Jervell and Lange-Nielsen syndrome 1

Summary

Jervell and Lange-Nielsen syndrome 1 (MONDO:0024540) is a disease caused by KCNQ1 (GenCC Definitive), with 5 cohort genes and 2 clinical trials. Top therapeutic interventions include diltiazem.

At a glance

• Causal gene: KCNQ1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 234
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Jervell and Lange-Nielsen syndrome 1
Mondo ID	MONDO:0024540
OMIM	220400
UMLS	C4551509
MedGen	1646925
GARD	0025421
Is cancer (heuristic)	no

Also known as: Jervell and Lange-Nielsen syndrome · Jervell and Lange-Nielsen syndrome 1 · Jervell and Lange-Nielsen syndrome caused by mutation in KCNQ1 · JLNS1 · KCNQ1 Jervell and Lange-Nielsen syndrome

Data availability: 234 ClinVar variants · 2 GenCC gene-disease records · 3 cell lines.

Disease family

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 › Jervell and Lange-Nielsen syndrome 1

Related subtypes (1): Jervell and Lange-Nielsen syndrome 2

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

234 retrieved; paginated sample, class counts are floors:

69 uncertain significance, 57 conflicting classifications of pathogenicity, 27 pathogenic, 26 benign/likely benign, 24 pathogenic/likely pathogenic, 10 benign, 10 likely pathogenic, 7 likely benign, 4 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3601178	NM_000219.6(KCNE1):c.122del (p.Lys41fs)	KCNE1	Pathogenic	criteria provided, single submitter
1452627	NM_000218.3(KCNQ1):c.771_775dup (p.Arg259fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3127	NM_000218.3(KCNQ1):c.914G>C (p.Trp305Ser)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3138	NM_000218.3(KCNQ1):c.1760C>T (p.Thr587Met)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
3139	KCNQ1, IVS1	KCNQ1	Pathogenic	no assertion criteria provided
3140	NM_000218.3(KCNQ1):c.1766G>A (p.Gly589Asp)	KCNQ1	Pathogenic	reviewed by expert panel
3144	NM_000218.3(KCNQ1):c.805G>A (p.Gly269Ser)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
3382790	NM_000218.3(KCNQ1):c.744G>A (p.Trp248Ter)	KCNQ1	Pathogenic	criteria provided, single submitter
3601179	NM_000218.3(KCNQ1):c.478-2A>G	KCNQ1	Pathogenic	criteria provided, single submitter
430941	NM_000218.3(KCNQ1):c.1534del (p.Ala512fs)	KCNQ1	Pathogenic	criteria provided, single submitter
438610	NM_000218.3(KCNQ1):c.733_734del (p.Gly245fs)	KCNQ1	Pathogenic	criteria provided, single submitter
449221	NM_000218.3(KCNQ1):c.200_210del (p.Pro67fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496690	NM_000218.3(KCNQ1):c.1426_1429del (p.Met476fs)	KCNQ1	Pathogenic	no assertion criteria provided
517664	NM_000218.3(KCNQ1):c.1732+5del	KCNQ1	Pathogenic	no assertion criteria provided
52930	NM_000218.3(KCNQ1):c.1014CTT[1] (p.Phe340del)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52946	NM_000218.3(KCNQ1):c.1066C>T (p.Gln356Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52950	NM_000218.3(KCNQ1):c.1075C>T (p.Gln359Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52953	NM_000218.3(KCNQ1):c.1085A>G (p.Lys362Arg)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52956	NM_000218.3(KCNQ1):c.1097G>A (p.Arg366Gln)	KCNQ1	Pathogenic/Likely 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
52978	NM_000218.3(KCNQ1):c.1343dup (p.Glu449fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52983	NM_000218.3(KCNQ1):c.1486_1487del (p.Leu496fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52996	NM_000218.3(KCNQ1):c.1588C>T (p.Gln530Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52998	NM_000218.3(KCNQ1):c.1615C>T (p.Arg539Trp)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52999	NM_000218.3(KCNQ1):c.1630_1635delinsGTTGAGA (p.Gln544fs)	KCNQ1	Pathogenic	criteria provided, single submitter
53003	NM_000218.3(KCNQ1):c.1664G>A (p.Arg555His)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53006	NM_000218.3(KCNQ1):c.1697C>T (p.Ser566Phe)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53009	NM_000218.3(KCNQ1):c.1702G>A (p.Gly568Arg)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53018	NM_000218.3(KCNQ1):c.1781G>A (p.Arg594Gln)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53025	NM_000218.3(KCNQ1):c.1892_1911del (p.Pro631fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 15 · 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
SMARCB1	Orphanet:1465	Coffin-Siris syndrome
SMARCB1	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCB1	Orphanet:2495	Meningioma
SMARCB1	Orphanet:263662	Familial multiple meningioma
SMARCB1	Orphanet:93921	Full schwannomatosis
SMARCB1	Orphanet:99966	Atypical teratoid rhabdoid tumor
KCNE1	Orphanet:101016	Romano-Ward syndrome
KCNE1	Orphanet:334	Hereditary atrial fibrillation
KCNE1	Orphanet:90647	Jervell and Lange-Nielsen syndrome
KCNQ1OT1	Orphanet:2128	Isolated hemihyperplasia
KCNQ1OT1	Orphanet:231117	Beckwith-Wiedemann syndrome due to imprinting defect of 11p15

Cohort genes → proteins

5 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	gencc,clinvar
SMARCB1	HGNC:11103	ENSG00000099956	Q12824	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	clinvar
KCNQ1-AS1	HGNC:42790	ENSG00000229414		KCNQ1 antisense RNA 1	clinvar
KCNE1	HGNC:6240	ENSG00000180509	P15382	Potassium voltage-gated channel subfamily E member 1	clinvar
KCNQ1OT1	HGNC:6295	ENSG00000269821		KCNQ1 opposite strand/antisense transcript 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.
SMARCB1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	Core component of the BAF (hSWI/SNF) complex.
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: 3 · Druggable fraction: 0.4

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	44.6×	0.002
Other/Unknown	3	1.1×	0.608

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
SMARCB1	Other/Unknown	no		SNF5, Sfh1/SNF5, INI1_DNA-bd
KCNQ1-AS1	Other/Unknown	no
KCNE1	Ion channel	yes		K_chnl_KCNE, KCNE1
KCNQ1OT1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	2
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
cortical plate	1
embryo	1
ganglionic eminence	1
hindlimb stylopod muscle	1
right ovary	1
blood	1
monocyte	1
cardiac muscle of right atrium	1
kidney epithelium	1
tibia	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
SMARCB1	214	ubiquitous	marker	embryo, ganglionic eminence, cortical plate
KCNQ1-AS1	87		yes	right ovary, hindlimb stylopod muscle, leukocyte
KCNE1	121	broad	marker	blood, monocyte, leukocyte
KCNQ1OT1	194	ubiquitous	marker	tibia, cardiac muscle of right atrium, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCB1	5,083
KCNQ1	3,235
KCNE1	1,005
KCNQ1-AS1	0
KCNQ1OT1	0

Intra-cohort edges

A	B	Sources
KCNE1	KCNQ1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ1	P51787	28
SMARCB1	Q12824	17
KCNE1	P15382	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 5 evidence-associated genes (3 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 3 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	761.3×	5e-05	KCNQ1, KCNE1
Phase 2 - plateau phase	2	507.6×	6e-05	KCNQ1, KCNE1
Cardiac conduction	2	72.5×	0.002	KCNQ1, KCNE1
Muscle contraction	2	51.4×	0.003	KCNQ1, KCNE1
Formation of the canonical BAF (cBAF) complex	1	211.5×	0.019	SMARCB1
Formation of the polybromo-BAF (pBAF) complex	1	211.5×	0.019	SMARCB1
Formation of the embryonic stem cell BAF (esBAF) complex	1	200.3×	0.019	SMARCB1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	152.3×	0.021	SMARCB1
Regulation of endogenous retroelements	1	122.8×	0.023	SMARCB1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	100.2×	0.026	SMARCB1
Regulation of MITF-M-dependent genes involved in pigmentation	1	88.5×	0.027	SMARCB1
Voltage gated Potassium channels	1	81.0×	0.027	KCNQ1
MITF-M-dependent gene expression	1	60.4×	0.033	SMARCB1
RMTs methylate histone arginines	1	48.8×	0.035	SMARCB1
Transcriptional regulation by RUNX1	1	48.8×	0.035	SMARCB1
Potassium Channels	1	44.8×	0.036	KCNQ1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	39.2×	0.038	SMARCB1
MITF-M-regulated melanocyte development	1	38.1×	0.038	SMARCB1
Chromatin organization	1	27.2×	0.050	SMARCB1
Chromatin modifying enzymes	1	24.1×	0.051	SMARCB1
Epigenetic regulation of gene expression	1	23.8×	0.051	SMARCB1
Neuronal System	1	14.8×	0.078	KCNQ1
RNA Polymerase II Transcription	1	7.5×	0.144	SMARCB1
Gene expression (Transcription)	1	6.0×	0.172	SMARCB1
Generic Transcription Pathway	1	5.0×	0.193	SMARCB1
Developmental Biology	1	4.8×	0.194	SMARCB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	1872.4×	2e-05	KCNQ1, KCNE1
cardiac muscle cell contraction	2	1123.5×	2e-05	KCNQ1, KCNE1
membrane repolarization during action potential	2	1123.5×	2e-05	KCNQ1, KCNE1
membrane repolarization during cardiac muscle cell action potential	2	1123.5×	2e-05	KCNQ1, KCNE1
membrane repolarization during ventricular cardiac muscle cell action potential	2	1123.5×	2e-05	KCNQ1, KCNE1
potassium ion export across plasma membrane	2	702.2×	3e-05	KCNQ1, KCNE1
ventricular cardiac muscle cell action potential	2	660.9×	3e-05	KCNQ1, KCNE1
positive regulation of potassium ion transmembrane transport	2	660.9×	3e-05	KCNQ1, KCNE1
regulation of ventricular cardiac muscle cell membrane repolarization	2	561.7×	4e-05	KCNQ1, KCNE1
regulation of heart rate by cardiac conduction	2	249.7×	2e-04	KCNQ1, KCNE1
cellular response to cAMP	2	193.7×	3e-04	KCNQ1, KCNE1
regulation of membrane potential	2	153.9×	4e-04	KCNQ1, KCNE1
gastrin-induced gastric acid secretion	1	5617.3×	9e-04	KCNQ1
single stranded viral RNA replication via double stranded DNA intermediate	1	5617.3×	9e-04	SMARCB1
negative regulation of voltage-gated potassium channel activity	1	5617.3×	9e-04	KCNQ1
potassium ion transmembrane transport	2	90.6×	9e-04	KCNQ1, KCNE1
rhythmic behavior	1	2808.7×	0.001	KCNQ1
vestibular nucleus development	1	2808.7×	0.001	KCNE1
corticosterone secretion	1	2808.7×	0.001	KCNQ1
stomach development	1	2808.7×	0.001	KCNQ1
sensory perception of sound	2	67.3×	0.001	KCNQ1, KCNE1
regulation of gastric acid secretion	1	1872.4×	0.002	KCNQ1
positive regulation of glucose mediated signaling pathway	1	1872.4×	0.002	SMARCB1
RNA polymerase I preinitiation complex assembly	1	1123.5×	0.003	SMARCB1
secretory granule organization	1	1123.5×	0.003	KCNE1
negative regulation of protein targeting to membrane	1	936.2×	0.003	KCNE1
membrane repolarization during atrial cardiac muscle cell action potential	1	936.2×	0.003	KCNQ1
iodide transport	1	802.5×	0.004	KCNQ1
regulation of atrial cardiac muscle cell membrane repolarization	1	802.5×	0.004	KCNQ1
DNA integration	1	702.2×	0.004	SMARCB1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
SMARCB1	0	0
KCNQ1-AS1	0	0
KCNQ1OT1	0	0

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
SMARCB1	7	Binding:7

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: 4; 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	3	SMARCB1, KCNQ1-AS1, KCNQ1OT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMARCB1	7	—
KCNQ1-AS1	0	—
KCNQ1OT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06534671	PHASE4	COMPLETED	Diltiazem in Jervell and Lange-Nielsen Syndrome
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DILTIAZEM	4	3