluation of Exercise Testing and Physical Activity in Children and Adolescents Living With Inherited Arrhythmias
NCT06887387	Not specified	RECRUITING	Wearable Devices for Patient Monitoring in Long QT Syndrome
NCT07233421	Not specified	ENROLLING_BY_INVITATION	Frequency of Hypoglycemia in Children With Beta-blocker Treated Long QT-syndrome
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IBUTILIDE	4	3
PROGESTERONE	4	3
DOFETILIDE	4	2
TESTOSTERONE	4	2
ADENOSINE	4	1
LUMACAFTOR	4	1
PREDNISONE	4	1
RANOLAZINE	4	1
ELECLAZINE	3	4
PRINABEREL	2	1
CHEMBL4746472	0	2
CHEMBL15720	0	1
CHEMBL606298	0	1