Jervell and Lange-Nielsen syndrome 2 (JLNS2) is an ultra-rare autosomal recessive cardioauditory channelopathy caused by biallelic loss-of-function variants in KCNE1, which encodes MinK, the single-transmembrane-domain beta subunit that assembles with the KCNQ1 alpha subunit to form the slow delayed-rectifier potassium (IKs) channel. JLNS2 is the allelic recessive counterpart of KCNE1-related autosomal dominant long QT syndrome (LQT5): a single heterozygous KCNE1 variant produces, at best, a low-penetrance dominant QT-prolongation phenotype, while biallelic loss essentially abolishes IKs current and produces the severe recessive JLNS phenotype. The IKs channel is expressed in both cardiac myocytes, where it contributes to repolarization of the ventricular action potential, and in the marginal cells of the stria vascularis of the inner ear, where it drives potassium secretion into the endolymph that generates and maintains the endocochlear potential required for hair-cell mechanotransduction. Biallelic KCNE1 loss therefore produces a two-organ phenotype: congenital profound bilateral sensorineural deafness from collapse of the endocochlear potential, together with marked QT-interval prolongation and a risk of torsade de pointes, ventricular fibrillation, syncope, and sudden cardiac death from loss of ventricular repolarization reserve. JLNS2 is distinguished from the more common JLNS1 (biallelic KCNQ1 variants) only by the causal gene, and the two are clinically similar at the bedside, but JLNS2 is markedly rarer - approximately 90% of JLNS cases are attributable to KCNQ1 and only about 10% to KCNE1 - and the limited comparative data available suggest a milder arrhythmic course than JLNS1. This entry is careful not to import JLNS1 (KCNQ1) case series, severity estimates, or vestibular-dysfunction findings, which are curated separately.
Ask a research question about Jervell and Lange-Nielsen Syndrome 2. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: Jervell and Lange-Nielsen Syndrome 2
creation_date: "2026-08-17T00:00:00Z"
description: >-
Jervell and Lange-Nielsen syndrome 2 (JLNS2) is an ultra-rare autosomal
recessive cardioauditory channelopathy caused by biallelic loss-of-function
variants in KCNE1, which encodes MinK, the single-transmembrane-domain beta
subunit that assembles with the KCNQ1 alpha subunit to form the slow
delayed-rectifier potassium (IKs) channel. JLNS2 is the allelic recessive
counterpart of KCNE1-related autosomal dominant long QT syndrome (LQT5):
a single heterozygous KCNE1 variant produces, at best, a low-penetrance
dominant QT-prolongation phenotype, while biallelic loss essentially
abolishes IKs current and produces the severe recessive JLNS phenotype. The
IKs channel is expressed in both cardiac myocytes, where it contributes to
repolarization of the ventricular action potential, and in the marginal
cells of the stria vascularis of the inner ear, where it drives potassium
secretion into the endolymph that generates and maintains the endocochlear
potential required for hair-cell mechanotransduction. Biallelic KCNE1 loss
therefore produces a two-organ phenotype: congenital profound bilateral
sensorineural deafness from collapse of the endocochlear potential, together
with marked QT-interval prolongation and a risk of torsade de pointes,
ventricular fibrillation, syncope, and sudden cardiac death from loss of
ventricular repolarization reserve. JLNS2 is distinguished from the more
common JLNS1 (biallelic KCNQ1 variants) only by the causal gene, and the two
are clinically similar at the bedside, but JLNS2 is markedly rarer -
approximately 90% of JLNS cases are attributable to KCNQ1 and only about 10%
to KCNE1 - and the limited comparative data available suggest a milder
arrhythmic course than JLNS1. This entry is careful not to import JLNS1
(KCNQ1) case series, severity estimates, or vestibular-dysfunction findings,
which are curated separately.
category: Mendelian
disease_term:
preferred_term: Jervell and Lange-Nielsen syndrome 2
term:
id: MONDO:0012871
label: Jervell and Lange-Nielsen syndrome 2
synonyms:
- JLNS2
- Jervell and Lange-Nielsen syndrome type 2
- Jervell and Lange-Nielsen syndrome caused by mutation in KCNE1
- KCNE1 Jervell and Lange-Nielsen syndrome
parents:
- Jervell and Lange-Nielsen Syndrome
- Cardiac Arrhythmia
- Channelopathy
- Sensorineural Hearing Loss
notes: >-
IDENTITY / NEC NOTE. MONDO:0012871 (OMIM:612347) is explicitly defined as
"Any Jervell and Lange-Nielsen syndrome in which the cause of the disease is
a mutation in the KCNE1 gene" and asserts RO:0004003 to HGNC:6240 (KCNE1);
it is_a both MONDO:0002441 (Jervell and Lange-Nielsen syndrome) and
MONDO:0013372 (long QT syndrome 5). This entry is curated strictly against
the KCNE1 identity. The allelic, more common recessive form caused by
biallelic KCNQ1 variants (JLNS1, MONDO:0024540) is curated separately and no
JLNS1-specific case data, prevalence figures, or phenotype findings
(including the KCNQ1-genotyped vestibular-dysfunction series of Winbo et al.,
PMID:25471708, whose 14/14 genotyped subjects all carried double KCNQ1
mutations) are imported here.
RARITY. JLNS2 is markedly rarer than JLNS1: approximately 90% of JLNS cases
are attributable to KCNQ1 variants and only about 10% to KCNE1 (PMID:42389506).
A 2025 functional-profiling study of 95 KCNE1 variants estimated a JLNS2
population carrier frequency of 1 in 1034 using Hardy-Weinberg principles
applied to gnomAD allele counts of dysfunctional variants (PMID:41200805).
The largest genotype-confirmed JLNS2 cohort assembled to date is 19 patients,
drawn from an international multicenter LQT5 study (PMID:31941373). Case
counts and severity figures in this entry are held to that scale rather than
to JLNS1's more extensively reported literature.
ALLELIC SPECTRUM. KCNE1 produces a genotype-phenotype spectrum rather than a
strict dominant/recessive dichotomy: heterozygous carriers of KCNE1
loss-of-function variants are usually clinically silent or show only a low
ECG penetrance (dominant LQT5), while biallelic null alleles are required for
the fully penetrant recessive JLNS2 phenotype (PMID:30461122, PMID:41200805).
ClinGen's gene curation working group considers the evidence for autosomal
dominant KCNE1-LQT5 causality disputed even though KCNE1 is an accepted
cause of recessive JLNS2 (PMID:41200805). Long_QT_Syndrome.yaml curates the
dominant LQT5 (Type 5) subtype of that spectrum; this entry curates the
distinct, more severe biallelic phenotype.
HUMAN/MOUSE VESTIBULAR MISMATCH. Kcne1-/- mice show clear structural and
functional vestibular involvement (endolymphatic-space abnormality,
vestibular dark cell and hair cell degeneration, impaired vestibular
function rescued by gene therapy; PMID:33514733). No genotype-confirmed
human vestibular data specific to KCNE1/JLNS2 patients have been identified;
the only quantitative human vestibular study of JLNS (PMID:25471708) enrolled
exclusively double-KCNQ1 (JLNS1) cases. This is recorded as a
HUMAN_MODEL_MISMATCH discussion rather than as an established human
phenotype.
MODULE CONFORMANCE SCOPE. The cardiac branch declares conforms_to against
cardiac_ion_channel_repolarization. The cochlear branch declares conforms_to
against sensorineural_hair_cell_loss starting at "Cochlear Ionic Homeostasis
Disruption and Oxidative Stress" (whose own description explicitly names
potassium-recycling/endocochlear-potential failure as a covered mechanism),
rather than at the module's "Cochlear Sensory Epithelium Insult" entry node,
because the primary JLNS2 lesion is a stria vascularis marginal-cell ionic
defect rather than a primary hair-cell stereociliary/mechanotransduction
defect.
mappings:
mondo_mappings:
- term:
id: MONDO:0012871
label: Jervell and Lange-Nielsen syndrome 2
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
MONDO:0012871 is the primary disease term for this entry, cross-referenced
to OMIM:612347, with KCNE1 (HGNC:6240) asserted as the causal gene via
RO:0004003.
inheritance:
- name: Autosomal Recessive
description: >-
JLNS2 is inherited in an autosomal recessive manner. Affected individuals
are homozygous or compound heterozygous for KCNE1 loss-of-function
variants; parents are typically heterozygous carriers who are usually
clinically unaffected or show only mild, incompletely penetrant QT
prolongation (the allelic dominant LQT5 phenotype). At conception, each
sib of an affected individual has a 25% chance of being affected, a 50%
chance of being an asymptomatic or mildly affected carrier, and a 25%
chance of being unaffected and non-carrier.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS are usually heterozygotes; rarely, only one parent is heterozygous"
explanation: >-
GeneReviews establishes the autosomal recessive inheritance pattern and
typical carrier status of parents.
- reference: PMID:30461122
reference_title: "Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2"
explanation: >-
Documents that biallelic KCNE1 loss of function, not heterozygosity, is
required for the fully penetrant JLNS2 phenotype.
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "At conception, each sib of an affected individual usually has a 25% chance of being affected with JLNS, a 50% chance of being a carrier of a JLNS-causing pathogenic variant and potentially at risk for LQTS, and a 25% chance of being unaffected and not a carrier."
explanation: >-
GeneReviews states the exact per-pregnancy recurrence-risk figures
(25% affected, 50% carrier, 25% unaffected non-carrier) summarized in
this node's description.
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: ULTRA_RARE
notes: >-
No direct birth-prevalence estimate for JLNS2 specifically has been
published; JLNS overall (both genes) is estimated at roughly 1 in 200,000
to 1 in 1,000,000, and approximately 90% of genotyped JLNS cases are
attributable to KCNQ1 rather than KCNE1, making JLNS2 a small minority of
an already rare disease.
evidence:
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: OTHER
snippet: "Approximately 90% of cases of JLNS are associated with KCNQ1 variants, and the remaining cases are attributable to KCNE1 variants"
explanation: >-
Establishes that KCNE1 (JLNS2) accounts for only a minority of genotyped
JLNS cases, the basis for treating JLNS2 as markedly rarer than JLNS1.
- population: Worldwide (carrier frequency, functional-variant estimate)
measure_type: CARRIER_FREQUENCY
prevalence_class: NOT_YET_DOCUMENTED
rate_per_100000: 96.7
notes: >-
Estimated by applying Hardy-Weinberg principles to gnomAD allele counts of
KCNE1 variants shown experimentally to reduce IKs current density below 50%
of wild type; 1 in 1034 converts to approximately 96.7 per 100,000. This is
a carrier-frequency estimate, not a measured disease birth prevalence.
evidence:
- reference: PMID:41200805
reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "The population carrier frequency of JLN2 was calculated as 1 in 1034."
explanation: >-
Direct quantitative carrier-frequency estimate for JLNS2 derived from
high-throughput functional profiling of KCNE1 variants combined with
population allele-frequency data.
genetic:
- name: KCNE1
notes: >-
KCNE1 (21q22.11) encodes MinK, a 129-amino-acid single-transmembrane-domain
protein that is the regulatory beta subunit of the IKs channel; it must
coassemble with the KCNQ1 (Kv7.1) alpha subunit to generate the slow
delayed-rectifier potassium current. A 2025 high-throughput voltage-clamp
screen of 95 KCNE1 variants found that about half exhibited peak current
densities significantly different from wild type when studied in the
homozygous state, with most dysfunctional variants showing loss-of-function
properties and no apparent dominant-negative effect on the specific
variant panel tested when variant and wild-type KCNE1 were coexpressed.
This is not a categorical claim that KCNE1 variants are never
dominant-negative: a separate study of KCNE1 nonsense alleles reports that
coassembly of certain other mutant KCNE1 monomers with wild-type KCNQ1
subunits does produce dominant Romano-Ward syndrome via a dominant-negative
mechanism. The two observations are reconciled, not contradictory, by
variant-specific mechanism: most loss-of-function KCNE1 alleles behave as
simple recessive nulls requiring biallelic loss for JLNS2, while a smaller
set of missense alleles instead act dominantly through interference with
wild-type KCNQ1/KCNE1 complexes.
gene_term:
preferred_term: KCNE1
term:
id: hgnc:6240
label: KCNE1
relationship_type: CAUSATIVE
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The diagnosis of JLNS is established in a child with congenital sensorineural deafness, long QT interval, and presence of biallelic pathogenic variants in either KCNQ1 or KCNE1."
explanation: >-
GeneReviews establishes KCNE1 as one of the two genes in which biallelic
pathogenic variants cause JLNS.
- reference: PMID:41200805
reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "KCNE1 is a recognized cause of the autosomal recessive Jervell and Lange-Nielson syndrome type 2 (JLN2)."
explanation: >-
Confirms KCNE1 as the accepted causal gene for the recessive JLNS2
phenotype curated in this entry.
- reference: PMID:41200805
reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Most dysfunctional variants exhibited loss-of-function properties. We observed no apparent dominant-negative effects when variant and wild-type KCNE1 were coexpressed."
explanation: >-
Direct functional electrophysiology showing loss-of-function as the
predominant mechanism of disease-associated KCNE1 variants, without
dominant-negative behavior, consistent with a recessive disease
mechanism.
- reference: PMID:33040543
reference_title: "Treatment on arrhythmia electric storm in a Jervell and Lange-Nielsen syndrome patient by ablation of the triggering premature ventricular contraction: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient has A to G missense mutation in KCNE1 gene, and a subunit with abnormal structure, which is the basis for congenital deafness."
explanation: >-
Independent clinical case confirming a KCNE1 missense variant as the
basis of a patient's congenital deafness component of JLNS.
pathophysiology:
- name: Biallelic KCNE1 Loss of Function
conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
role: trigger
biological_scale: MOLECULAR
description: >-
Biallelic loss-of-function variants in KCNE1 abolish or severely reduce
the regulatory (beta-subunit) contribution of MinK to the IKs channel
complex. Because KCNE1 must coassemble with KCNQ1 to generate a normal IKs
current, homozygous or compound heterozygous KCNE1 variants produce the
same downstream functional deficit as biallelic KCNQ1 loss (JLNS1), even
though the two genes encode structurally distinct subunits of the same
channel. High-throughput voltage-clamp profiling shows that most
disease-associated KCNE1 variants reduce IKs current density in the
homozygous state without dominant-negative behavior on coexpressed
wild-type subunits, consistent with a recessive disease mechanism.
genes:
- preferred_term: KCNE1
term:
id: hgnc:6240
label: KCNE1
molecular_functions:
- preferred_term: ion channel regulator activity
term:
id: GO:0099106
label: ion channel regulator activity
modifier: DECREASED
biological_processes:
- preferred_term: potassium ion transmembrane transport
term:
id: GO:0071805
label: potassium ion transmembrane transport
modifier: DECREASED
evidence:
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: OTHER
snippet: "KCNE1 specifically encodes the beta subunit (mink) of IKs"
explanation: >-
Establishes KCNE1/MinK as the regulatory beta subunit whose biallelic
loss is the molecular trigger of JLNS2.
- reference: PMID:41200805
reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Approximately half (47 of 95) of the KCNE1 variants tested in the homozygous state exhibited peak current densities significantly different from WT IKs."
explanation: >-
Direct high-throughput functional data quantifying the frequency and
magnitude of IKs current disruption caused by KCNE1 variants in the
homozygous state.
downstream:
- target: Loss of IKs Current in Cardiac Myocytes
description: >-
IKs generated by the KCNQ1/KCNE1 complex is a major repolarizing current
in cardiac myocytes; loss of KCNE1 function reduces this current in the
heart.
causal_link_type: DIRECT
evidence:
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: OTHER
snippet: "The ion channel subunits encoded by KCNQ1 and KCNE1 generate slow delayed rectifier potassium currents (IKs), which are essential for endolymph production in the inner ear and cardiomyocyte action potential (AP)"
explanation: >-
States both the cardiac and cochlear roles of the KCNQ1/KCNE1 IKs
complex, the basis of this branch of the fork.
- target: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
description: >-
The same KCNQ1/KCNE1 IKs channel complex is expressed on the apical
membrane of marginal cells of the stria vascularis, where it drives
potassium secretion into the endolymph; loss of KCNE1 function reduces
this current in the inner ear.
causal_link_type: DIRECT
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the inner ear, KCNQ1/KCNE1 potassium channels are expressed exclusively in the apical membrane of marginal cells (MCs) in the stria vascularis (SV) and in vestibular dark cells"
explanation: >-
Establishes the specific inner-ear cellular localization of the
KCNQ1/KCNE1 channel complex whose loss initiates the cochlear branch
of the phenotype.
- name: Loss of IKs Current in Cardiac Myocytes
conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
role: intermediate
biological_scale: CELLULAR
description: >-
Reduced IKs current diminishes repolarization reserve and delays
completion of the ventricular action potential, prolonging the QT
interval measured on the surface ECG.
cell_types:
- preferred_term: cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: potassium ion transmembrane transport
term:
id: GO:0071805
label: potassium ion transmembrane transport
modifier: DECREASED
- preferred_term: membrane repolarization during cardiac muscle cell action potential
term:
id: GO:0086013
label: membrane repolarization during cardiac muscle cell action potential
modifier: DYSREGULATED
molecular_functions:
- preferred_term: monoatomic ion channel activity
term:
id: GO:0005216
label: monoatomic ion channel activity
modifier: ABNORMAL
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
explanation: >-
GeneReviews documents the marked QTc prolongation that results from
reduced ventricular repolarization reserve in JLNS.
downstream:
- target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
description: >-
Markedly prolonged repolarization creates a substrate for triggered
activity and re-entrant ventricular tachyarrhythmia, including torsade
de pointes and ventricular fibrillation.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Prolongation of the QTc interval is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death."
explanation: >-
GeneReviews directly links QTc prolongation to the tachyarrhythmic and
fatal outcomes of JLNS.
- name: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
role: intermediate
biological_scale: TISSUE
description: >-
Prolonged, heterogeneous ventricular repolarization predisposes to
early afterdepolarizations and re-entrant torsade de pointes, which can
degenerate into sustained ventricular tachycardia or ventricular
fibrillation. Available comparative data suggest that this arrhythmic risk
is present but lower in genotype-confirmed JLNS2 (biallelic KCNE1) than in
JLNS1 (biallelic KCNQ1).
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
evidence:
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Children carrying KCNQ1 variants exhibit an approximately sixfold higher risk of ventricular arrhythmia than those with KCNE1 variants."
explanation: >-
Directly quantifies the reduced (but nonzero) ventricular arrhythmia
risk specific to KCNE1 (JLNS2) relative to KCNQ1 (JLNS1) genotypes,
supporting the entry's emphasis on JLNS2-specific severity data rather
than JLNS1 figures.
- reference: PMID:31941373
reference_title: "An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5%"
explanation: >-
Directly quantifies the definite arrhythmic event rate (10.5%, 2 of 19
genotype-confirmed patients) in the largest reported JLNS2 cohort,
providing a JLNS2-specific severity estimate rather than an imported
JLNS1 figure.
downstream:
- target: Syncope and Sudden Cardiac Death
description: >-
Sustained ventricular tachyarrhythmia can cause hemodynamic collapse,
manifesting as syncope, and can be fatal if not promptly terminated.
causal_link_type: DIRECT
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "More than half of untreated children with JLNS die before age 15 years."
explanation: >-
GeneReviews documents the high untreated mortality of JLNS overall,
underscoring the clinical severity of the arrhythmic branch even
though JLNS2 specifically carries a lower event rate than JLNS1.
- name: Syncope and Sudden Cardiac Death
conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
role: effector
biological_scale: ORGANISM
description: >-
The clinical endpoint of the cardiac branch of JLNS2: exertion-, emotion-,
or auditory-stimulus-triggered syncope, and a risk of sudden cardiac death
from malignant ventricular arrhythmia, most pronounced in early childhood.
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. Fifty percent of individuals with JLNS had cardiac events before age three years."
explanation: >-
GeneReviews describes the classic clinical presentation and early
childhood timing of cardiac events in JLNS overall.
- name: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
conforms_to: "sensorineural_hair_cell_loss#Cochlear Ionic Homeostasis Disruption and Oxidative Stress"
role: intermediate
biological_scale: CELLULAR
description: >-
KCNQ1/KCNE1 IKs channels on the apical membrane of stria vascularis
marginal cells drive the transepithelial potassium flux that generates and
maintains the endocochlear potential, the unusually positive extracellular
potential in the endolymph that provides the electrochemical driving force
for hair-cell mechanotransduction. Loss of KCNE1 function collapses this
potassium-secretory current, disrupting cochlear ionic homeostasis.
cell_types:
- preferred_term: strial marginal cell
term:
id: CL:0002492
label: strial marginal cell
biological_processes:
- preferred_term: potassium ion transmembrane transport
term:
id: GO:0071805
label: potassium ion transmembrane transport
modifier: DECREASED
locations:
- preferred_term: stria vascularis of cochlear duct
term:
id: UBERON:0002282
label: stria vascularis of cochlear duct
- preferred_term: cochlea
term:
id: UBERON:0001844
label: cochlea
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the inner ear, KCNQ1/KCNE1 potassium channels are expressed exclusively in the apical membrane of marginal cells (MCs) in the stria vascularis (SV) and in vestibular dark cells"
explanation: >-
Confirms the strial marginal cell localization of the KCNQ1/KCNE1
channel complex central to this node.
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: OTHER
snippet: "The K+ concentration is markedly increased in the endolymph, and the influx of K+ into hair cells upon stimulation plays a pivotal role in transducing sound into neural signals."
explanation: >-
Establishes the mechanistic link between strial potassium secretion,
the endolymph's high K+ concentration, and hair-cell mechanotransduction.
downstream:
- target: Endocochlear Potential Collapse and Hair Cell Degeneration
description: >-
Loss of strial potassium secretion collapses the endocochlear potential
and the driving force for hair-cell mechanotransduction.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Both Kcne1−/− and Kcnq1−/− mice exhibit an abnormal development of the endolymphatic space, severe degeneration of the hair cells (HCs), and spiral ganglion neurons (SGNs)"
explanation: >-
Direct mouse-model evidence that Kcne1 loss produces endolymphatic
abnormality and hair cell/spiral ganglion degeneration, mirroring the
Kcnq1 (JLNS1) model.
- name: Endocochlear Potential Collapse and Hair Cell Degeneration
conforms_to: "sensorineural_hair_cell_loss#Hair Cell Mechanotransduction Failure and Death"
role: intermediate
biological_scale: CELLULAR
description: >-
Without the endocochlear potential, hair-cell mechanotransduction fails
and cochlear hair cells undergo degeneration. Because mammalian cochlear
hair cells do not regenerate, this loss is irreversible.
locations:
- preferred_term: cochlea
term:
id: UBERON:0001844
label: cochlea
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Results showed early treatment prevented collapse of the Reissner's membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells."
explanation: >-
Demonstrates, by rescue, that untreated Kcne1 loss causes structural
collapse of the cochlear duct and degeneration of inner ear cells.
downstream:
- target: Congenital Profound Bilateral Sensorineural Hearing Loss
description: >-
Irreversible hair-cell loss and collapse of the endocochlear potential
produce permanent, congenital sensorineural hearing loss.
causal_link_type: DIRECT
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
explanation: >-
GeneReviews establishes congenital profound bilateral sensorineural
hearing loss as a defining, present-from-birth feature of JLNS.
- name: Congenital Profound Bilateral Sensorineural Hearing Loss
conforms_to: "sensorineural_hair_cell_loss#Progressive Sensorineural Hearing Loss"
role: effector
biological_scale: ORGANISM
description: >-
The clinical endpoint of the cochlear branch of JLNS2: congenital,
profound, bilateral sensorineural hearing loss present from birth. Unlike
several other conformers of this module (e.g., noise- or age-related
hearing loss), the JLNS deficit is typically already maximal at birth
rather than accruing progressively over time; conformance here reflects
the shared irreversible, non-regenerating hair-cell-loss endpoint rather
than a claim of ongoing postnatal worsening.
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
explanation: >-
GeneReviews defines the congenital, profound, bilateral character of the
hearing loss.
mechanistic_hypotheses:
- hypothesis_group_id: variant_specific_dominant_negative_vs_haploinsufficiency
hypothesis_label: Variant-specific dominant-negative versus simple loss-of-function/haploinsufficiency KCNE1 mechanism
status: EMERGING
description: >-
KCNE1 loss-of-function variants appear to split mechanistically by
variant. A large 2025 functional screen found no apparent dominant-negative
effect on wild-type IKs current among the KCNE1 variants it tested when
coexpressed with wild-type KCNE1, consistent with a simple recessive
loss-of-function/haploinsufficiency mechanism requiring biallelic loss for
JLNS2. However, an independent study of KCNE1 nonsense and missense
alleles reports that coassembly of certain other mutant KCNE1 monomers
with wild-type KCNQ1 subunits produces dominant Romano-Ward syndrome via a
dominant-negative mechanism. Whether these are truly non-overlapping
variant classes, or whether the discrepancy partly reflects differences in
the specific variants and assay conditions tested, is not yet resolved.
evidence:
- reference: PMID:41200805
reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We observed no apparent dominant-negative effects when variant and wild-type KCNE1 were coexpressed."
explanation: >-
Direct functional data supporting a simple loss-of-function/
haploinsufficiency mechanism for the specific KCNE1 variant panel tested.
- reference: PMID:30461122
reference_title: "Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism."
explanation: >-
Independent evidence that at least some KCNE1 missense variants act
dominantly through a dominant-negative mechanism, the counterpoint this
hypothesis has to reconcile with the functional screen's negative
finding.
discussions:
- discussion_id: jlns2_vestibular_human_model_mismatch
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- "pathophysiology#Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells"
prompt: >-
Do genotype-confirmed human JLNS2 (biallelic KCNE1) patients have
clinically significant vestibular dysfunction, as Kcne1-/- mice do?
rationale: >-
Kcne1-/- mice show clear structural and functional vestibular involvement:
KCNQ1/KCNE1 channels are expressed in vestibular dark cells as well as
strial marginal cells, and untreated Kcne1-/- mice show abnormal
endolymphatic-space development, vestibular hair cell degeneration, and
impaired vestibular behavior that gene therapy can rescue (PMID:33514733).
However, the only quantitative human vestibular study of JLNS
(PMID:25471708) genotyped its cohort and found all 14 tested cases carried
double KCNQ1 (JLNS1) mutations, not KCNE1. Whether the mouse vestibular
phenotype translates to genotype-confirmed human JLNS2 patients is
therefore untested, and this entry deliberately does not curate vestibular
dysfunction as an established JLNS2 phenotype.
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction."
explanation: >-
Source of the mouse-model vestibular-dysfunction claim that motivates
this discussion.
proposed_experiments:
- experiment_id: exp_jlns2_genotype_stratified_vestibular_function
name: Genotype-stratified human vestibular function study in JLNS2
description: >-
Vestibular function testing (post-rotatory nystagmus, video head impulse
testing) in a cohort of genotype-confirmed KCNE1/JLNS2 patients,
analogous to the KCNQ1-genotyped study already published for JLNS1
(PMID:25471708).
phenotypes:
- category: Ear
name: Congenital Profound Bilateral Sensorineural Hearing Loss
description: >-
Congenital, profound, bilateral sensorineural hearing loss is a defining
feature of JLNS, present from birth or identified on newborn hearing
screening.
phenotype_term:
preferred_term: Congenital sensorineural hearing impairment
term:
id: HP:0008527
label: Congenital sensorineural hearing impairment
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
explanation: >-
GeneReviews establishes congenital profound bilateral sensorineural
hearing loss as a defining feature of JLNS.
- category: Cardiovascular
name: Prolonged QT Interval
description: >-
Marked prolongation of the corrected QT interval (QTc), usually greater
than 500 msec, is a defining feature of JLNS.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Prolonged QT interval
term:
id: HP:0001657
label: Prolonged QT interval
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
explanation: >-
GeneReviews establishes marked QTc prolongation as a defining feature of
JLNS.
- category: Cardiovascular
name: Ventricular Arrhythmia
description: >-
Genotype-confirmed KCNE1 (JLNS2) patients are at risk of definite
arrhythmic events (appropriate ICD shock, aborted cardiac arrest, or
sudden cardiac death), reported at a lower rate than in KCNQ1 (JLNS1)
patients in the largest comparative cohort to date.
phenotype_term:
preferred_term: Ventricular tachycardia
term:
id: HP:0004756
label: Ventricular tachycardia
evidence:
- reference: PMID:31941373
reference_title: "An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5%"
explanation: >-
Direct quantitative arrhythmic event rate in the largest reported
genotype-confirmed JLNS2 cohort.
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Children carrying KCNQ1 variants exhibit an approximately sixfold higher risk of ventricular arrhythmia than those with KCNE1 variants."
explanation: >-
Quantifies the reduced, but nonzero, ventricular arrhythmia risk
associated specifically with KCNE1 (JLNS2) genotypes relative to KCNQ1
(JLNS1).
- category: Cardiovascular
name: Torsade de Pointes
description: >-
QTc prolongation in JLNS is associated with episodes of torsade de pointes
ventricular tachycardia, which may culminate in syncope or sudden death.
phenotype_term:
preferred_term: Torsade de pointes
term:
id: HP:0001664
label: Torsade de pointes
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Prolongation of the QTc interval is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death."
explanation: >-
GeneReviews documents torsade de pointes as a characteristic
tachyarrhythmia in JLNS.
- category: Cardiovascular
name: Syncope
description: >-
The classic presentation of JLNS is a deaf child who experiences
syncopal episodes during periods of stress, exercise, or fright.
phenotype_term:
preferred_term: Syncope
term:
id: HP:0001279
label: Syncope
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright."
explanation: >-
GeneReviews describes the classic exertion/emotion-triggered syncopal
presentation of JLNS.
- category: Cardiovascular
name: Sudden Cardiac Death Risk
description: >-
Untreated JLNS carries a high risk of premature death from malignant
ventricular arrhythmia; more than half of untreated children die before
age 15 years.
phenotype_term:
preferred_term: Sudden death
term:
id: HP:0001699
label: Sudden death
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "More than half of untreated children with JLNS die before age 15 years."
explanation: >-
GeneReviews establishes the high untreated mortality of JLNS overall.
- category: Hematologic
name: Iron-Deficiency Anemia
description: >-
Iron-deficient anemia is a frequent, non-cardioauditory feature of JLNS,
of uncertain mechanistic relationship to the primary channelopathy.
phenotype_term:
preferred_term: Iron deficiency anemia
term:
id: HP:0001891
label: Iron deficiency anemia
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."
explanation: >-
GeneReviews lists iron-deficient anemia among the frequent additional
features of JLNS.
- category: Gastrointestinal
name: Elevated Serum Gastrin
description: >-
Elevated serum gastrin levels are a frequent, non-cardioauditory feature
of JLNS.
phenotype_term:
preferred_term: Hypergastrinemia
term:
id: HP:0500167
label: Hypergastrinemia
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."
explanation: >-
GeneReviews lists elevated gastrin as a frequent additional feature of
JLNS.
environmental:
- name: Exertion, Emotional Stress, or Sudden Fright
exposure_term:
preferred_term: exposure to strenuous exercise
term:
id: ECTO:6000031
label: exposure to strenuous exercise
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright."
explanation: >-
Establishes that exertion is a recognized exposure in JLNS rather
than an inferred one. The mechanism link below carries its own
evidence for the separate claim that this exposure acts on the
arrhythmogenic substrate node.
influences_mechanisms:
- target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
environmental_effect: TRIGGERS
causal_link_type: DIRECT
description: >-
Exertion, emotional stress, and sudden fright are the classic
adrenergic triggers for syncopal arrhythmic events in JLNS; the same
triggers motivate the anti-adrenergic rationale of beta-blocker
therapy and the exercise/trigger-avoidance counseling in
treatments.
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright."
explanation: >-
GeneReviews documents exertion, emotional stress, and sudden fright
as the classic triggers of syncopal arrhythmic events in JLNS.
notes: >-
Modeled here specifically for exertion/exercise, the concept with an
available ECTO exposure term (ECTO:6000031, exposure to strenuous
exercise); emotional stress and sudden fright are named in the same
GeneReviews sentence but have no comparably specific ECTO exposure term
and are recorded only in this node's free-text description.
treatments:
- name: Beta-Blocker Therapy
description: >-
First-line anti-adrenergic pharmacotherapy for JLNS, though reported to be
only partially effective; arrhythmia persists in a substantial proportion
of patients despite beta-blocker treatment.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: beta-blocker therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: beta-adrenergic antagonist
term:
id: NCIT:C29576
label: Beta-Adrenergic Antagonist
target_mechanisms:
- target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
treatment_effect: INHIBITS
description: >-
Anti-adrenergic therapy reduces the likelihood that exertion- or
emotion-related sympathetic triggers will precipitate malignant
ventricular arrhythmia.
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "beta-adrenergic blockers for long QT interval (Note: Beta-blocker treatment is only partially effective.)"
explanation: >-
GeneReviews recommends beta-blockers as first-line therapy while
explicitly noting only partial effectiveness in JLNS.
evidence:
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The efficacy of beta‐blockers and left cardiac sympathetic denervation is limited in patients with JLNS, as arrhythmia persists in 51%–85% of cases despite beta‐blocker treatment"
explanation: >-
Quantifies the limited efficacy of beta-blocker therapy in JLNS,
motivating escalation to device therapy in many patients.
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Beta-blocker dose should be regularly assessed for efficacy and adverse effects, with evaluation every three to six months during rapid growth phases"
explanation: >-
GeneReviews surveillance guidance: beta-blocker dosing requires
periodic reassessment, especially during rapid childhood growth
phases, because weight-based dosing can fall out of therapeutic range.
notes: >-
GeneReviews recommends reassessing beta-blocker dose for efficacy and
adverse effects every three to six months during rapid growth phases.
- name: Implantable Cardioverter-Defibrillator Placement
description: >-
Device therapy for patients with a history of cardiac arrest, malignant
events despite beta-blocker therapy, or otherwise judged high risk.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: implantable cardioverter-defibrillator placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "implantable cardioverter defibrillators (ICDs) for those with a history of cardiac arrest and/or failure to respond to other treatments"
explanation: >-
GeneReviews recommends ICD placement for high-risk or treatment-refractory
JLNS patients.
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "periodic evaluations of ICDs for inappropriate shocks and pocket or lead complications"
explanation: >-
GeneReviews surveillance guidance: implanted devices require periodic
evaluation for inappropriate shocks and pocket/lead complications.
notes: >-
GeneReviews recommends periodic ICD evaluation for inappropriate shocks
and pocket or lead complications.
- name: Left Cardiac Sympathetic Denervation
description: >-
Surgical anti-adrenergic escalation considered when arrhythmia persists
despite beta-blocker therapy or when device therapy is unsuitable; a
review of JLNS management describes beta-blocker and left cardiac
sympathetic denervation efficacy as both limited, since arrhythmia
persists in 51-85% of cases despite beta-blocker treatment.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: left cardiac sympathetic denervation
term:
id: NCIT:C15329
label: Surgical Procedure
target_mechanisms:
- target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
treatment_effect: INHIBITS
description: >-
Left cardiac sympathetic denervation reduces arrhythmia-provoking
sympathetic input when pharmacologic anti-adrenergic therapy (beta
blockade) is insufficient.
evidence:
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The efficacy of beta‐blockers and left cardiac sympathetic denervation is limited in patients with JLNS, as arrhythmia persists in 51%–85% of cases despite beta‐blocker treatment"
explanation: >-
States that left cardiac sympathetic denervation is used alongside
beta-blockade in JLNS management, though the same review notes both
interventions have limited efficacy against persistent arrhythmia.
evidence:
- reference: PMID:42389506
reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "left cervical sympathectomy is planned if malignant ventricular arrhythmias recur"
explanation: >-
Documents left cardiac sympathetic denervation (cervical sympathectomy)
as the planned escalation step in JLNS patients with recurrent
malignant ventricular arrhythmia.
notes: >-
Efficacy data are JLNS-wide (both JLNS1 and JLNS2) rather than
KCNE1-genotype-specific; no genotype-stratified LCSD outcome data for
JLNS2 alone were identified.
- name: Catheter Ablation of Triggering Ectopy
description: >-
Radiofrequency catheter ablation of the premature ventricular contraction
that triggers arrhythmia storm has been reported as an effective
alternative or adjunct to device therapy in an individual genotype-confirmed
KCNE1 (JLNS2) patient who could not undergo ICD implantation.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: cardiac radiofrequency ablation
term:
id: NCIT:C170884
label: Cardiac Radiofrequency Ablation
evidence:
- reference: PMID:33040543
reference_title: "Treatment on arrhythmia electric storm in a Jervell and Lange-Nielsen syndrome patient by ablation of the triggering premature ventricular contraction: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ablation was successfully performed to eliminate the triggering PVC... During the 12-month follow-up, no syncope or fatal arrhythmia was found in this patient."
explanation: >-
Direct clinical case report of successful radiofrequency ablation
controlling fatal arrhythmia in a genotype-confirmed KCNE1 patient.
notes: >-
Reported in a single genotype-confirmed KCNE1 patient who could not
undergo ICD implantation for economic reasons; not established as a
JLNS2-specific standard of care.
- name: Cochlear Implantation
description: >-
Surgical cochlear implantation to treat the congenital profound
sensorineural hearing loss of JLNS.
therapeutic_modality: SURGERY
action_category: THERAPEUTIC
treatment_term:
preferred_term: cochlear implantation
term:
id: NCIT:C15329
label: Surgical Procedure
target_phenotypes:
- preferred_term: Congenital sensorineural hearing impairment
term:
id: HP:0008527
label: Congenital sensorineural hearing impairment
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Cochlear implantation to treat hearing loss"
explanation: >-
GeneReviews lists cochlear implantation as standard management of
hearing loss in JLNS.
notes: >-
A JLNS review notes that among documented cases, some patients undergoing
cochlear implantation experienced significant arrhythmic events
perioperatively, underscoring the importance of anesthetic and
perioperative arrhythmia precautions in this population (PMID:42389506).
- name: Avoidance of QT-Prolonging Drugs and Arrhythmia Triggers
description: >-
Avoidance of drugs that further prolong the QT interval and of activities
or circumstances known to precipitate syncopal events, plus special
anesthetic precautions given the increased risk of arrhythmia during
anesthesia.
therapeutic_modality: BEHAVIORAL
action_category: COUNSELING_INFORMATIONAL
treatment_term:
preferred_term: risk factor avoidance counseling
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Agents/circumstances to avoid: Drugs that cause further prolongation of the QT interval; activities known to precipitate syncopal events in persons with long QT syndrome."
explanation: >-
GeneReviews specifies the agents and circumstances to avoid in JLNS
management.
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Training for family members in cardiopulmonary resuscitation; use of an ID bracelet explaining the diagnosis; notifying local emergency medical services of high-risk persons with JLNS."
explanation: >-
GeneReviews recommends family CPR training and emergency-preparedness
measures as part of routine JLNS risk-factor avoidance and emergency
planning.
notes: >-
GeneReviews also recommends ensuring availability of automated external
defibrillators where appropriate, family training in cardiopulmonary
resuscitation, use of a medical-alert ID bracelet, and notifying local
emergency medical services of high-risk individuals.
- name: Genetic Counseling
description: >-
Autosomal recessive genetic counseling for families, including the 25%
per-pregnancy recurrence risk for carrier couples, evaluation of at-risk
relatives by newborn hearing screening and ECG, and consideration of
whether a mother carrying an affected fetus herself has long QT syndrome.
therapeutic_modality: OTHER
action_category: COUNSELING_INFORMATIONAL
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "At conception, each sib of an affected individual usually has a 25% chance of being affected with JLNS, a 50% chance of being a carrier of a JLNS-causing pathogenic variant and potentially at risk for LQTS, and a 25% chance of being unaffected and not a carrier."
explanation: >-
GeneReviews specifies the recurrence-risk figures used in genetic
counseling for JLNS families.
animal_models:
- name: Kcne1 knockout mouse
species: Mouse
genotype: Kcne1-/-
publication: PMID:33514733
modeled_mechanisms:
- target: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Kcne1-/- mice lack Kcne1 expression in strial marginal cells and
vestibular dark cells, the same cell types that express the KCNQ1/KCNE1
complex in humans, and show abnormal endolymphatic-space development.
limitations: >-
Mouse cochlear structure, developmental timing, and the extent of
vestibular involvement are not identical to human JLNS2; no
genotype-confirmed human vestibular data exist for direct comparison
(see the HUMAN_MODEL_MISMATCH discussion on this node).
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Both Kcne1−/− and Kcnq1−/− mice exhibit an abnormal development of the endolymphatic space, severe degeneration of the hair cells (HCs), and spiral ganglion neurons (SGNs)"
explanation: >-
Supports treating the Kcne1-/- mouse as informative for the
strial-marginal-cell potassium-secretion node: it reproduces the
expected downstream endolymphatic and hair-cell consequences of losing
the same channel complex.
readouts:
- name: Reissner's membrane and vestibular wall collapse
target: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
direction: RESTORED
interpretation: >-
Early AAV1-CB7-Kcne1 gene therapy via the posterior semicircular canal
prevented collapse of Reissner's membrane and the vestibular wall and
preserved normal semicircular canal size, demonstrating the causal role
of Kcne1 loss in this structural degeneration.
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Results showed early treatment prevented collapse of the Reissner's membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells."
explanation: >-
Rescue experiment demonstrating that structural cochlear/vestibular
degeneration in Kcne1-/- mice is caused by loss of Kcne1 function.
- name: Auditory brainstem response threshold
target: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
direction: RESTORED
interpretation: >-
High-dosage gene therapy preserved auditory function in 16 of 20
treated Kcne1-/- mice for at least five months, supporting a causal
link between restored strial Kcne1 expression and preserved hearing.
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months."
explanation: >-
Dose-dependent, quantitative auditory and vestibular functional
rescue data from the Kcne1-/- mouse gene-therapy study.
evidence:
- reference: PMID:33514733
reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1-/- mice to treat both the hearing and vestibular symptoms."
explanation: >-
Establishes the Kcne1-/- mouse as a genetically precise model of the
human KCNE1 loss-of-function lesion underlying JLNS2.
diagnosis:
- name: Combined Clinical and Molecular Diagnostic Criteria
description: >-
JLNS2 is diagnosed by the combination of the characteristic phenotype
(congenital sensorineural deafness plus a prolonged QT interval) and
confirmatory molecular testing showing biallelic pathogenic KCNE1
variants.
results: >-
A child presenting with congenital sensorineural deafness and a
prolonged QT interval, in whom molecular testing identifies biallelic
pathogenic KCNE1 (or KCNQ1) variants, meets the diagnostic criteria for
JLNS.
diagnosis_term:
preferred_term: clinical assessment
term:
id: NCIT:C124351
label: Clinical Evaluation
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The diagnosis of JLNS is established in a child with congenital sensorineural deafness, long QT interval, and presence of biallelic pathogenic variants in either KCNQ1 or KCNE1."
explanation: >-
GeneReviews states the combined clinical-plus-molecular diagnostic
criteria for JLNS, of which the KCNE1 arm defines JLNS2.
- name: Molecular Genetic Testing
description: >-
Molecular confirmation of biallelic KCNE1 pathogenic variants is
required to distinguish JLNS2 from JLNS1 (biallelic KCNQ1) and from
heterozygous KCNE1-related dominant LQT5, which lacks congenital
deafness.
results: >-
Detection of two pathogenic KCNE1 alleles (homozygous or compound
heterozygous) in trans confirms JLNS2 and distinguishes it from the
allelic dominant LQT5 phenotype, in which only one KCNE1 allele is
affected.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
evidence:
- reference: PMID:30461122
reference_title: "Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2"
explanation: >-
Establishes that molecular zygosity (biallelic versus heterozygous) is
the diagnostic feature that separates JLNS2 from the milder dominant
KCNE1 phenotype.
- name: Resting Electrocardiography with QTc Assessment
description: >-
Baseline 12-lead ECG measurement of the corrected QT interval is the core
diagnostic procedure for identifying the QT-prolongation component of
JLNS2.
results: >-
A markedly prolonged QTc, usually >500 msec in JLNS, supports the
cardiac component of the diagnosis.
diagnosis_term:
preferred_term: clinical assessment
term:
id: NCIT:C124351
label: Clinical Evaluation
notes: >-
NCIT does not provide an ECG-specific diagnostic term here, so the
preferred term is narrowed in the name and description.
evidence:
- reference: DOI:10.3390/children11050582
reference_title: "Congenital Long QT Syndrome in Children and Adolescents: A General Overview"
supports: SUPPORT
evidence_source: OTHER
snippet: "characterized by a prolongation of QTc interval on ECG"
explanation: >-
A 2024 congenital LQTS review states that ECG-measured QTc
prolongation is the defining diagnostic feature of the QT-prolongation
component shared by all congenital LQTS subtypes, including JLNS.
clinical_trials:
- name: NCT06534671
phase: PHASE_IV
status: COMPLETED
description: >-
A single-participant Vanderbilt University Medical Center trial testing
the acute effect of a single intravenous dose of diltiazem, a calcium
channel blocker, on the QT interval in a genetically confirmed JLNS
patient. The trial's public summary does not specify whether the
participant carried KCNQ1 or KCNE1 variants, so it is recorded here as
JLNS-wide (not confirmed JLNS2-specific) evidence.
target_phenotypes:
- preferred_term: Prolonged QT interval
term:
id: HP:0001657
label: Prolonged QT interval
evidence:
- reference: clinicaltrials:NCT06534671
reference_title: "Diltiazem in Jervell and Lange-Nielsen Syndrome"
supports: SUPPORT
snippet: "This study will test the effect of diltiazem, a calcium channel blocking drug, on the QT interval in patients with Jervell and Lange-Nielsen syndrome. This will be a single IV dose and acute effects (within minutes) will be observed."
explanation: >-
ClinicalTrials.gov summary of the only identified JLNS-specific
interventional trial testing a candidate acute QT-shortening agent.
notes: >-
Completed October 2024 with a single enrolled participant; no
peer-reviewed efficacy results have been identified. Experimental, not a
standard-of-care treatment; not added to the treatments section pending
published results.
datasets: []
references:
- reference: PMID:20301579
title: Jervell and Lange-Nielsen Syndrome.
tags:
- GeneReviews
findings: []
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Jervell and Lange-Nielsen Syndrome 2 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Search first: CTD, PubMed, PheGenI, GxE databases
Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC
For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser
Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Search first: CDC databases, WHO, PubMed, NHANES
Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON
Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Search first: PubMed, Gene Ontology, Reactome
Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Search first: OMIM, Orphanet, HPO, PubMed
Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.
Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Search first: NSGC resources, ACMG guidelines, GeneReviews
Search first: Clinical guidelines, FDA approvals, PubMed
Search first: NCBI Taxonomy
Search first: VBO (Vertebrate Breed Ontology)
Search first: NCBI Gene
Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Jervell and Lange-Nielsen syndrome 2 (JLNS2) is an exceptionally rare, severe, autosomal-recessive cardio-auditory channelopathy caused by biallelic pathogenic loss-of-function variants in KCNE1. Its defining combination is congenital, usually profound bilateral sensorineural hearing loss and long-QT syndrome (LQTS), which predisposes to torsades de pointes, ventricular fibrillation, syncope, seizure-like episodes, cardiac arrest, and sudden death. It must be distinguished from JLNS1, caused by biallelic KCNQ1 variants, and from autosomal-dominant KCNE1-related Romano-Ward syndrome/LQT5, which lacks congenital deafness. The strongest JLNS2-specific clinical evidence remains small family series rather than large cohorts; therefore, numerical prognosis and most treatment recommendations necessarily derive from JLNS overall or congenital LQTS guidance and are labeled accordingly. (faridi2019mutationalandphenotypic pages 9-11, faridi2019mutationalandphenotypic pages 8-9, faridi2019mutationalandphenotypic pages 1-3)
| Domain | Database-ready summary | Key ontology / identifiers | Evidence type | Key citations |
|---|---|---|---|---|
| Identity | Jervell and Lange-Nielsen syndrome 2 (JLNS2) is a rare cardio-auditory channelopathy defined by congenital profound bilateral sensorineural hearing loss plus long-QT syndrome with risk of ventricular arrhythmia and sudden death; it is distinct from JLNS1, which is caused by biallelic KCNQ1 variants. | OMIM: 612347; MONDO: disease-level JLNS available as MONDO_0002441; HPO candidates: congenital sensorineural hearing impairment, long QT interval | Human clinical families; disease-gene curation | (faridi2019mutationalandphenotypic pages 1-3, OpenTargets Search: Jervell and Lange-Nielsen syndrome-KCNE1) |
| Causal gene / inheritance | Cause: biallelic loss-of-function variants in KCNE1, encoding the potassium voltage-gated channel subfamily E regulatory subunit 1, an accessory subunit for KCNQ1/Kv7.1. Inheritance is autosomal recessive; heterozygous loss-of-function carriers may have normal hearing and normal QT, while some heterozygous missense alleles can cause Romano-Ward syndrome via dominant-negative effects. | Gene: KCNE1; HGNC-approved symbol: KCNE1; HPO candidate: autosomal recessive inheritance | Human clinical genetics; mechanistic interpretation | (faridi2019mutationalandphenotypic pages 1-3, faridi2019mutationalandphenotypic pages 8-9, faridi2019mutationalandphenotypic pages 9-11) |
| Cardinal phenotypes | Core phenotype is congenital, severe-to-profound, bilateral sensorineural deafness with prolonged QTc. Reported JLNS2 families had QTcF about 487-495 ms and QTcB about 503-518 ms; syncopal events may be absent in some genetically confirmed cases, so hearing-loss-first presentation is possible. | HPO candidates: profound sensorineural hearing impairment; bilateral hearing impairment; long QT interval; syncope; sudden cardiac death | Human clinical families | (faridi2019mutationalandphenotypic pages 8-9, faridi2019mutationalandphenotypic pages 1-3) |
| Mechanism / pathophysiology | Upstream defect: KCNE1 deficiency impairs the IKs channel complex with KCNQ1. In heart, reduced repolarizing current delays ventricular repolarization, prolonging QT and increasing torsades/ventricular arrhythmia risk. In inner ear stria vascularis, KCNE1/KCNQ1 dysfunction disrupts K+ secretion into endolymph and collapses the endocochlear potential required for hair-cell depolarization, causing deafness; paralog compensation appears insufficient in inner ear. | GO candidates: potassium ion transmembrane transport; regulation of cardiac action potential repolarization; sensory perception of sound; CL candidate: strial marginal cell; UBERON candidate: stria vascularis, cochlea, heart ventricle | Human molecular genetics; animal model; auditory cell biology | (faridi2019mutationalandphenotypic pages 9-11, faridi2019mutationalandphenotypic pages 3-4) |
| Diagnostic anchors | Diagnostic confirmation rests on syndromic phenotype plus ECG and molecular testing. Contemporary congenital LQTS anchors: QTc ≥480 ms, or modified Schwartz score >3; in symptomatic patients, QTc ≥460 ms can suffice. Because a proportion of gene-confirmed LQTS can have normal-range resting QTc, KCNE1-inclusive NGS panels/exome testing are important in deaf children or families with cardio-auditory findings. | HPO candidates: abnormal electrocardiogram, long QT interval; test concepts: ECG, molecular genetic testing | Human clinical guidelines/review; human genetic diagnosis | (balestra2024congenitallongqt pages 4-5, balestra2024congenitallongqt pages 5-8, qiu2020jervellandlangenielsen pages 1-2) |
| Standard management | Management is largely extrapolated from congenital LQTS/JLNS practice: nonselective beta-blockers (nadolol or propranolol) are first-line; avoidance of QT-prolonging drugs and trigger management are standard. ICD is recommended after cardiac arrest and considered for persistent symptoms despite beta-blockers; left cardiac sympathetic denervation is used when events recur or ICD is unsuitable. Cochlear implantation can improve hearing, but peri-anesthetic arrhythmia risk requires careful planning and monitoring. | NCIT candidates: Beta Adrenergic Receptor Blocking Agent Therapy; Implantable Cardioverter Defibrillator; Sympathectomy; Cochlear Implantation | Guidelines/review; case report real-world implementation | (balestra2024congenitallongqt pages 5-8, balestra2024congenitallongqt pages 8-9, qiu2020jervellandlangenielsen pages 5-7) |
| Emerging research / latest developments | Recent work emphasizes precision medicine in congenital LQTS using patient-specific iPSC-derived cardiomyocytes, CRISPR-enabled variant validation, and high-throughput drug testing. A completed 2024 phase 4 JLNS trial tested acute IV diltiazem effects on QT interval in 1 genetically confirmed adult participant; results were submitted for publication after trial completion. | Research concepts: iPSC disease modeling; CRISPR genome editing; ClinicalTrials.gov NCT06534671 | In vitro precision-medicine review; clinical trial | (yu2023precisionmedicinefor pages 1-2, yu2023precisionmedicinefor pages 7-8, NCT06534671 chunk 1) |
| Major evidence gaps | JLNS2-specific epidemiology, penetrance, carrier frequency, founder-variant frequencies, longitudinal survival, quality-of-life metrics, and genotype-specific treatment outcomes remain sparse because published evidence is limited to few families/case-based data. No confident JLNS2-specific epigenomic, transcriptomic, proteomic, metabolomic, or large natural-history datasets were identified in the retrieved evidence. | No supported disease-specific ontology additions beyond above | Evidence-gap synthesis | (faridi2019mutationalandphenotypic pages 1-3, faridi2019mutationalandphenotypic pages 8-9, NCT06534671 chunk 1) |
Table: This table summarizes the most actionable database-ready facts for Jervell and Lange-Nielsen syndrome 2, including identity, gene, mechanism, diagnosis, management, recent research, and explicit evidence gaps. It is designed to support structured knowledge-base entry creation while avoiding unsupported identifiers.
Open Targets identifies KCNE1 (ENSG00000180509) as the principal evidence-supported target for the general JLNS record, with an association score of 0.804 and supporting literature including PMID 30461122. Low-scoring neighboring-gene associations in that resource should not be interpreted as additional causal JLNS2 genes. (OpenTargets Search: Jervell and Lange-Nielsen syndrome-KCNE1)
The information here is aggregated disease-level evidence from literature, disease resources, and trial registries. Individual-patient evidence appears only in published family/case reports and is not derived from an accessible EHR cohort.
JLNS2 results from germline biallelic KCNE1 pathogenic variants, usually homozygous in consanguineous families or compound heterozygous. KCNE1 encodes the minK regulatory β-subunit of the KCNQ1/Kv7.1 potassium channel complex. Biallelic loss reduces the slow delayed-rectifier potassium current, I(Ks). (faridi2019mutationalandphenotypic pages 9-11, faridi2019mutationalandphenotypic pages 1-3)
The key publication states directly: “Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization” and that “biallelic null alleles are associated with JLNS2.” This is human clinical-genetic evidence from Faridi et al., Human Mutation, published December 2019, PMID 30461122, DOI: https://doi.org/10.1002/humu.23689. (faridi2019mutationalandphenotypic pages 1-3)
Population allele frequencies must be retrieved variant-by-variant from the current gnomAD release. A single JLNS2-wide carrier frequency cannot be assigned from the available evidence. Causal alleles are expected to be individually rare; variants too common for a severe recessive cardio-auditory disorder require reassessment.
No JLNS2-specific modifier gene has been validated. Variability among individuals with KCNE1 deficiency implies additional genetic, physiologic, treatment, or exposure modifiers, but the evidence is insufficient for a curated modifier annotation. The apparent capacity of other KCNE paralogs to compensate partially in heart—but not in inner ear—is a mechanistic hypothesis, not a clinically validated protective genotype. (faridi2019mutationalandphenotypic pages 8-9, faridi2019mutationalandphenotypic pages 3-4)
Environmental factors do not cause JLNS2, but can expose its arrhythmia substrate. Relevant triggers include exertion, swimming, emotional stress, sudden auditory stimuli, fever, electrolyte depletion, anesthesia, and QT-prolonging medication. Maintaining normal potassium and magnesium, avoiding QT-prolonging drugs, adherence to β-blockade, and trigger-specific precautions reduce event risk but do not prevent congenital deafness or remove the genotype. (balestra2024congenitallongqt pages 5-8, balestra2024congenitallongqt pages 4-5, qiu2020jervellandlangenielsen pages 5-7)
Smoking, diet, alcohol, infection, pollution, radiation, and occupational exposure have no established etiologic role. Infection matters only indirectly through fever, dehydration, electrolyte disturbance, or exposure to QT-prolonging antimicrobials.
| Phenotype | Type and course | Frequency/evidence | Suggested HPO term |
|---|---|---|---|
| Congenital bilateral sensorineural deafness | Physical/functional; present at birth, severe-to-profound and generally permanent | Defining feature in reported JLNS2; homozygous null families had severe-to-profound deafness | Congenital sensorineural hearing impairment; profound sensorineural hearing impairment; bilateral hearing impairment |
| Long QT interval | ECG abnormality; congenital substrate, magnitude can vary over time and with rate/exposure | Defining cardiac feature; reported QTcF 487–495 ms and QTcB 503–518 ms | HP:0001657 Long QT interval |
| Ventricular tachyarrhythmia/torsades | Episodic, potentially fatal | Recognized disease risk; sparse JLNS2-specific frequency data | Ventricular tachycardia; torsade de pointes |
| Syncope | Episodic, often triggered; may begin in childhood | Variable; absent in some molecularly confirmed null-allele individuals | HP:0001279 Syncope |
| Seizure-like episodes | Symptom, usually cerebral hypoperfusion rather than primary epilepsy | Reported in JLNS and frequently causes diagnostic delay | Seizure; episodic loss of consciousness |
| Cardiac arrest/sudden cardiac death | Acute complication | Major untreated risk, but no reliable JLNS2-only percentage | Cardiac arrest; sudden cardiac death |
| Vestibular dysfunction | Clinical sign; variable | Supported in JLNS and Kcne1-null animals, but JLNS2 human frequency is unknown | Vestibular dysfunction |
The Faridi families show why symptoms cannot be used to exclude disease: individuals with profound deafness and QTcB 503–518 ms reported no syncope. (faridi2019mutationalandphenotypic pages 8-9)
Profound prelingual deafness affects language acquisition, education, communication, social participation, and caregiver burden. Cardiac risk imposes medication, exercise, medication-screening, emergency-planning, and procedural-anesthesia burdens. ICD shocks and activity restriction may add psychological morbidity. No JLNS2-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life dataset was found.
Penetrance for congenital deafness appears high with biallelic null variants, whereas cardiac severity and events show variable expressivity. Precise age-dependent penetrance estimates are unavailable.
JLNS2 is not infectious, toxic, nutritional, occupational, or lifestyle-caused. Clinically important interactions are mainly arrhythmia triggers:
A published cochlear-implant case with biallelic KCNQ1—therefore JLNS1, not JLNS2—developed life-threatening arrhythmia around anesthesia. It demonstrates a clinically plausible JLNS-wide procedural hazard but cannot establish a JLNS2-specific event rate. Defibrillation capability, continuous monitoring, electrolyte optimization, continuation/planning of cardiac medication, and coordination among electrophysiology, anesthesia, and otology teams are prudent. (qiu2020jervellandlangenielsen pages 5-7, qiu2020jervellandlangenielsen pages 1-2)
Biallelic KCNE1 loss → deficient KCNE1–KCNQ1 channel complex → reduced/altered I(Ks) → impaired phase-3 ventricular repolarization and reduced repolarization reserve → prolonged action potential and QTc → early afterdepolarizations and spatial dispersion → torsades de pointes/ventricular fibrillation → syncope, hypoxic convulsion, cardiac arrest, or sudden death.
Relevant cells are ventricular cardiomyocytes. Suggested terms include CL:0000746 cardiac muscle cell/cardiomyocyte, GO “potassium ion transmembrane transport,” “regulation of cardiac muscle cell action potential,” “cardiac muscle cell action potential involved in contraction,” and “membrane repolarization during cardiac action potential.” The relevant subcellular compartment is the plasma membrane and voltage-gated potassium-channel complex.
Biallelic KCNE1 loss → defective apical KCNQ1/KCNE1 current in strial marginal cells → impaired potassium secretion into scala-media endolymph → loss of the positive endocochlear potential and potassium homeostasis → failure of hair-cell depolarization plus secondary Reissner-membrane collapse/hair-cell degeneration → congenital profound sensorineural deafness. KCNE paralogs apparently do not compensate adequately in the inner ear. (faridi2019mutationalandphenotypic pages 9-11, faridi2019mutationalandphenotypic pages 3-4)
Suggested annotations are GO “potassium ion transport,” “sensory perception of sound,” and “inner ear development”; CL “strial marginal cell,” “inner hair cell,” and “outer hair cell”; and UBERON “cochlea,” “stria vascularis,” “scala media,” “endolymph,” “organ of Corti,” and “Reissner membrane.”
There is no established primary immune, inflammatory, fibrotic, neoplastic, or metabolic mechanism. Tissue injury in the cochlea is downstream of ionic failure rather than autoimmunity or infection.
No disease-defining JLNS2 transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic signature was identified. Current LQTS precision research uses patient-specific induced pluripotent stem cell-derived cardiomyocytes, whole-genome sequencing, CRISPR correction/engineering, machine learning, and high-throughput drug testing. These platforms can test causality and variant-specific responses, but they are research tools rather than validated JLNS2 diagnostics or treatments. The 2023 review’s abstract states that “Deep phenotyping and high-throughput drug testing using LQTS patient-specific cardiomyocytes herald the upcoming precision medicine in LQTS.” Publication: January 2023; DOI: https://doi.org/10.1017/erm.2022.43. (yu2023precisionmedicinefor pages 1-2, yu2023precisionmedicinefor pages 7-8)
Suggested UBERON terms: heart, cardiac ventricle, ventricular myocardium, inner ear, cochlea, cochlear duct, stria vascularis, organ of Corti, and vestibular labyrinth. Suggested GO cellular components: plasma membrane, voltage-gated potassium-channel complex, and KCNQ1–KCNE1 complex where supported.
The molecular defect is present from conception. Hearing loss is congenital and lifelong. QT prolongation is congenital or detectable in infancy/childhood, although resting QTc and clinical expression can fluctuate. Arrhythmic events are episodic and trigger-dependent rather than steadily progressive. The disorder itself is lifelong; there is no spontaneous remission of the genotype or deafness.
Critical windows are:
QTc above 500 ms is generally high risk and above 600 ms extremely high risk in congenital LQTS. Syncope before age seven predicts recurrent events despite β-blockade in broader LQTS data. (balestra2024congenitallongqt pages 4-5)
JLNS2 is autosomal recessive: for two carrier parents, each pregnancy has a 25% probability of an affected child, 50% probability of a heterozygous child, and 25% probability of inheriting neither familial allele. Both sexes should be affected equally.
JLNS overall has been estimated at roughly 1 per 200,000 to 1 per 1,000,000, but this range is not JLNS2-specific and likely varies with consanguinity and founder effects. Approximately 90% of JLNS in some series is attributed to KCNQ1, making KCNE1-related JLNS2 the minority subtype. (faridi2019mutationalandphenotypic pages 1-3, qiu2020jervellandlangenielsen pages 1-2)
Consanguinity increases the probability that two relatives carry the same rare allele; the reported p.Trp17Ter and p.Tyr46Ter homozygotes were found in consanguineous Pakistani families. This is ascertainment evidence, not proof of restriction to any ancestry. (faridi2019mutationalandphenotypic pages 8-9)
No robust JLNS2-specific incidence, prevalence, sex ratio, carrier frequency, geographic distribution, or founder-allele frequency was identified. Such fields should be recorded as unknown, not populated using all-JLNS or all-LQTS estimates.
A normal resting QTc does not exclude inherited LQTS: recent reviews estimate 20–25%, and in some selected genetically confirmed series up to approximately 40%, may have normal-range resting QTc. These differing figures reflect study populations and should not be treated as a JLNS2-specific frequency. (balestra2024congenitallongqt pages 5-8, yu2023precisionmedicinefor pages 1-2, yu2023precisionmedicinefor pages 2-2)
The preferred approach is a validated hereditary arrhythmia or combined hearing-loss/cardio-auditory panel including at minimum KCNE1 and *KCNQ1*, with deletion/duplication analysis. A broad hearing-loss panel that omits arrhythmia genes can miss the life-threatening diagnosis. If panel testing is negative or the phenotype is atypical, exome or genome sequencing with copy-number and splice-aware analysis is appropriate. Sanger sequencing is useful for confirmation and segregation.
CMA, karyotype, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless other clinical findings suggest an alternative disorder. RNA analysis may clarify suspected splice variants but is not routine. Variant interpretation must incorporate allele frequency, segregation, phenotype, functional data, and ACMG/AMP criteria; a VUS does not independently confirm JLNS2.
All infants with severe/profound congenital hearing loss should receive an ECG or prompt cardiac assessment where JLNS is plausible. Once familial variants are known, targeted cascade testing is more efficient than repeated broad sequencing. At-risk relatives need ECG assessment even when hearing is normal because heterozygous missense effects and incomplete cardiac expression can complicate segregation. Prenatal diagnosis and preimplantation genetic testing are technically possible for known familial pathogenic variants.
Untreated JLNS is one of the highest-risk congenital LQTS presentations, but JLNS2-only survival and mortality curves are unavailable. Profound deafness does not spontaneously recover. Arrhythmia risk is lifelong but can be substantially reduced by early recognition, trigger avoidance, nonselective β-blockade, and escalation to device or surgical therapy when indicated.
In broader symptomatic congenital LQTS, β-blockers reportedly reduced annual mortality from approximately 60% to below 2% over the ten years after an arrhythmic event; this historical statistic is not a JLNS2-specific response rate. (balestra2024congenitallongqt pages 5-8)
Adverse prognostic features include prior cardiac arrest, recurrent syncope on therapy, very prolonged QTc, early-childhood events, poor adherence, electrolyte disturbance, QT-prolonging medication, and potentially a second arrhythmia-associated variant. Absence of previous syncope is not reassuring enough to omit treatment because molecularly confirmed JLNS2 can be asymptomatic despite QTc above 500 ms. (faridi2019mutationalandphenotypic pages 8-9, balestra2024congenitallongqt pages 4-5)
Mexiletine is genotype-directed mainly for sodium-channel LQTS3 and is not established targeted treatment for KCNE1-JLNS2. No validated pharmacogenomic dosing rule specific to KCNE1 was found.
Hearing aids may provide limited benefit when loss is profound. Cochlear implantation can provide useful auditory access, coupled with early speech-language therapy, educational support, and Deaf-community/family-centered communication planning. Surgery requires a JLNS-aware anesthesia protocol and continuous postoperative monitoring. The strongest retrieved procedural case was KCNQ1-related JLNS1, so efficacy and anesthesia precautions are extrapolated to JLNS2 on syndrome-wide grounds. (qiu2020jervellandlangenielsen pages 5-7)
No approved gene, RNA, cell, or CRISPR therapy corrects JLNS2. Patient-specific iPSC cardiomyocytes and CRISPR-based isogenic controls are being developed for functional variant adjudication and individualized drug testing, but remain preclinical. (yu2023precisionmedicinefor pages 1-2, yu2023precisionmedicinefor pages 7-8)
NCT06534671, “Diltiazem in Jervell and Lange-Nielsen Syndrome,” was a completed Phase 4 Vanderbilt study in 2024. One genetically confirmed adult received IV diltiazem 0.25 mg/kg, with a possible 0.35 mg/kg second dose, and ECG/telemetry assessment for acute QT shortening. Enrollment was one, completion was October 23, 2024, and no efficacy conclusion should be drawn without posted peer-reviewed results. Diltiazem is therefore experimental, not standard JLNS2 treatment. (NCT06534671 chunk 1)
Primary prevention of the genotype is possible only through informed reproductive choices: carrier testing in at-risk relatives, genetic counseling, prenatal diagnosis, donor gametes, or preimplantation genetic testing. There is no vaccine or environmental primary prevention.
Secondary prevention consists of newborn hearing screening followed by ECG/genetic evaluation, cascade testing, early β-blockade, and identification of concealed disease. Tertiary prevention includes medication adherence, QT-drug avoidance, electrolyte management, emergency action plans, supervised exercise decisions, ICD/LCSD where indicated, and safe anesthesia planning.
Families should be counseled about autosomal-recessive recurrence, variable cardiac expression, CPR/AED access, recognition of arrhythmic syncope, and informing schools, dentists, surgeons, and anesthesiologists. Public-health sanitation or infectious-disease control is not relevant.
No well-established naturally occurring veterinary syndrome equivalent to human JLNS2 was identified. There is no zoonotic potential or cross-species transmission because this is an inherited channelopathy.
Orthologous Kcne1 is conserved in laboratory mouse, Mus musculus, NCBI Taxonomy 10090. The relevant comparative biology is experimental rather than a common spontaneous veterinary disease. A spontaneous mouse nonsense allele, Kcne1^pkr (“punk rocker,” p.Arg67Ter), produces an auditory/vestibular phenotype. (faridi2019mutationalandphenotypic pages 9-11)
Three Kcne1-null mouse alleles are reported: two engineered coding-exon deletions and the spontaneous p.Arg67Ter punk-rocker allele. Homozygous animals are deaf; heterozygotes have normal hearing. Cochlear findings include collapsed Reissner membrane and hair-cell degeneration, and punk-rocker mice display head tossing consistent with vestibular dysfunction. These findings strongly recapitulate the recessive inner-ear component of human JLNS2. (faridi2019mutationalandphenotypic pages 9-11)
Cardiac recapitulation is inconsistent: one line showed longer QT at slow rates and shorter QT at fast rates, another increased inducible arrhythmia, and another no ECG difference. A major limitation is the mouse resting heart rate of approximately 500–700 beats/minute, which complicates QT measurement and makes the model less faithful for human ventricular repolarization. Mouse inner-ear architecture is much more suitable for studying the auditory mechanism. (faridi2019mutationalandphenotypic pages 9-11)
Suggested model annotations include mammalian genetic knockout, homozygous null, nonsense knock-in/spontaneous mutant, auditory brainstem response, ECG/telemetry, cochlear histopathology, strial marginal cell, hair cell, and vestibular dark cell. Patient-derived iPSC cardiomyocytes are the leading human cellular model for variant causality and drug testing, although a large JLNS2-specific iPSC dataset was not identified. (yu2023precisionmedicinefor pages 1-2)
References
(faridi2019mutationalandphenotypic pages 9-11): Rabia Faridi, Risa Tona, Alessandra Brofferio, Michael Hoa, Rafal Olszewski, Isabelle Schrauwen, Muhammad Z.K. Assir, Akhtar A. Bandesha, Asma A. Khan, Atteeq U. Rehman, Carmen Brewer, Wasim Ahmed, Suzanne M. Leal, Sheikh Riazuddin, Steven E. Boyden, and Thomas B. Friedman. Mutational and phenotypic spectra of kcne1 deficiency in jervell and lange‐nielsen syndrome and romano‐ward syndrome. Human Mutation, 40:162-176, Dec 2019. URL: https://doi.org/10.1002/humu.23689, doi:10.1002/humu.23689. This article has 47 citations and is from a domain leading peer-reviewed journal.
(faridi2019mutationalandphenotypic pages 8-9): Rabia Faridi, Risa Tona, Alessandra Brofferio, Michael Hoa, Rafal Olszewski, Isabelle Schrauwen, Muhammad Z.K. Assir, Akhtar A. Bandesha, Asma A. Khan, Atteeq U. Rehman, Carmen Brewer, Wasim Ahmed, Suzanne M. Leal, Sheikh Riazuddin, Steven E. Boyden, and Thomas B. Friedman. Mutational and phenotypic spectra of kcne1 deficiency in jervell and lange‐nielsen syndrome and romano‐ward syndrome. Human Mutation, 40:162-176, Dec 2019. URL: https://doi.org/10.1002/humu.23689, doi:10.1002/humu.23689. This article has 47 citations and is from a domain leading peer-reviewed journal.
(faridi2019mutationalandphenotypic pages 1-3): Rabia Faridi, Risa Tona, Alessandra Brofferio, Michael Hoa, Rafal Olszewski, Isabelle Schrauwen, Muhammad Z.K. Assir, Akhtar A. Bandesha, Asma A. Khan, Atteeq U. Rehman, Carmen Brewer, Wasim Ahmed, Suzanne M. Leal, Sheikh Riazuddin, Steven E. Boyden, and Thomas B. Friedman. Mutational and phenotypic spectra of kcne1 deficiency in jervell and lange‐nielsen syndrome and romano‐ward syndrome. Human Mutation, 40:162-176, Dec 2019. URL: https://doi.org/10.1002/humu.23689, doi:10.1002/humu.23689. This article has 47 citations and is from a domain leading peer-reviewed journal.
(OpenTargets Search: Jervell and Lange-Nielsen syndrome-KCNE1): Open Targets Query (Jervell and Lange-Nielsen syndrome-KCNE1, 8 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(faridi2019mutationalandphenotypic pages 3-4): Rabia Faridi, Risa Tona, Alessandra Brofferio, Michael Hoa, Rafal Olszewski, Isabelle Schrauwen, Muhammad Z.K. Assir, Akhtar A. Bandesha, Asma A. Khan, Atteeq U. Rehman, Carmen Brewer, Wasim Ahmed, Suzanne M. Leal, Sheikh Riazuddin, Steven E. Boyden, and Thomas B. Friedman. Mutational and phenotypic spectra of kcne1 deficiency in jervell and lange‐nielsen syndrome and romano‐ward syndrome. Human Mutation, 40:162-176, Dec 2019. URL: https://doi.org/10.1002/humu.23689, doi:10.1002/humu.23689. This article has 47 citations and is from a domain leading peer-reviewed journal.
(balestra2024congenitallongqt pages 4-5): Elia Balestra, Marco Bobbo, Marco Cittar, Daniela Chicco, Biancamaria D’Agata Mottolese, Egidio Barbi, and Thomas Caiffa. Congenital long qt syndrome in children and adolescents: a general overview. Children, 11:582, May 2024. URL: https://doi.org/10.3390/children11050582, doi:10.3390/children11050582. This article has 20 citations.
(balestra2024congenitallongqt pages 5-8): Elia Balestra, Marco Bobbo, Marco Cittar, Daniela Chicco, Biancamaria D’Agata Mottolese, Egidio Barbi, and Thomas Caiffa. Congenital long qt syndrome in children and adolescents: a general overview. Children, 11:582, May 2024. URL: https://doi.org/10.3390/children11050582, doi:10.3390/children11050582. This article has 20 citations.
(qiu2020jervellandlangenielsen pages 1-2): Yue Qiu, Sen Chen, Xia Wu, Wen-Juan Zhang, Wen Xie, Yuan Jin, Le Xie, Kai Xu, Xue Bai, Hui-Min Zhang, Xiao-Zhou Liu, Xiao-Hui Wang, Yu Sun, and Wei-Jia Kong. Jervell and lange-nielsen syndrome due to a novel compound heterozygous kcnq1 mutation in a chinese family. Neural Plasticity, 2020:1-8, May 2020. URL: https://doi.org/10.1155/2020/3569359, doi:10.1155/2020/3569359. This article has 14 citations and is from a peer-reviewed journal.
(balestra2024congenitallongqt pages 8-9): Elia Balestra, Marco Bobbo, Marco Cittar, Daniela Chicco, Biancamaria D’Agata Mottolese, Egidio Barbi, and Thomas Caiffa. Congenital long qt syndrome in children and adolescents: a general overview. Children, 11:582, May 2024. URL: https://doi.org/10.3390/children11050582, doi:10.3390/children11050582. This article has 20 citations.
(qiu2020jervellandlangenielsen pages 5-7): Yue Qiu, Sen Chen, Xia Wu, Wen-Juan Zhang, Wen Xie, Yuan Jin, Le Xie, Kai Xu, Xue Bai, Hui-Min Zhang, Xiao-Zhou Liu, Xiao-Hui Wang, Yu Sun, and Wei-Jia Kong. Jervell and lange-nielsen syndrome due to a novel compound heterozygous kcnq1 mutation in a chinese family. Neural Plasticity, 2020:1-8, May 2020. URL: https://doi.org/10.1155/2020/3569359, doi:10.1155/2020/3569359. This article has 14 citations and is from a peer-reviewed journal.
(yu2023precisionmedicinefor pages 1-2): Yang Yu, Isabelle Deschenes, and Ming-Tao Zhao. Precision medicine for long qt syndrome: patient-specific ipscs take the lead. Expert Reviews in Molecular Medicine, Jan 2023. URL: https://doi.org/10.1017/erm.2022.43, doi:10.1017/erm.2022.43. This article has 23 citations and is from a peer-reviewed journal.
(yu2023precisionmedicinefor pages 7-8): Yang Yu, Isabelle Deschenes, and Ming-Tao Zhao. Precision medicine for long qt syndrome: patient-specific ipscs take the lead. Expert Reviews in Molecular Medicine, Jan 2023. URL: https://doi.org/10.1017/erm.2022.43, doi:10.1017/erm.2022.43. This article has 23 citations and is from a peer-reviewed journal.
(NCT06534671 chunk 1): Prince Joseph Kannankeril. Diltiazem in Jervell and Lange-Nielsen Syndrome. Vanderbilt University Medical Center. 2024. ClinicalTrials.gov Identifier: NCT06534671
(yu2023precisionmedicinefor pages 2-2): Yang Yu, Isabelle Deschenes, and Ming-Tao Zhao. Precision medicine for long qt syndrome: patient-specific ipscs take the lead. Expert Reviews in Molecular Medicine, Jan 2023. URL: https://doi.org/10.1017/erm.2022.43, doi:10.1017/erm.2022.43. This article has 23 citations and is from a peer-reviewed journal.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 4 |
| Resolved | 4 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 4 |
| On topic | 1 |
| Off topic | 0 |
All extracted references resolved successfully.