Jervell and Lange-Nielsen syndrome

Summary

Jervell and Lange-Nielsen syndrome (MONDO:0002441) is a disease caused by KCNQ1 (GenCC Definitive), with 2 cohort genes and 4 clinical trials. Top therapeutic interventions include diltiazem, ibutilide, and progesterone.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KCNQ1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 14
• Phenotypes (HPO): 11
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.3	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0005184	Prolonged QTc interval	Very frequent (80-99%)
HP:0008619	Bilateral sensorineural hearing impairment	Very frequent (80-99%)
HP:0011476	Profound sensorineural hearing impairment	Very frequent (80-99%)
HP:0001279	Syncope	Frequent (30-79%)
HP:0001664	Torsade de pointes	Frequent (30-79%)
HP:0007185	Loss of consciousness	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0030973	Postexertional malaise	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001663	Ventricular fibrillation	Occasional (5-29%)
HP:0001891	Iron deficiency anemia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Jervell and Lange-Nielsen syndrome
Mondo ID	MONDO:0002441
MeSH	D029593
OMIM	220400
Orphanet	90647
DOID	DOID:2842
NCIT	C84793
SNOMED CT	373905003
UMLS	C0022387
MedGen	5929
GARD	0003048
MedDRA	10057936
NORD	1310
Is cancer (heuristic)	no

Also known as: Cardioauditory syndrome of Jervell and Lange-Nielsen · deafness, congenital, and functional heart disease · Jervell and Lange Nielsen syndrome · Jervell and Lange-Nielsen syndrome 1 · Jervell and Lange-Nielsen syndrome type 1 · Jervell Lange-Nielsen syndrome · JLNS1 · long QT interval-deafness syndrome · prolonged QT interval in EKG and sudden death · Surdo-cardiac syndrome

Data availability: 14 ClinVar variants · 1 GenCC gene-disease record · 3 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › long QT syndrome › familial long QT syndrome › Jervell and Lange-Nielsen syndrome

Related subtypes (18): 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

Subtypes (2): Jervell and Lange-Nielsen syndrome 2, Jervell and Lange-Nielsen 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

14 retrieved; paginated sample, class counts are floors:

6 pathogenic/likely pathogenic, 4 likely pathogenic, 3 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
200891	NM_000218.3(KCNQ1):c.403del (p.Val135fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3118	NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)	KCNQ1	Pathogenic	reviewed by expert panel
405268	NM_000218.3(KCNQ1):c.1175G>A (p.Trp392Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52974	NM_000218.3(KCNQ1):c.1265dup (p.Phe423fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53050	NM_000218.3(KCNQ1):c.488del (p.Leu163fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53072	NM_000218.3(KCNQ1):c.573_577del (p.Arg192fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
53077	NM_000218.3(KCNQ1):c.604G>A (p.Asp202Asn)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53084	NM_000218.3(KCNQ1):c.683+5G>A	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53092	NM_000218.3(KCNQ1):c.728G>A (p.Arg243His)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189232	NM_000218.3(KCNQ1):c.826del (p.Ser276fs)	KCNQ1	Likely pathogenic	criteria provided, single submitter
3075923	NM_000218.3(KCNQ1):c.1732+1G>T	KCNQ1	Likely pathogenic	criteria provided, single submitter
3384908	NM_000218.3(KCNQ1):c.1686-2A>C	KCNQ1	Likely pathogenic	criteria provided, single submitter
53047	NM_000218.3(KCNQ1):c.477+5G>A	KCNQ1	Likely pathogenic	reviewed by expert panel
13477	NM_000219.6(KCNE1):c.226G>A (p.Asp76Asn)	KCNE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 7 · 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 recessive	Jervell and Lange-Nielsen syndrome	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
KCNE1	Orphanet:101016	Romano-Ward syndrome
KCNE1	Orphanet:334	Hereditary atrial fibrillation
KCNE1	Orphanet:90647	Jervell and Lange-Nielsen syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	gencc,clinvar
KCNE1	HGNC:6240	ENSG00000180509	P15382	Potassium voltage-gated channel subfamily E member 1	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.
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	2	111.5×	8e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNQ1	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1
KCNE1	Ion channel	yes		K_chnl_KCNE, KCNE1

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
blood	1
leukocyte	1
monocyte	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
KCNE1	121	broad	marker	blood, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ1	3,235
KCNE1	1,005

Intra-cohort edges

A	B	Sources
KCNE1	KCNQ1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ1	P51787	28
KCNE1	P15382	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Phase 3 - rapid repolarisation	2	1142.0×	5e-06	KCNQ1, KCNE1
Phase 2 - plateau phase	2	761.3×	6e-06	KCNQ1, KCNE1
Cardiac conduction	2	108.8×	2e-04	KCNQ1, KCNE1
Muscle contraction	2	77.2×	3e-04	KCNQ1, KCNE1
Voltage gated Potassium channels	1	121.5×	0.012	KCNQ1
Potassium Channels	1	67.2×	0.017	KCNQ1
Neuronal System	1	22.1×	0.045	KCNQ1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of delayed rectifier potassium channel activity	2	2808.7×	4e-06	KCNQ1, KCNE1
cardiac muscle cell contraction	2	1685.2×	4e-06	KCNQ1, KCNE1
membrane repolarization during action potential	2	1685.2×	4e-06	KCNQ1, KCNE1
membrane repolarization during cardiac muscle cell action potential	2	1685.2×	4e-06	KCNQ1, KCNE1
membrane repolarization during ventricular cardiac muscle cell action potential	2	1685.2×	4e-06	KCNQ1, KCNE1
potassium ion export across plasma membrane	2	1053.2×	7e-06	KCNQ1, KCNE1
ventricular cardiac muscle cell action potential	2	991.3×	7e-06	KCNQ1, KCNE1
positive regulation of potassium ion transmembrane transport	2	991.3×	7e-06	KCNQ1, KCNE1
regulation of ventricular cardiac muscle cell membrane repolarization	2	842.6×	9e-06	KCNQ1, KCNE1
regulation of heart rate by cardiac conduction	2	374.5×	4e-05	KCNQ1, KCNE1
cellular response to cAMP	2	290.6×	6e-05	KCNQ1, KCNE1
regulation of membrane potential	2	230.8×	9e-05	KCNQ1, KCNE1
potassium ion transmembrane transport	2	135.9×	2e-04	KCNQ1, KCNE1
sensory perception of sound	2	100.9×	4e-04	KCNQ1, KCNE1
gastrin-induced gastric acid secretion	1	8426.0×	4e-04	KCNQ1
negative regulation of voltage-gated potassium channel activity	1	8426.0×	4e-04	KCNQ1
rhythmic behavior	1	4213.0×	7e-04	KCNQ1
vestibular nucleus development	1	4213.0×	7e-04	KCNE1
corticosterone secretion	1	4213.0×	7e-04	KCNQ1
stomach development	1	4213.0×	7e-04	KCNQ1
regulation of gastric acid secretion	1	2808.7×	0.001	KCNQ1
secretory granule organization	1	1685.2×	0.002	KCNE1
negative regulation of protein targeting to membrane	1	1404.3×	0.002	KCNE1
membrane repolarization during atrial cardiac muscle cell action potential	1	1404.3×	0.002	KCNQ1
iodide transport	1	1203.7×	0.002	KCNQ1
regulation of atrial cardiac muscle cell membrane repolarization	1	1203.7×	0.002	KCNQ1
positive regulation of cardiac muscle contraction	1	1053.2×	0.002	KCNQ1
regulation of potassium ion transport	1	936.2×	0.002	KCNE1
auditory receptor cell development	1	936.2×	0.002	KCNQ1
adrenergic receptor signaling pathway	1	936.2×	0.002	KCNQ1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
KCNE1	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ1	15	4
KCNE1	14	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	KCNE1, KCNQ1
DULOXETINE	4	KCNE1, KCNQ1
PALONOSETRON	4	KCNE1, KCNQ1
DARUNAVIR	4	KCNE1, KCNQ1
DARIFENACIN	4	KCNE1, KCNQ1
TOLTERODINE	4	KCNE1, KCNQ1
SOLIFENACIN	4	KCNE1, KCNQ1
EVEROLIMUS	4	KCNE1, KCNQ1
RALTEGRAVIR	4	KCNE1, KCNQ1
MARAVIROC	4	KCNE1, KCNQ1
ALVIMOPAN	4	KCNE1, KCNQ1
NEBIVOLOL	4	KCNE1, KCNQ1
SUNITINIB	4	KCNE1, KCNQ1
NELFINAVIR	4	KCNE1, KCNQ1
VOLINANSERIN	3	KCNQ1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5
KCNE1	117	Functional:63, Binding:47, ADMET:6, Toxicity: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
KCNE1	117

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

15 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	KCNE1, KCNQ1
PALONOSETRON	4	KCNE1, KCNQ1
DARUNAVIR	4	KCNE1, KCNQ1
DARIFENACIN	4	KCNE1, KCNQ1
TOLTERODINE	4	KCNE1, KCNQ1
SOLIFENACIN	4	KCNE1, KCNQ1
EVEROLIMUS	4	KCNE1, KCNQ1
RALTEGRAVIR	4	KCNE1, KCNQ1
MARAVIROC	4	KCNE1, KCNQ1
ALVIMOPAN	4	KCNE1, KCNQ1
NEBIVOLOL	4	KCNE1, KCNQ1
SUNITINIB	4	KCNE1, KCNQ1
NELFINAVIR	4	KCNE1, KCNQ1
VOLINANSERIN	3	KCNQ1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KCNQ1, KCNE1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06534671	PHASE4	COMPLETED	Diltiazem in Jervell and Lange-Nielsen Syndrome
NCT01929083	PHASE2	COMPLETED	Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DILTIAZEM	4	3
IBUTILIDE	4	1
PROGESTERONE	4	1