Jervell and Lange-Nielsen syndrome 1 (JLNS1) is a rare, severe autosomal recessive cardioauditory channelopathy caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in KCNQ1, the gene encoding the pore-forming alpha subunit (Kv7.1/KvLQT1) of the slow delayed-rectifier potassium channel (I_Ks). It is the allelic, biallelic counterpart of autosomal dominant LQT1 (heterozygous KCNQ1 variants, curated in Familial Long QT Syndrome): near-complete loss of KCNQ1-KCNE1 channel function abolishes both cardiac I_Ks-mediated repolarization and the stria vascularis marginal-cell K+-secretion current that maintains the endocochlear potential, producing the syndrome's defining combination of congenital profound bilateral sensorineural hearing loss and markedly prolonged QTc with high risk of torsades de pointes, syncope, and sudden cardiac death from early childhood. This entry is the KCNQ1-caused subtype (JLNS1, ~90% of JLNS cases); the allelic KCNE1-caused subtype (JLNS2, MONDO:0012871) is curated separately.
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name: Jervell and Lange-Nielsen Syndrome 1
creation_date: "2026-08-17T00:00:00Z"
category: Mendelian
description: >-
Jervell and Lange-Nielsen syndrome 1 (JLNS1) is a rare, severe autosomal
recessive cardioauditory channelopathy caused by biallelic (homozygous or
compound heterozygous) loss-of-function variants in KCNQ1, the gene
encoding the pore-forming alpha subunit (Kv7.1/KvLQT1) of the slow
delayed-rectifier potassium channel (I_Ks). It is the allelic, biallelic
counterpart of autosomal dominant LQT1 (heterozygous KCNQ1 variants,
curated in Familial Long QT Syndrome): near-complete loss of KCNQ1-KCNE1
channel function abolishes both cardiac I_Ks-mediated repolarization and
the stria vascularis marginal-cell K+-secretion current that maintains the
endocochlear potential, producing the syndrome's defining combination of
congenital profound bilateral sensorineural hearing loss and markedly
prolonged QTc with high risk of torsades de pointes, syncope, and sudden
cardiac death from early childhood. This entry is the KCNQ1-caused subtype
(JLNS1, ~90% of JLNS cases); the allelic KCNE1-caused subtype (JLNS2,
MONDO:0012871) is curated separately.
disease_term:
preferred_term: Jervell and Lange-Nielsen syndrome 1
term:
id: MONDO:0024540
label: Jervell and Lange-Nielsen syndrome 1
synonyms:
- Jervell and Lange-Nielsen syndrome
- JLNS1
- KCNQ1 Jervell and Lange-Nielsen syndrome
- Jervell and Lange-Nielsen syndrome caused by mutation in KCNQ1
- cardioauditory syndrome of Jervell and Lange-Nielsen, KCNQ1-related
- surdocardiac syndrome
parents:
- Cardiac Arrhythmia
- Channelopathy
- Sensorineural Hearing Loss
notes: >-
Curated as the KCNQ1-caused subtype of Jervell and Lange-Nielsen syndrome
per the MONDO gene-specific disease-series pattern. Distinct from the
allelic dominant Romano-Ward/LQT1 entry (Familial Long QT Syndrome,
MONDO:0019171), which is heterozygous and not associated with congenital
deafness, and from JLNS2 (MONDO:0012871, KCNE1), curated separately.
Deep-research preflight (`just preflight-dr`) returned WARN on the falcon
report because KCNE1 (JLNS2's gene) is discussed alongside KCNQ1 throughout
the source literature (both genes cause the same clinical syndrome and are
reviewed together, e.g. GeneReviews and the Schwartz 2006 187-patient
cohort) rather than because of entity confusion; the report itself
explicitly separates JLNS1/KCNQ1 from JLNS2/KCNE1 in a scope statement, and
only KCNQ1-attributed genetic and mechanistic claims were curated into this
entry.
references:
- reference: PMID:20301579
title: "Jervell and Lange-Nielsen Syndrome."
tags:
- GeneReviews
pathophysiology:
- name: Biallelic KCNQ1 Loss-of-Function Variants
biological_scale: MOLECULAR
role: trigger
conforms_to: cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant
description: >-
Homozygous or compound heterozygous germline loss-of-function variants
(missense, nonsense, frameshift, or splice-site) in KCNQ1 disrupt voltage
sensing, pore conductance, tetramer assembly, KCNE1 co-assembly, or
plasma-membrane trafficking of the Kv7.1 channel subunit. Because the
heart tolerates I_Ks loss far less well than the inner ear, JLNS
(cardioauditory disease) requires near-complete loss of KCNQ1 function
(reported as <10% of normal channel protein level in one mechanistic
study), whereas milder residual-function biallelic genotypes instead
produce recessive LQT1 without deafness.
genes:
- preferred_term: KCNQ1
term:
id: hgnc:6294
label: KCNQ1
molecular_functions:
- preferred_term: delayed rectifier potassium channel activity
term:
id: GO:0005251
label: delayed rectifier potassium channel activity
modifier: LOSS_OF_FUNCTION
genetic_context:
gene:
preferred_term: KCNQ1
term:
id: hgnc:6294
label: KCNQ1
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
allele_type: >-
missense, nonsense, frameshift, or splice-site; biallelic
(homozygous or compound heterozygous)
description: >-
Reported JLNS1 genotypes include homozygous c.728G>A (p.Arg243His),
compound heterozygous c.477+1G>A / c.520C>T (p.Arg174Cys), homozygous
c.1097G>A (p.Arg366Gln), and compound heterozygous c.1741A>T
(p.Lys581Ter) / c.477+5G>A.
evidence:
- reference: PMID:9020846
reference_title: "A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal
domain of this gene was detected in three affected children of two
families.
explanation: >-
Original report identifying a homozygous KVLQT1 (KCNQ1) mutation as the
cause of Jervell and Lange-Nielsen syndrome, establishing the
biallelic loss-of-function trigger.
- reference: PMID:41147441
reference_title: "Molecular mechanisms of function deficiencies in KCNQ1 variants associated with Jervell and Lange-Nielsen syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The results demonstrated that all the variants resulted in functional
deficiencies, with impaired localization in the plasma membrane being
the most common cause.
explanation: >-
Systematic electrophysiological and trafficking characterization of 18
JLNS-associated KCNQ1 variants shows loss-of-function through impaired
membrane trafficking or disrupted KCNQ1-KCNE1/calmodulin interaction.
- reference: PMID:33498651
reference_title: "Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
it was shown that only KCNQ1 protein levels lower than 10% of the
normal level lead to JLNS
explanation: >-
Establishes the gene-dosage threshold distinguishing the severe
cardioauditory JLNS phenotype from milder residual-function biallelic
KCNQ1 genotypes (recessive LQT1 without deafness).
downstream:
- target: Near-Complete Loss of Cardiac I_Ks Repolarizing Current
description: >-
Loss-of-function KCNQ1 alleles abolish the KCNQ1-KCNE1 I_Ks current in
ventricular cardiomyocytes.
- target: Loss of Stria Vascularis Endolymphatic K+ Secretion
description: >-
The same loss-of-function alleles abolish the KCNQ1-KCNE1 apical
potassium-secretion current in stria vascularis marginal cells.
- target: Impaired Gastric Parietal Cell Luminal K+ Recycling
description: >-
KCNQ1 also provides the apical luminal K+-recycling current required
for H+/K+-ATPase-driven gastric acid secretion in parietal cells.
- name: Near-Complete Loss of Cardiac I_Ks Repolarizing Current
biological_scale: CELLULAR
role: central_effector
conforms_to: cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling
description: >-
With both KCNQ1 alleles nonfunctional, the KCNQ1-KCNE1 slow delayed
rectifier current (I_Ks) that normally mediates phase-3 repolarization
and heart-rate-dependent shortening of the action potential is nearly
abolished, sharply reducing repolarization reserve in ventricular
cardiomyocytes.
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
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
evidence:
- reference: PMID:33498651
reference_title: "Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Together with its ß-subunit KCNE1, also denoted as minK, this channel
generates the slowly activating cardiac delayed rectifier current IKs,
which is a key regulator of the heart rate dependent adaptation of the
cardiac action potential duration (APD).
explanation: >-
Establishes the KCNQ1-KCNE1 I_Ks current as the cardiac repolarizing
current lost when KCNQ1 is biallelically nonfunctional.
- reference: PMID:11226272
reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
ECGs recorded from Kcnq1(-/-) mice demonstrated abnormal T- and P-wave
morphologies and prolongation of the QT and JT intervals when measured
in vivo, but not in isolated hearts.
explanation: >-
Direct electrophysiological evidence that complete loss of Kcnq1
prolongs cardiac repolarization intervals in vivo.
downstream:
- target: Markedly Prolonged QTc and Arrhythmogenic Substrate
description: >-
Loss of I_Ks-mediated repolarization prolongs ventricular action
potential duration, especially at higher heart rates, and creates
dispersion of repolarization.
- name: Markedly Prolonged QTc and Arrhythmogenic Substrate
biological_scale: TISSUE
role: amplifier
conforms_to: cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity
description: >-
Loss of repolarization reserve produces markedly prolonged QTc (mean
557+/-65 ms in a 187-patient cohort, most >500 ms) with early
afterdepolarizations and regional dispersion of repolarization,
generating the arrhythmogenic substrate for torsades de pointes. JLNS is
typically more severely affected than heterozygous (Romano-Ward) LQT1
and than the allelic KCNE1-caused JLNS2.
cell_types:
- preferred_term: cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: cardiac muscle cell action potential
term:
id: GO:0086001
label: cardiac muscle cell action potential
modifier: ABNORMAL
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Their QTc was markedly prolonged (557+/-65 ms).
explanation: >-
Quantifies the markedly prolonged QTc across a 187-patient J-LN cohort,
the tissue-level arrhythmogenic substrate.
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1
gene are associated with a more benign course.
explanation: >-
Establishes that KCNQ1-related JLNS1 carries a more severe course than
the allelic KCNE1-related JLNS2, supporting the disease-level severity
note.
downstream:
- target: Torsades de Pointes and Ventricular Fibrillation
description: >-
The arrhythmogenic substrate supports triggered and reentrant
malignant ventricular tachyarrhythmia.
- name: Torsades de Pointes and Ventricular Fibrillation
biological_scale: ORGANISM
role: effector
conforms_to: cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia
description: >-
Triggered activity on the dispersed-repolarization substrate produces
torsades de pointes, which may degenerate into ventricular fibrillation.
Nearly all arrhythmic events (95%) are precipitated by adrenergic
triggers (emotion, exercise, sudden auditory stimuli, fever, or
anesthesia), reflecting the severely reduced repolarization reserve.
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most of the arrhythmic events (95%) were triggered by emotions or
exercise.
explanation: >-
Documents the adrenergic/physiologic trigger pattern for malignant
ventricular tachyarrhythmia in JLNS.
- reference: PMID:32508908
reference_title: "Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
life-threatening arrhythmias occurred with a trigger of anesthesia
after the end of the CI surgery
explanation: >-
Case report documenting anesthesia-triggered life-threatening
ventricular arrhythmia in a KCNQ1-JLNS1 patient, illustrating the
trigger-susceptibility mechanism.
downstream:
- target: Syncope, Cardiac Arrest, and Sudden Cardiac Death
description: >-
Sustained ventricular tachyarrhythmia abolishes effective cardiac
output, causing syncope and, if unresolved, sudden cardiac death.
- name: Syncope, Cardiac Arrest, and Sudden Cardiac Death
biological_scale: ORGANISM
role: outcome
conforms_to: cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death
description: >-
Loss of effective cardiac output during ventricular tachyarrhythmia
causes syncope, sometimes misdiagnosed as a seizure, and, if the rhythm
does not terminate, cardiac arrest or sudden death. JLNS has an early
onset and a malignant course: 86% of patients had cardiac events, half
were already symptomatic by age three, and more than half of untreated
children died before age 15.
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Most patients (86%) had cardiac events, and 50% were already
symptomatic by age 3.
explanation: >-
Quantifies the early, malignant clinical course of JLNS from the
largest published cohort.
- 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 summary of the natural history mortality burden without
treatment, the terminal outcome of this node.
- name: Loss of Stria Vascularis Endolymphatic K+ Secretion
biological_scale: CELLULAR
role: amplifier
conforms_to: sensorineural_hair_cell_loss#Cochlear Ionic Homeostasis Disruption and Oxidative Stress
description: >-
KCNQ1 co-assembles with KCNE1 at the apical membrane of stria vascularis
marginal cells, where the resulting K+-diffusion current is one of two
mechanisms (alongside the Kir4.1-dependent intrastrial potential)
generating the highly positive endocochlear potential and secreting K+
into endolymph. Biallelic KCNQ1 loss abolishes this apical current,
collapsing K+ secretion and the endocochlear potential.
cell_types:
- preferred_term: strial marginal cell
term:
id: CL:0002492
label: strial marginal cell
biological_processes:
- preferred_term: potassium ion homeostasis
term:
id: GO:0055075
label: potassium ion homeostasis
modifier: DYSREGULATED
locations:
- preferred_term: stria vascularis of cochlear duct
term:
id: UBERON:0002282
label: stria vascularis of cochlear duct
evidence:
- reference: PMID:20012478
reference_title: "How is the highly positive endocochlear potential formed? The specific architecture of the stria vascularis and the roles of the ion-transport apparatus."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
An additional K+-diffusion potential formed by KCNQ1/KCNE1-K(+)
channels at the apical membranes of marginal cells also contributes to
the EP.
explanation: >-
Mechanistic review establishing the KCNQ1/KCNE1 apical channel as one
of the two K+-diffusion potentials that form the endocochlear
potential in stria vascularis marginal cells.
- reference: PMID:9020846
reference_title: "A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We found that KVLQT1 is expressed in the stria vascularis of mouse
inner ear by in situ hybridization.
explanation: >-
Localizes KCNQ1 (KVLQT1) expression to the stria vascularis, the site
of endolymphatic K+ secretion.
downstream:
- target: Organ of Corti Hair Cell Degeneration
description: >-
Collapse of endolymph volume and the endocochlear potential
precipitates structural collapse and secondary hair-cell injury.
- name: Organ of Corti Hair Cell Degeneration
biological_scale: CELLULAR
role: central_effector
conforms_to: sensorineural_hair_cell_loss#Hair Cell Mechanotransduction Failure and Death
description: >-
Loss of endolymph volume and the endocochlear potential causes collapse
of Reissner's membrane and the endolymphatic compartments, with
consequent degeneration of the organ of Corti hair cells, which do not
regenerate in mammals.
cell_types:
- preferred_term: cochlear hair cell
term:
id: CL:0000855
label: sensory hair cell
biological_processes:
- preferred_term: apoptotic process
term:
id: GO:0006915
label: apoptotic process
modifier: INCREASED
locations:
- preferred_term: organ of Corti
term:
id: UBERON:0002227
label: spiral organ of cochlea
evidence:
- reference: PMID:15891643
reference_title: "Inner ear abnormalities in a Kcnq1 (Kvlqt1) knockout mouse: a model of Jervell and Lange-Nielsen syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Kcnq1 knockout mice were deaf and demonstrated circling behavior. They
exhibited a marked atrophy of the stria vascularis, contraction of the
endolymphatic compartments, and collapse and adhesion of surrounding
membranes. There was a complete degeneration of the organ of Corti and
an associated degeneration of the spiral ganglion.
explanation: >-
Direct histopathologic evidence that loss of functional Kcnq1
produces stria vascularis atrophy, endolymphatic compartment collapse,
and organ of Corti hair-cell degeneration.
downstream:
- target: Spiral Ganglion Neuron Degeneration and Loss of Cochlear Amplification
description: >-
Hair-cell loss removes cochlear amplification and deafferents the
auditory nerve, driving spiral ganglion neuron degeneration.
- name: Spiral Ganglion Neuron Degeneration and Loss of Cochlear Amplification
biological_scale: CELLULAR
role: effector
conforms_to: sensorineural_hair_cell_loss#Cochlear Amplification Loss and Spiral Ganglion Neuron Degeneration
description: >-
Deafferentation following hair-cell loss, combined with the reduced
endocochlear potential, abolishes active cochlear amplification and
drives degeneration of the afferent spiral ganglion neurons that form
the auditory nerve.
cell_types:
- preferred_term: spiral ganglion neuron
term:
id: CL:0011113
label: spiral ganglion neuron
biological_processes:
- preferred_term: neuron apoptotic process
term:
id: GO:0051402
label: neuron apoptotic process
modifier: INCREASED
evidence:
- reference: PMID:15891643
reference_title: "Inner ear abnormalities in a Kcnq1 (Kvlqt1) knockout mouse: a model of Jervell and Lange-Nielsen syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
There was a complete degeneration of the organ of Corti and an
associated degeneration of the spiral ganglion.
explanation: >-
Documents spiral ganglion degeneration coupled to hair-cell loss in
the Kcnq1 knockout mouse model.
downstream:
- target: Congenital Profound Bilateral Sensorineural Hearing Loss
description: >-
Combined irreversible loss of hair cells, cochlear amplification, and
spiral ganglion neurons produces permanent hearing loss.
- name: Congenital Profound Bilateral Sensorineural Hearing Loss
biological_scale: ORGANISM
role: consequence
conforms_to: sensorineural_hair_cell_loss#Progressive Sensorineural Hearing Loss
description: >-
The combined cochlear injury produces profound bilateral sensorineural
hearing loss present from birth or recognized in early infancy. Unlike
the noise/age/ototoxic triggers of the generic module, the JLNS1 deficit
is congenital and essentially maximal at onset rather than progressive,
but it shares the module's irreversibility because the mammalian cochlea
does not regenerate.
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
explanation: >-
GeneReviews defines the syndrome's cochlear consequence as congenital
profound bilateral sensorineural hearing loss.
- reference: PMID:11226272
reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Behavioral analysis revealed that the Kcnq1(-/-) mice are deaf and
exhibit a shaker/waltzer phenotype.
explanation: >-
Confirms complete deafness (plus vestibular shaker/waltzer behavior)
in the Kcnq1 knockout mouse, recapitulating the human hearing-loss
consequence.
- name: Impaired Gastric Parietal Cell Luminal K+ Recycling
biological_scale: CELLULAR
role: amplifier
description: >-
KCNQ1 (paired with KCNE2, not KCNE1, in the stomach) provides the apical
luminal K+-recycling current required to sustain H+/K+-ATPase-driven
gastric acid secretion in parietal cells; no other gastric K+ channel
substitutes for this function.
cell_types:
- preferred_term: gastric parietal cell
term:
id: CL:0000162
label: parietal cell
biological_processes:
- preferred_term: gastric acid secretion
term:
id: GO:0001696
label: gastric acid secretion
modifier: DECREASED
locations:
- preferred_term: stomach
term:
id: UBERON:0000945
label: stomach
evidence:
- reference: PMID:19491250
reference_title: "KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The study demonstrates that the KCNQ1 channel provides K(+) to the
extracellular K(+) binding site of the H(+)/K(+)-ATPase during acid
secretion, and no other gastric K(+) channel can substitute for this
function.
explanation: >-
Kcnq1-knockout mouse gastric mucosa study establishing KCNQ1 as the
obligate luminal K+-recycling channel for parietal-cell acid
secretion.
- reference: PMID:19491250
reference_title: "KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
basal acid secretion was absent and forskolin-stimulated acid output
reduced by approximately 90% in KCNQ1(-/-) gastric mucosa
explanation: >-
Quantifies the near-abolition of stimulated gastric acid secretion in
Kcnq1-null mucosa, the cellular basis of the achlorhydria/hypergastrinemia
branch.
downstream:
- target: Achlorhydria, Hypergastrinemia, and Iron Deficiency Anemia
description: >-
Reduced gastric acid secretion causes compensatory hypergastrinemia
and impairs the acid-dependent conversion of dietary iron needed for
absorption.
- name: Achlorhydria, Hypergastrinemia, and Iron Deficiency Anemia
biological_scale: ORGANISM
role: consequence
description: >-
Loss of KCNQ1-dependent gastric acid secretion produces achlorhydria,
with compensatory elevation of serum gastrin (loss of acid-mediated
negative feedback on G cells) and iron-deficiency anemia from impaired
acid-dependent dietary iron absorption. GeneReviews lists both as
frequent, non-cardioauditory features of JLNS.
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 documents iron-deficiency anemia and hypergastrinemia as
frequent extracardiac, extra-auditory features of JLNS, consistent
with the gastric parietal-cell mechanism.
phenotypes:
- name: Congenital Profound Bilateral Sensorineural Hearing Loss
category: Congenital
phenotype_term:
preferred_term: Profound sensorineural hearing impairment
term:
id: HP:0011476
label: Profound sensorineural hearing impairment
onset:
onset_category: CONGENITAL
description: >-
Bilateral, profound sensorineural deafness present from birth or
recognized in early infancy; the cardinal auditory feature of JLNS.
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 profound congenital bilateral sensorineural hearing loss as a cardinal feature.
- name: Prolonged QTc Interval
phenotype_term:
preferred_term: Prolonged QTc interval
term:
id: HP:0005184
label: Prolonged QTc interval
description: >-
Markedly prolonged corrected QT interval on ECG, mean 557+/-65 ms in the
largest published cohort, commonly used as a diagnostic threshold (>500
ms) for JLNS.
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Their QTc was markedly prolonged (557+/-65 ms)."
explanation: Quantifies the markedly prolonged QTc across a 187-patient J-LN cohort.
- name: Torsade de Pointes
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 of JLNS.
- name: Ventricular Fibrillation
phenotype_term:
preferred_term: Ventricular fibrillation
term:
id: HP:0001663
label: Ventricular fibrillation
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 ventricular fibrillation as a characteristic tachyarrhythmia of JLNS.
- name: Syncope
phenotype_term:
preferred_term: Syncope
term:
id: HP:0001279
label: Syncope
temporality: RECURRENT
frequency: FREQUENT
description: >-
Episodic loss of consciousness, typically triggered by emotion or
exercise, often the presenting symptom in a child later found to be
deaf.
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most of the arrhythmic events (95%) were triggered by emotions or exercise."
explanation: Documents the frequency and adrenergic trigger pattern of arrhythmic syncopal events.
- name: Sudden Cardiac Death
phenotype_term:
preferred_term: Sudden cardiac death
term:
id: HP:0001645
label: Sudden cardiac death
description: >-
Unexpected death from an unterminated ventricular tachyarrhythmia; more
than half of untreated children with JLNS die before age 15.
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 natural-history statement on JLNS mortality without treatment.
- reference: PMID:32508908
reference_title: "Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia"
explanation: Independent case-report source quantifying sudden cardiac death risk in JLNS.
- name: Seizure-Like Episodes
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
description: >-
Arrhythmia-induced anoxic/seizure-like episodes from cerebral
hypoperfusion during ventricular tachyarrhythmia; frequently misdiagnosed
as epilepsy in deaf children who are not yet known to have JLNS.
evidence:
- reference: PMID:29037160
reference_title: "\"Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports\"."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three patients were admitted into hospital due to recurrent
seizures/syncope, intrauterine and postnatal bradycardia respectively;
moreover all three patients had congenital sensorineural hearing-loss.
explanation: Case series documenting seizure-like presenting episodes alongside congenital deafness in KCNQ1-JLNS.
- name: Bradycardia
phenotype_term:
preferred_term: Bradycardia
term:
id: HP:0001662
label: Bradycardia
description: >-
Intrauterine or neonatal bradycardia has been reported as an early
presenting cardiac sign in severe KCNQ1-JLNS.
evidence:
- reference: PMID:29037160
reference_title: "\"Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports\"."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three patients were admitted into hospital due to recurrent
seizures/syncope, intrauterine and postnatal bradycardia respectively
explanation: Documents intrauterine/postnatal bradycardia as a presenting feature in a KCNQ1-JLNS case series.
- name: Iron Deficiency Anemia
phenotype_term:
preferred_term: Iron deficiency anemia
term:
id: HP:0001891
label: Iron deficiency anemia
frequency: FREQUENT
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 documents iron-deficiency anemia as a frequent non-cardioauditory feature.
- name: Hypergastrinemia
phenotype_term:
preferred_term: Hypergastrinemia
term:
id: HP:0500167
label: Hypergastrinemia
frequency: FREQUENT
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 documents elevated gastrin as a frequent non-cardioauditory feature.
- name: Achlorhydria
phenotype_term:
preferred_term: Achlorhydria
term:
id: HP:0032448
label: Achlorhydria
description: >-
Loss of gastric acid secretion is the mechanistic link explaining the
frequent hypergastrinemia and iron-deficiency anemia documented in human
JLNS; direct measurement of absent gastric acid secretion is from the
Kcnq1-knockout mouse model rather than a human JLNS cohort.
evidence:
- reference: PMID:19491250
reference_title: "KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
basal acid secretion was absent and forskolin-stimulated acid output
reduced by approximately 90% in KCNQ1(-/-) gastric mucosa
explanation: >-
Direct measurement of achlorhydria (absent basal and near-abolished
stimulated gastric acid secretion) in the Kcnq1-null mouse gastric
mucosa.
- 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 documents the downstream human consequences of
achlorhydria (hypergastrinemia, iron-deficiency anemia) as frequent
features, providing indirect (partial) human corroboration; it does
not directly measure gastric acid secretion in JLNS patients.
genetic:
- name: KCNQ1
gene_term:
preferred_term: KCNQ1
term:
id: hgnc:6294
label: KCNQ1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
frequency: >-
the major molecular subtype of JLNS, accounting for the large majority
of cases
case_fractions:
- population: JLNS cases (mixed-cohort/case-based literature)
case_fraction_percent: 90.0
notes: >-
Approximately 90% of JLNS cases are attributable to biallelic KCNQ1
variants; the remainder are attributable to KCNE1 (JLNS2).
evidence:
- reference: PMID:32508908
reference_title: "Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family."
supports: SUPPORT
evidence_source: OTHER
snippet: "Approximately 90% of JLNS cases are caused by KCNQ1 gene mutations."
explanation: Quantifies the KCNQ1 (JLNS1) share of all JLNS cases.
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course."
explanation: Independent cohort confirms the ~90% KCNQ1 share and the more severe course relative to KCNE1-related JLNS2.
- reference: PMID:37872640
reference_title: "Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
both PTCs and missense variants leading to LoF of KCNQ1 are associated
with LQTS and Jervell Lange-Nielsen syndrome
explanation: >-
Structured ClinGen-aligned gene-disease curation confirms KCNQ1
loss-of-function (protein-truncating and missense) as the JLNS1
mechanism, classified with biallelic autosomal requirement.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
penetrance: INCOMPLETE
description: >-
JLNS1 requires biallelic (homozygous or compound heterozygous)
loss-of-function KCNQ1 variants. Heterozygous carrier parents are usually
unaffected or, less often, manifest dominant Romano-Ward LQT1; each
sibling of an affected individual has a 25% chance of being affected, a
50% chance of being a carrier, and a 25% chance of being unaffected and
not a carrier. Penetrance of the classic cardioauditory phenotype is high
but not complete: some biallelic genotypes with residual channel
function instead cause recessive LQT1 without deafness.
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
explanation: GeneReviews describes the autosomal recessive inheritance pattern and typical carrier-parent status.
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
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 quantifies the recurrence risk to full siblings under autosomal recessive transmission.
prevalence:
- population: Worldwide (all JLNS, KCNQ1 ~90% of cases)
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_1000000
rate_per_100000: 0.3
rate_low: 0.1
rate_high: 0.5
notes: >-
JLNS overall (JLNS1 + JLNS2) is estimated at 1 per 1,000,000 to 1 per
200,000 worldwide; KCNQ1 (JLNS1) accounts for ~90% of these cases.
evidence:
- reference: PMID:32508908
reference_title: "Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family."
supports: SUPPORT
evidence_source: OTHER
snippet: "The prevalence of JLNS is about 1/1000000 to 1/200000 around the world."
explanation: Source for the worldwide JLNS prevalence range.
treatments:
- name: Beta-Blocker Therapy
description: >-
First-line anti-adrenergic pharmacotherapy; nonselective agents (nadolol
or propranolol) are generally preferred over metoprolol for congenital
LQTS. Efficacy is only partial in JLNS: about half of treated patients
still had breakthrough events in the largest cohort.
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: Torsades de Pointes and Ventricular Fibrillation
treatment_effect: INHIBITS
description: >-
Beta-blockade reduces adrenergically triggered arrhythmic events but
has only partial efficacy in JLNS.
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
beta-Blockers have only partial efficacy; 51% of the patients had
events despite therapy and 27% had CA/SD.
explanation: >-
Quantifies the partial efficacy of beta-blocker therapy in the
largest JLNS cohort.
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 management recommendation and efficacy caveat.
- name: Implantable Cardioverter-Defibrillator Placement
description: >-
Device therapy recommended for patients with a history of cardiac
arrest, ventricular fibrillation, or failure to respond to beta-blocker
therapy, given the malignant natural history of JLNS.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: implantable cardioverter-defibrillator placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
target_mechanisms:
- target: Syncope, Cardiac Arrest, and Sudden Cardiac Death
treatment_effect: INHIBITS
description: >-
ICD therapy terminates sustained ventricular tachyarrhythmia before it
progresses to sudden cardiac death.
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 management recommendation for ICD placement.
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Early therapy with implanted cardioverter/defibrillators must be considered."
explanation: Cohort-based recommendation for early ICD consideration given the malignant course of JLNS.
- name: Left Cardiac Sympathetic Denervation
description: >-
Surgical anti-adrenergic escalation considered for recurrent syncope or
breakthrough ventricular arrhythmia despite full-dose beta-blockade, or
when ICD implantation is declined or contraindicated.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: left cardiac sympathetic denervation
term:
id: NCIT:C15329
label: Surgical Procedure
target_mechanisms:
- target: Torsades de Pointes and Ventricular Fibrillation
treatment_effect: INHIBITS
description: >-
Left cardiac sympathetic denervation reduces arrhythmia-provoking
sympathetic input when pharmacologic anti-adrenergic therapy is
insufficient.
evidence:
- reference: PMID:18606002
reference_title: Congenital long QT syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
If the patient has one more syncope despite a full dose
beta-blockade, left cardiac sympathetic denervation (LCSD) should be
performed without hesitation
explanation: >-
General congenital-LQTS review recommendation for LCSD escalation,
applicable to JLNS's high breakthrough-event rate on beta-blockers.
evidence:
- reference: PMID:18606002
reference_title: Congenital long QT syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
If the patient has one more syncope despite a full dose beta-blockade,
left cardiac sympathetic denervation (LCSD) should be performed
without hesitation
explanation: Review recommendation for LCSD after recurrent syncope on full-dose beta-blockade.
- name: Cochlear Implantation
description: >-
Standard hearing rehabilitation for profound congenital sensorineural
hearing loss when hearing aids are inadequate; can substantially improve
auditory function, but surgery requires cardiology and anesthesia
planning because peri-anesthetic sympathetic and electrolyte shifts can
trigger life-threatening arrhythmia in JLNS.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: cochlear device implantation
term:
id: NCIT:C15329
label: Surgical Procedure
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: cochlear implant
term:
id: NCIT:C157820
label: Cochlear Implant
notes: >-
The treatment term is the generic surgical action, which is what implantation is.
NCIT:C157820 `Cochlear Implant` exists but denotes the device, not a clinical
action, and is not reachable from NCIT:C25218, so it cannot be the `term:` of a
TreatmentTerm (same gap documented in AFG2A-Related_Encephalopathy.yaml). The
specificity is carried by `preferred_term`, and the device is attached as a
qualifier so it stays queryable. An earlier version bound NCIT:C15315
Rehabilitation.
target_mechanisms:
- target: Congenital Profound Bilateral Sensorineural Hearing Loss
treatment_effect: RESTORES
description: >-
Cochlear implantation bypasses the degenerated cochlear sensory
apparatus to restore auditory input.
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 management recommendation for cochlear implantation.
evidence:
- reference: PMID:32508908
reference_title: "Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The hearing of this patient improved significantly with the help of
cochlear implantation (CI). But life-threatening arrhythmias occurred
with a trigger of anesthesia after the end of the CI surgery.
explanation: >-
Case report demonstrating both the auditory benefit and the
peri-anesthetic arrhythmia risk of cochlear implantation in a
KCNQ1-JLNS1 patient.
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Special precautions during anesthesia are necessary because of the
increased risk for cardiac arrhythmia.
explanation: GeneReviews explicitly flags anesthesia precautions relevant to cochlear implant surgery.
- name: QT-Prolonging Drug and Trigger Avoidance
description: >-
Avoidance of drugs that further prolong the QT interval, and of
activities known to precipitate syncopal events, is a core management
measure because repolarization reserve is already severely reduced.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: risk-factor and trigger-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: >-
Drugs that cause further prolongation of the QT interval; activities
known to precipitate syncopal events in persons with long QT syndrome.
explanation: GeneReviews lists agents and circumstances to avoid for JLNS.
- name: Genetic Counseling
description: >-
Genetic counseling for families, including carrier testing for at-risk
relatives and prenatal or preimplantation testing when familial KCNQ1
variants are known, given the 25% recurrence risk for full siblings.
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: >-
Carrier testing for at-risk relatives and prenatal testing for
pregnancies at increased risk are possible if the pathogenic variants
in the family are known.
explanation: GeneReviews genetic counseling recommendation.
diagnosis:
- name: Integrated Clinical and Molecular Diagnostic Criteria
description: >-
The diagnosis is established clinically by the combination of congenital
sensorineural deafness and a long QT interval, and confirmed molecularly
by identification of biallelic pathogenic variants in KCNQ1 (this
subtype, JLNS1) or KCNE1 (JLNS2).
diagnosis_term:
preferred_term: clinical assessment
term:
id: NCIT:C124351
label: Clinical Evaluation
results: >-
Congenital sensorineural deafness plus a long QT interval, with biallelic
pathogenic KCNQ1 or KCNE1 variants on molecular testing, establishes the
diagnosis.
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 DIAGNOSIS/TESTING section states the integrated clinical and molecular diagnostic criteria.
- name: Resting 12-Lead Electrocardiography with QTc Measurement
description: >-
A resting 12-lead ECG with manual QTc measurement is the core diagnostic
procedure for identifying the markedly prolonged QTc characteristic of
JLNS; secondary (acquired) causes of QTc prolongation, including
electrolyte imbalance, must be excluded before a congenital diagnosis is
made.
diagnosis_term:
preferred_term: clinical assessment
term:
id: NCIT:C124351
label: Clinical Evaluation
results: >-
Markedly prolonged QTc, mean 557+/-65 ms in the largest published cohort,
commonly >500 ms.
notes: >-
NCIT does not provide an ECG-specific diagnostic term here, so the
preferred term is narrowed in the name and description, following the
same pattern used in Familial Long QT Syndrome.
evidence:
- reference: PMID:16461811
reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Their QTc was markedly prolonged (557+/-65 ms)."
explanation: Quantifies the QTc finding on ECG that anchors the diagnosis in the largest published JLNS cohort.
- reference: PMID:38790576
reference_title: "Congenital Long QT Syndrome in Children and Adolescents: A General Overview."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Before diagnosing LQTS on the basis of prolonged QTc, secondary causes
of QTc prolongation must be excluded (e.g., drugs, acquired cardiac
conditions, electrolyte imbalance).
explanation: >-
General congenital-LQTS pediatric overview documents the requirement to
exclude secondary/acquired causes, including electrolyte imbalance,
before a congenital diagnosis is confirmed; applicable to JLNS's
ECG-based diagnostic workup.
- name: Ambulatory Holter Monitoring
description: >-
Ambulatory ECG (Holter) monitoring may be used alongside resting ECG to
assess cardiac rhythm and identify arrhythmic events supporting the
diagnosis.
diagnosis_term:
preferred_term: Holter monitoring
term:
id: NCIT:C38064
label: Holter Monitoring
evidence:
- reference: PMID:39027806
reference_title: "Management of Long QT Syndrome: A Systematic Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Additional investigations, including exercise stress tests and Holter
monitoring, may be warranted to assess cardiac function and identify
arrhythmic events
explanation: >-
Systematic review of LQTS management documents Holter monitoring as an
additional diagnostic investigation alongside ECG, applicable to JLNS's
cardiac diagnostic workup.
- name: Exercise Cardiac Stress Testing
description: >-
Exercise stress testing may be used to assess cardiac function and
provoke arrhythmic events as part of the diagnostic workup.
diagnosis_term:
preferred_term: Exercise cardiac stress test
term:
id: NCIT:C168192
label: Exercise Cardiac Stress Test
evidence:
- reference: PMID:39027806
reference_title: "Management of Long QT Syndrome: A Systematic Review."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Additional investigations, including exercise stress tests and Holter
monitoring, may be warranted to assess cardiac function and identify
arrhythmic events
explanation: >-
Systematic review of LQTS management documents exercise stress testing
as an additional diagnostic investigation, applicable to JLNS's cardiac
diagnostic workup.
- name: Audiological Screening and Molecular Testing of At-Risk Relatives
description: >-
At-risk siblings should receive standard newborn hearing screening and
ECG, with molecular genetic testing to confirm or exclude the diagnosis
when the familial KCNQ1 variants are known.
diagnosis_term:
preferred_term: audiological and molecular genetic screening
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:20301579
reference_title: "Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Hearing evaluation by standard newborn hearing screening programs and
electrocardiograms for at-risk sibs; molecular genetic testing to
confirm the diagnosis if the pathogenic variants in an affected family
member are known.
explanation: >-
GeneReviews describes the audiological, electrocardiographic, and
molecular-genetic evaluation protocol for at-risk relatives.
- name: Targeted Arrhythmia and Deafness Gene Panel Sequencing
description: >-
Molecular confirmation is obtained by next-generation sequencing of
KCNQ1 (and KCNE1), often as part of a broader targeted cardiac
arrhythmia gene panel, which can also identify candidate modifier
variants in other arrhythmia genes.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
results: >-
Identification of biallelic (homozygous or compound heterozygous)
pathogenic KCNQ1 variants confirms JLNS1.
evidence:
- reference: PMID:32508908
reference_title: "Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
using next-generation sequencing (NGS), we identified a compound
heterozygosity for two mutations c.1741A>T (novel) and c.477+5G>A
(known) in KCNQ1 gene
explanation: Case report demonstrating NGS-based molecular confirmation of compound heterozygous KCNQ1 variants.
- reference: PMID:29037160
reference_title: "\"Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports\"."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Further targeted next generation sequencing of cardiac panel comprising
68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in
RYR2 gene
explanation: >-
Case series demonstrating use of a targeted 68-gene arrhythmia panel
for molecular diagnosis and candidate-modifier discovery in KCNQ1-JLNS.
clinical_trials:
- name: NCT06534671
phase: PHASE_IV
status: COMPLETED
description: >-
Single-group, open-label phase 4 study of a single intravenous dose of
diltiazem (calcium channel blocker) in genetically confirmed adult JLNS,
measuring acute (within-minutes) effects on the QT interval. The trial
enrolled only one participant (completed 2024-10-23), so this is
exploratory single-subject evidence and does not establish diltiazem as
a treatment recommendation for JLNS.
target_phenotypes:
- preferred_term: Prolonged QTc interval
term:
id: HP:0005184
label: Prolonged QTc interval
evidence:
- reference: clinicaltrials:NCT06534671
reference_title: Diltiazem in Jervell and Lange-Nielsen Syndrome
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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 confirms the trial's disease-specific,
single-dose, acute-effect design.
animal_models:
- name: Kcnq1-null mouse (Kcnq1-/-)
species: Mouse
genotype: Kcnq1 targeted disruption, homozygous null
publication: PMID:11226272
evidence:
- reference: PMID:11226272
supports: SUPPORT
evidence_source: MODEL_ORGANISM
reference_title: Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome.
snippet: >-
Together, these data suggest that Kcnq1(-/-) mice are a potentially
valuable animal model of JLNS.
explanation: >-
Founding publication establishing this line as a mouse model of JLNS,
recapitulating both the cardiac and cochlear consequences of biallelic
Kcnq1 loss.
modeled_mechanisms:
- target: Near-Complete Loss of Cardiac I_Ks Repolarizing Current
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
Kcnq1-/- mice show ECG repolarization abnormalities, but the
prolongation was observed in vivo and not in isolated hearts,
suggesting extracardiac (e.g., autonomic/electrolyte) contributions
rather than a pure cell-autonomous cardiomyocyte I_Ks defect.
limitations: >-
QT/JT prolongation and T/P-wave abnormalities were not reproduced in
isolated hearts, indicating the murine cardiac phenotype depends on
extracardiac signals and may not directly recapitulate the
cell-autonomous human cardiomyocyte I_Ks loss.
readouts:
- name: In vivo ECG QT and JT interval
target: Near-Complete Loss of Cardiac I_Ks Repolarizing Current
direction: INCREASED
interpretation: >-
Prolonged QT and JT intervals recorded in vivo, but not in isolated
hearts, in Kcnq1-/- mice.
evidence:
- reference: PMID:11226272
reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
ECGs recorded from Kcnq1(-/-) mice demonstrated abnormal T- and
P-wave morphologies and prolongation of the QT and JT intervals
when measured in vivo, but not in isolated hearts.
explanation: Direct in vivo ECG measurement supporting the readout.
evidence:
- reference: PMID:11226272
reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These changes are indicative of cardiac repolarization defects that
appear to be induced by extracardiac signals.
explanation: >-
Author interpretation that the murine repolarization defect is
informative for the cardiac node but not a pure recapitulation of
the cell-autonomous mechanism.
- target: Organ of Corti Hair Cell Degeneration
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Kcnq1-/- mice reproduce the collapsed endolymphatic compartments and
organ of Corti degeneration seen in human JLNS temporal bone
pathology.
readouts:
- name: Inner ear histopathology
target: Organ of Corti Hair Cell Degeneration
direction: ABOLISHED
interpretation: >-
Marked stria vascularis atrophy, endolymphatic compartment collapse,
and complete organ of Corti degeneration.
evidence:
- reference: PMID:15891643
reference_title: "Inner ear abnormalities in a Kcnq1 (Kvlqt1) knockout mouse: a model of Jervell and Lange-Nielsen syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Kcnq1 knockout mice exhibit histopathologic findings that are
comparable to those reported in human temporal bone cases of
Jervell and Lange-Nielsen syndrome
explanation: Direct comparison of mouse histopathology to human JLNS temporal bone findings.
evidence:
- reference: PMID:11226272
reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Histological analysis of the inner ear structures of Kcnq1(-/-) mice
revealed gross morphological anomalies because of the drastic
reduction in the volume of endolymph.
explanation: Founding description of the Kcnq1-/- mouse inner ear phenotype.
- target: Congenital Profound Bilateral Sensorineural Hearing Loss
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Kcnq1-/- mice are behaviorally deaf, directly recapitulating the human
congenital profound sensorineural hearing loss consequence.
readouts:
- name: Behavioral deafness and vestibular (shaker/waltzer) phenotype
target: Congenital Profound Bilateral Sensorineural Hearing Loss
direction: ABOLISHED
interpretation: Complete behavioral deafness with vestibular dysfunction.
evidence:
- reference: PMID:11226272
reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Behavioral analysis revealed that the Kcnq1(-/-) mice are deaf and
exhibit a shaker/waltzer phenotype.
explanation: Direct behavioral evidence of deafness in the knockout mouse.
- name: Vestibular apparatus histopathology
target: Congenital Profound Bilateral Sensorineural Hearing Loss
direction: ABOLISHED
interpretation: >-
Collapse of the vestibular membrane and profound morphological
abnormalities of the saccule, utricle, and semicircular ducts,
underlying the behavioral vestibular dysfunction. Human vestibular
involvement in JLNS1 is not independently evidenced in the cited
human-clinical literature; this readout is model-derived only.
evidence:
- reference: PMID:11226272
reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These mice suffer from deafness and vestibular dysfunction because
of profound morphological abnormalities of the inner ear.
explanation: >-
Direct histopathologic evidence that Kcnq1 loss produces vestibular
(in addition to cochlear) morphological abnormality in the mouse
model; no quotable human-clinical source for vestibular
involvement in JLNS1 was found, so no human phenotype term is
asserted.
evidence:
- reference: PMID:11226272
reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Together, these data suggest that Kcnq1(-/-) mice are a potentially
valuable animal model of JLNS.
explanation: Author summary establishing the model's informativeness for JLNS overall.
- name: AAV1-Kcnq1 gene-replacement-treated Kcnq1-/- mouse
species: Mouse
genotype: Kcnq1 targeted disruption, homozygous null, treated with AAV1-Kcnq1 endolymphatic gene replacement
publication: PMID:26084842
evidence:
- reference: PMID:26084842
supports: SUPPORT
evidence_source: MODEL_ORGANISM
reference_title: Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome.
snippet: >-
Our results demonstrate the first successful gene therapy treatment for
gene defects specifically affecting the function of the stria
vascularis, which is a major site affected by genetic mutations in
inherited hearing loss.
explanation: >-
Establishes this treated Kcnq1-/- line as informative for evaluating
gene-replacement rescue of the stria-vascularis-dependent hearing-loss
mechanism in JLNS.
modeled_mechanisms:
- target: Congenital Profound Bilateral Sensorineural Hearing Loss
relationship: RESCUES
fidelity: HIGH
description: >-
Postnatal endolymphatic injection of an AAV1-Kcnq1 construct into
Kcnq1-/- mice restored Kcnq1 expression in stria vascularis marginal
cells, corrected the collapse of Reissner's membrane and hair-cell
degeneration, restored normal endocochlear potential, and produced
significant hearing preservation.
limitations: >-
Treatment was delivered postnatally (P0-P2) in the immature mouse
cochlea; efficacy and safety of comparable timing/delivery in the
more mature human cochlea at diagnosis is unestablished, and this is
a preclinical proof-of-concept rather than a validated human therapy.
readouts:
- name: Auditory brainstem response threshold
target: Congenital Profound Bilateral Sensorineural Hearing Loss
direction: RESTORED
interpretation: >-
Hearing preservation in treated ears ranged from 20 dB improvement
to complete correction of the deafness phenotype.
evidence:
- reference: PMID:26084842
reference_title: "Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
auditory brainstem responses showed significant hearing
preservation in the injected ears, ranging from 20 dB improvement
to complete correction of the deafness phenotype
explanation: Direct functional-hearing readout of gene-therapy rescue.
evidence:
- reference: PMID:26084842
reference_title: "Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Examination of cochlear morphology showed that the collapse of the
Reissner's membrane and degeneration of hair cells (HCs) and cells
in the spiral ganglia were corrected in Kcnq1(-/-) mice.
explanation: >-
Demonstrates structural rescue of the cochlear degeneration
phenotype by Kcnq1 gene replacement, supporting the therapeutic
relevance of this node for future gene-therapy approaches.
Jervell and Lange-Nielsen syndrome 1 (JLNS1) is specifically the biallelic KCNQ1-related disorder. It must be distinguished from JLNS2, caused by biallelic KCNE1 variants, and from broader congenital long-QT syndrome (LQTS) evidence. Where subtype-specific data are unavailable, this report labels evidence as applying to all JLNS or general LQTS rather than assuming it is JLNS1-specific. Most available information is aggregated from disease resources, cohorts, and published families—not individual electronic health records.
A knowledge-base-ready summary is provided below.
| Domain | JLNS1 (KCNQ1) summary | JLNS2 distinction / caveat | Key supported numbers | Ontology suggestions | Evidence |
|---|---|---|---|---|---|
| Identity / identifiers | Jervell and Lange-Nielsen syndrome 1 is the KCNQ1-related form of autosomal-recessive cardioauditory long-QT syndrome with congenital sensorineural deafness and marked QT prolongation; disease-level resources support MONDO:0024540 for JLNS1, while the broader syndrome is MONDO:0002441. | JLNS2 is the KCNE1-related subtype; do not merge subtype-specific assertions when a source discusses broader JLNS. | None subtype-specific beyond MONDO assignment in retrieved evidence. | MONDO:0024540; MeSH: Jervell-Lange Nielsen Syndrome; HP:0000365; HP:0001649 | (OpenTargets Search: Jervell and Lange-Nielsen syndrome-KCNQ1, oertli2021molecularmechanismof pages 1-2, oertli2021molecularmechanismof pages 12-13, oertli2021molecularmechanismof pages 2-4) |
| Causal gene and inheritance | Primary causal gene is KCNQ1; inheritance is autosomal recessive / biallelic with loss-of-function mechanism. Both truncating and missense variants leading to loss of function are relevant for LQTS/JLNS. | KCNE1 causes JLNS2; KCNE1 cases appear less common and may have a less severe clinical course than KCNQ1-associated JLNS. | Approximately 90% of JLNS cases are due to KCNQ1 mutations in one review/case-based source. | HGNC:6294 (KCNQ1); GO:0006813; GO:0005267 | (qiu2020jervellandlangenielsen pages 1-2, josephs2023beyondgenediseasevalidity pages 9-10, crotti2008congenitallongqt pages 4-5) |
| Cardinal phenotypes and frequencies | Core phenotype is profound congenital bilateral sensorineural hearing loss plus prolonged QTc, often with syncope/seizures and risk of torsades/ventricular fibrillation/sudden death. Onset is often congenital/early childhood. | Severity appears worse in JLNS1/KCNQ1 than JLNS2/KCNE1 in cohort/review evidence. | In a cooperative study of 187 J-LN patients, almost 90% had cardiac events, 50% were symptomatic by age 3 years, mean QTc was 557 ± 65 ms; JLNS is commonly defined by QTc >500 ms. | HP:0000365; HP:0001649; HP:0001279; HP:0002133; HP:0011675 | (uysal2017“homozygousandcompound pages 1-2, qiu2020jervellandlangenielsen pages 1-2, crotti2008congenitallongqt pages 4-5) |
| Triggers / natural history | Events are precipitated by adrenergic or physiologic stressors; misdiagnosis as epilepsy can occur because arrhythmic syncope may present with seizure-like episodes. | Trigger data are largely reported for broader JLNS rather than subtype-exclusive JLNS1 cohorts. | Reported triggers include exercise, emotion, swimming, auditory stimuli, anesthesia, and fever; >25% sudden cardiac death reported in one review/case-based source. | HP:0001250; NCIT:C50595 (Syncope) | (uysal2017“homozygousandcompound pages 6-7, qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7) |
| Molecular mechanism | KCNQ1 encodes Kv7.1, which with KCNE1 forms the IKs channel. In heart, loss of IKs delays repolarization and prolongs action potential duration/QT. In inner ear stria vascularis, impaired K+ secretion/endocochlear potential disrupts potassium homeostasis causing deafness; severe loss can also associate with vestibular dysfunction and hair-cell loss in models. Residual function may explain atypical recessive LQT1 without deafness. | JLNS2 shares pathway logic through KCNE1 but subtype-specific gene/protein defect differs. | One mechanistic review notes JLNS can occur when KCNQ1 protein level falls below about 10% of normal. | GO:0002027; GO:1903779; GO:0060088; UBERON:0002046; CL:0000586 | (oertli2021molecularmechanismof pages 1-2, oertli2021molecularmechanismof pages 2-4, qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7) |
| Pathogenic variant spectrum / modifiers | Reported JLNS1 variants include homozygous missense, nonsense/frameshift, splice-site, and compound heterozygous combinations; examples include p.Arg243His, c.477+1G>A, p.Arg174Cys, p.Arg366Gln, c.1741A>T (p.Lys581Ter), and c.477+5G>A. Additional variants in other arrhythmia genes (for example RYR2, NKX2-5 in one case) were proposed as possible severity modifiers. | Modifier evidence is limited and case-based, not established as routine causal annotation. | Exact example QTc values in case reports included 520 ms and 530 ms. | SO:0001583; SO:0001587; SO:0001627; SO:0001578 | (uysal2017“homozygousandcompound pages 2-5, uysal2017“homozygousandcompound pages 5-6, uysal2017“homozygousandcompound pages 1-2, qiu2020jervellandlangenielsen pages 5-7) |
| Diagnostics | Diagnosis is based on ECG plus congenital deafness phenotype and confirmatory molecular testing. Suggested workup: 12-lead ECG/QTc, hearing evaluation/audiology, family history, and targeted sequencing/panel testing; exome/genome sequencing can support diagnosis in rare disease workflows. | Subtype resolution requires genetic testing because both KCNQ1 and KCNE1 can cause JLNS. | QTc >500 ms is a common diagnostic clue; one report used a 127-gene deafness panel/NGS, and another emphasized broad targeted cardiac panels. | LOINC/ECG concept; HP:0001649; HP:0000365; NCIT:C47891 (Genetic Testing) | (uysal2017“homozygousandcompound pages 1-2, uysal2017“homozygousandcompound pages 6-7, qiu2020jervellandlangenielsen pages 1-2, yu2023precisionmedicinefor pages 1-2) |
| Treatment / real-world management | First-line therapy is beta-blockade, with non-selective agents such as nadolol or propranolol generally preferred in LQTS guidance. ICD is used for cardiac arrest survivors or persistent breakthrough events; LCSD is used in refractory/intolerant high-risk cases. Cochlear implantation can substantially improve hearing but requires peri-anesthetic arrhythmia precautions. | JLNS1 often has particularly high arrhythmic risk, so escalation beyond beta-blockers is common; KCNE1-associated JLNS may be milder. | In general LQTS guidance, arrhythmic recurrence after cardiac arrest is about 14% within 5 years despite therapy; one review states LCSD can reduce cardiac events by about 90% in high-risk LQTS; in a JLNS cohort/review, beta-blockers had limited efficacy and LCSD appeared ineffective. | NCIT:C945 (Beta Adrenergic Receptor Blocker Therapy); NCIT:C27996 (Implantable Cardioverter Defibrillator); NCIT:C80466 (Sympathectomy); NCIT:C15220 (Cochlear Implantation) | (uysal2017“homozygousandcompound pages 5-6, uysal2017“homozygousandcompound pages 6-7, qiu2020jervellandlangenielsen pages 5-7, balestra2024congenitallongqt pages 8-9, hauwanga2024managementoflong pages 5-6, crotti2008congenitallongqt pages 4-5) |
| Prognosis | Prognosis remains guarded relative to many other LQTS forms because events begin early and treatment may be less protective; however outcomes improve with recognition, arrhythmia prevention, and hearing intervention. | Worse prognosis is particularly associated with KCNQ1-mutant J-LN in expert review. | Untreated LQTS mortality within 1 year was cited as 21% in one case-based review; >25% sudden cardiac death reported for JLNS in another source. | HP:0001699; NCIT:C28554 (Sudden Cardiac Death) | (uysal2017“homozygousandcompound pages 5-6, qiu2020jervellandlangenielsen pages 1-2, crotti2008congenitallongqt pages 4-5) |
| Model organisms / systems | Kcnq1-null mice recapitulate major JLNS traits including deafness, vestibular dysfunction, altered cardiac repolarization, collapsed Reissner membrane, and massive hair-cell loss. Human iPSC-cardiomyocyte models are being used to study KCNQ1-related LQTS/JLNS mechanisms and therapeutic screening; CRISPR correction and gene-replacement concepts are preclinical. | No established naturally occurring veterinary JLNS1 model was identified in retrieved evidence. | None beyond qualitative recapitulation. | NCBITaxon:10090; CL:0000746 (cardiomyocyte); UBERON:0001851 (stria vascularis) | (qiu2020jervellandlangenielsen pages 1-2, yu2023precisionmedicinefor pages 1-2) |
| 2023-2024 developments | 2023 CardiacG2P provided structured curation that specifically states both PTCs and missense KCNQ1 loss-of-function variants are relevant to LQTS/JLNS and improves variant prioritization. 2023-2024 reviews highlight patient-specific iPSC models, CRISPR-enabled precision-medicine workflows, and updated pediatric/ESC-aligned management. A phase 4 single-subject trial tested acute IV diltiazem QT effects in genetically confirmed JLNS (NCT06534671; first posted 2024-08-02; completed 2024-10-23). | These are emerging or platform-level advances; none constitute an approved JLNS1 molecular therapy. | CardiacG2P sensitivity for retained P/LP variants was 281/285 (98.6%) in benchmark testing; the diltiazem study enrolled 1 participant. | NCIT:C15206 (Clinical Trial); NCIT:C129000 (Induced Pluripotent Stem Cell) | (NCT06534671 chunk 1, josephs2023beyondgenediseasevalidity pages 1-2, josephs2023beyondgenediseasevalidity pages 9-10, balestra2024congenitallongqt pages 8-9, hauwanga2024managementoflong pages 5-6, yu2023precisionmedicinefor pages 1-2) |
Table: This table condenses subtype-specific knowledge for Jervell and Lange-Nielsen syndrome 1 into knowledge-base-ready rows covering identity, mechanism, phenotypes, diagnosis, treatment, prognosis, models, and recent developments. It emphasizes the distinction between KCNQ1-related JLNS1 and KCNE1-related JLNS2 and includes ontology suggestions for downstream annotation.
JLNS1 is a rare, severe, congenital cardioauditory ion-channel disorder characterized by profound bilateral sensorineural hearing loss and markedly prolonged ventricular repolarization, usually QTc >500 ms, with susceptibility to torsades de pointes, ventricular fibrillation, syncope, seizure-like episodes, cardiac arrest, and sudden death. It results from two pathogenic alleles in KCNQ1, whereas JLNS2 is attributable to KCNE1. Open Targets associates JLNS1 (MONDO:0024540) most strongly with KCNQ1; its weaker KCNE1 association likely reflects cross-mapping of the broader JLNS concept and should not redefine subtype 1. (OpenTargets Search: Jervell and Lange-Nielsen syndrome-KCNQ1, oertli2021molecularmechanismof pages 1-2, qiu2020jervellandlangenielsen pages 1-2)
Exact abstract wording: “JLNS is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds).” Qiu et al., published 16 May 2020, DOI: 10.1155/2020/3569359. (qiu2020jervellandlangenielsen pages 1-2)
JLNS1 is a Mendelian autosomal-recessive disorder caused by germline biallelic loss-of-function KCNQ1 variants, either homozygous or compound heterozygous. Disease-relevant classes include missense variants that impair channel function or trafficking, nonsense and frameshift variants, splice-altering variants, and less commonly exon-level copy-number changes. A 2023 expert-curated CardiacG2P analysis explicitly concluded that both protein-truncating and missense loss-of-function KCNQ1 variants cause LQTS/JLNS. (josephs2023beyondgenediseasevalidity pages 1-2, josephs2023beyondgenediseasevalidity pages 9-10)
Reported JLNS1 genotypes include:
These examples are not a substitute for current ClinVar assertions. Variant classification should use ACMG/AMP criteria, segregation, population frequency, phenotype specificity, RNA evidence for splice variants, and functional electrophysiology. Pathogenic alleles are expected to be individually rare in gnomAD; no universal allele-frequency value applies. The variants are germline, not somatic.
Residual Kv7.1/IKs activity is a major biological modifier: severe reduction tends to produce cardioauditory disease, whereas partial function can produce recessive LQT1 without deafness. In vitro work on homozygous c.1892_1893insC (p.Pro631fs*20) showed loss of IKs only in homomeric mutant complexes, while wild-type-containing complexes were rescued by KCNE1, explaining unaffected heterozygotes and atypical recessive LQTS. (oertli2021molecularmechanismof pages 1-2, oertli2021molecularmechanismof pages 2-4)
One severe case also carried RYR2 p.Ile449Arg and NKX2-5 p.Cys270Tyr, proposed as modifiers; this remains a single-family hypothesis, not a validated modifier panel. (uysal2017“homozygousandcompound pages 2-5, uysal2017“homozygousandcompound pages 1-2)
No reproducible protective allele, diet, supplement, or environmental exposure preventing JLNS1 occurrence has been established. Clinically protective measures instead reduce arrhythmic risk after disease is present.
The genotype creates reduced repolarization reserve. Adrenergic stimulation and physiological stress—exercise, swimming, emotion, sudden sound, fever—and peri-anesthetic factors can then trigger ventricular arrhythmia. QT-prolonging drugs, hypokalemia, hypomagnesemia, bradycardia, and poor medication adherence can further erode repolarization reserve. A KCNQ1-JLNS child developed life-threatening arrhythmia after cochlear-implant anesthesia, directly illustrating this interaction. (qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7)
Smoking, alcohol, diet, infection, occupation, pollution, and toxins are not causal factors for this Mendelian syndrome. Fever or electrolyte loss can nevertheless act as event triggers.
| Phenotype | Type and characteristics | Frequency/onset | Suggested HPO |
|---|---|---|---|
| Bilateral sensorineural hearing loss | Congenital or very early, usually severe-to-profound and persistent; impairs speech/language without intervention | Cardinal phenotype, although rare residual-function exceptions occur | HP:0000365, HP:0000407 |
| Long QT interval | ECG sign; typically marked, persistent QTc prolongation | Mean QTc 557±65 ms in a 187-patient JLNS cohort; commonly >500 ms | HP:0001657 / long QT interval |
| Syncope | Episodic, often exertional or emotion-triggered; may be recurrent | Almost 90% of the cohort experienced cardiac events | HP:0001279 |
| Seizure-like episodes/anoxic seizures | Behavioral/neurologic manifestation secondary to cerebral hypoperfusion; frequently mistaken for epilepsy | Variable; often childhood | HP:0001250 |
| Torsades/ventricular tachyarrhythmia | Episodic, severe, potentially degenerating to ventricular fibrillation | High-risk defining complication | HP:0001664, HP:0004756 |
| Sudden cardiac arrest/death | Catastrophic complication | One review reported >25% sudden cardiac death | HP:0001699 |
| Congenital/fetal or neonatal bradycardia | Clinical/ECG sign in some severe cases | Variable | HP:0001662 |
| Vestibular dysfunction/balance impairment | Inner-ear manifestation supported strongly by knockout models and clinical reports | Frequency not robustly quantified here | HP:0001751, HP:0001288 |
Cohort evidence indicates a severe early course: almost 90% of 187 JLNS patients had cardiac events, 50% were symptomatic by age three, and mean QTc was 557±65 ms. This cohort combined KCNQ1- and KCNE1-related JLNS, but KCNQ1 disease had the more severe course. (crotti2008congenitallongqt pages 4-5)
Quality-of-life burdens include communication and educational disability from deafness, activity restrictions, medication burden, anxiety concerning sudden death, recurrent hospitalization, ICD shocks, and family/caregiver stress. No JLNS1-specific EQ-5D, SF-36, or PROMIS dataset was identified.
Pathogenic variants can cause defective voltage sensing/gating, pore conductance, tetramer assembly, KCNE1 interaction, protein stability, trafficking, or cell-surface expression. The p.Lys581Ter variant removes part of the C-terminal A-domain needed for normal channel trafficking/assembly. (qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7)
The predominant mechanism is loss of function, not gain of function. Dominant-negative effects may occur for particular alleles, but JLNS1 requires a disease-causing allele on each homolog. Large chromosomal abnormalities are not the usual mechanism; deletion/duplication analysis remains relevant when sequencing finds only one allele. No consistent disease-specific DNA-methylation, histone, or chromatin signature is established. KCNQ1 resides within an imprinted region, but JLNS1 itself is not ordinarily classified as an imprinting disorder.
There is no infectious, toxic, nutritional, radiation, pollution, occupational, or lifestyle cause. Relevant acquired arrhythmia modifiers include:
Exercise, emotion, swimming, auditory stimuli, anesthesia, and fever are specifically reported event triggers in children with JLNS. (qiu2020jervellandlangenielsen pages 1-2)
Biallelic KCNQ1 loss of function → reduced Kv7.1/KCNE1 IKs → impaired phase-3 repolarizing K+ current and reduced adaptation to faster heart rates → prolonged cardiomyocyte action-potential duration → prolonged QTc and increased dispersion of repolarization → early afterdepolarizations/torsades de pointes → syncope, anoxic seizure, ventricular fibrillation, or sudden death. (oertli2021molecularmechanismof pages 1-2, oertli2021molecularmechanismof pages 2-4, yu2023precisionmedicinefor pages 1-2)
Relevant cell type: ventricular cardiomyocyte (CL:0000746). Suggested GO terms include potassium-ion transmembrane transport (GO:0071805), regulation of cardiac muscle-cell action potential (GO:0098901), cardiac muscle-cell action-potential repolarization (GO:0086009), and voltage-gated potassium-channel complex (GO:0008076).
Loss of Kv7.1/KCNE1 in stria-vascularis marginal cells → impaired K+ secretion into endolymph → loss of endocochlear potential and endolymph homeostasis → collapse of cochlear structures and secondary sensory-hair-cell degeneration → congenital severe-to-profound sensorineural deafness. Vestibular dark-cell dysfunction can similarly disturb vestibular endolymph. Kcnq1-null mice show collapsed Reissner membrane, massive hair-cell loss, and malformed saccule, utricle, and semicircular ducts. (qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7)
Suggested terms: sensory epithelial cell of cochlea/hair cell (CL:0000202), marginal cell of stria vascularis, potassium-ion homeostasis (GO:0055075), sensory perception of sound (GO:0007605), cochlea (UBERON:0001844), stria vascularis (UBERON:0001851), and vestibular apparatus (UBERON:0004681).
No validated JLNS1-specific clinical transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic signature was identified. Patient-specific iPSC-cardiomyocytes are increasingly used for mechanistic phenotyping and drug testing, but their immaturity and cellular heterogeneity limit direct clinical extrapolation. (yu2023precisionmedicinefor pages 1-2)
Suggested anatomy terms include heart (UBERON:0000948), myocardium (UBERON:0002349), cochlea (UBERON:0001844), stria vascularis (UBERON:0001851), organ of Corti (UBERON:0002227), and plasma membrane (GO:0005886). Hearing loss is bilateral; cardiac disease has no meaningful lateralization.
JLNS1 is congenital and lifelong. Hearing loss is present at birth or recognized in infancy; cardiac manifestations may begin prenatally with bradycardia or during early childhood with syncope/seizures. Half of patients in the mixed-JLNS cohort were symptomatic by age three. (crotti2008congenitallongqt pages 4-5)
The course is chronic with episodic acute arrhythmias, not conventionally staged and not relapsing-remitting. Deafness generally does not remit spontaneously. Arrhythmic risk persists lifelong but is modifiable by treatment and avoidance of triggers. Critical windows include fetal/neonatal detection, infancy before a first cardiac event, cochlear-implant timing for language acquisition, medication initiation, and all anesthetic procedures.
Worldwide prevalence has been estimated at approximately 1 per 1,000,000 to 1 per 200,000. Approximately 90% of all JLNS was attributed to KCNQ1 in the 2020 report, making JLNS1 the major molecular subtype. These estimates are uncertain because the disorder is exceptionally rare, can be misdiagnosed as epilepsy, and may be enriched in founder or consanguineous populations. (qiu2020jervellandlangenielsen pages 1-2)
No robust annual incidence, sex ratio, or age-stratified population estimate was identified. Both sexes are genetically affected equally; sex and hormonal state can modify arrhythmic risk in LQTS generally.
For two heterozygous carrier parents, each pregnancy has a theoretical 25% affected, 50% carrier, and 25% non-carrier probability. Penetrance of the classic cardioauditory phenotype is high but not absolute: residual-function biallelic genotypes can cause recessive LQTS without deafness, demonstrating variable expressivity. Heterozygous relatives may be asymptomatic or manifest dominant LQT1 depending on the allele’s functional effect. (uysal2017“homozygousandcompound pages 5-6, oertli2021molecularmechanismof pages 1-2)
Consanguinity increases the probability that both parents carry the same rare allele. Founder effects are reported in Scandinavian populations, but no precise founder-variant frequency was adequately retrieved. Anticipation is not expected; germline mosaicism is theoretically possible but not a recognized major mechanism.
Recommended evaluation comprises:
Profound congenital deafness plus QTc >500 ms is highly suggestive, but molecular confirmation is required to assign JLNS1 rather than JLNS2. (uysal2017“homozygousandcompound pages 1-2, qiu2020jervellandlangenielsen pages 1-2)
Differentials include Romano-Ward LQT1; JLNS2/KCNE1; acquired long QT; Timothy syndrome; Andersen-Tawil syndrome; catecholaminergic polymorphic ventricular tachycardia; epilepsy; vasovagal syncope; and nonsyndromic congenital deafness such as GJB2- or SLC26A4-related disease. The combination of profound congenital deafness, marked QT prolongation, and biallelic KCNQ1 variants distinguishes JLNS1.
All first-degree relatives should receive ECG and targeted familial-variant testing. Hearing screening alone is insufficient because a child can pass newborn screening and later be recognized as hearing impaired, as occurred in the reported KCNQ1 family. (qiu2020jervellandlangenielsen pages 1-2)
Population ECG/genomic newborn screening remains investigational; cascade screening is the established high-yield approach.
JLNS is among the most malignant LQTS forms. In the 187-patient cohort, almost 90% experienced cardiac events and half were symptomatic by age three. KCNQ1-associated disease had a substantially more severe course than KCNE1-associated disease. (crotti2008congenitallongqt pages 4-5)
A separate review reported sudden cardiac death in >25%, although this is historical/mixed-management evidence and should not be interpreted as a contemporary treated JLNS1 mortality rate. (qiu2020jervellandlangenielsen pages 1-2)
Poor prognostic factors include very long QTc, early symptoms, prior cardiac arrest, recurrent events despite β-blockade, KCNQ1 rather than KCNE1 etiology, nonadherence, and exposure to avoidable triggers. No validated JLNS1-specific five- or ten-year survival estimate or prognostic molecular biomarker was identified.
Hearing generally does not recover medically, but cochlear implantation can produce good auditory performance. ICD shocks and activity restrictions may cause substantial psychosocial morbidity. Recovery from the genetic disorder is not expected; risk management is lifelong.
Suggested NCIt intervention concepts: beta-adrenergic receptor blocker therapy; implantable cardioverter-defibrillator; sympathectomy/LCSD; cochlear implantation; genetic counseling.
No gene, RNA, or cell therapy is approved for JLNS1. Preclinical approaches include KCNQ1 gene replacement, CRISPR correction, patient-specific iPSC drug screening, and suppression-and-replacement constructs. Kcnq1 replacement in immature mouse scala media improved hearing, cochlear morphology, and vestibular function, but this has not established human safety or efficacy. (qiu2020jervellandlangenielsen pages 1-2, yu2023precisionmedicinefor pages 1-2)
NCT06534671, first posted 2 August 2024, was a completed phase-4, open-label, single-group study of acute IV diltiazem in genetically confirmed adult JLNS. It enrolled one participant and measured short-term QT effects after 0.25 mg/kg, with a possible 0.35 mg/kg second dose. This is exploratory single-subject evidence and does not support routine diltiazem treatment. ClinicalTrials.gov record. (NCT06534671 chunk 1)
Primary prevention of de novo disease in an individual is not possible after conception, but reproductive options include carrier testing, partner testing, prenatal diagnosis, and preimplantation genetic testing when familial variants are known.
Secondary prevention consists of early ECG/genetic diagnosis in deaf infants, cascade testing, and immediate treatment before a first arrhythmia. Tertiary prevention includes strict β-blocker adherence; avoidance of QT-prolonging drugs; prompt correction of potassium, magnesium, and calcium abnormalities; fever/dehydration management; individualized exercise/swimming precautions; supervised anesthesia; and ICD/LCSD escalation when indicated. There is no JLNS-specific vaccine or infectious prophylaxis.
No well-established naturally occurring companion-animal or wildlife disease directly equivalent to human KCNQ1-JLNS1 was identified. Therefore, breed ontology, veterinary prevalence, transmission, and zoonotic potential are not applicable/unknown. The disorder is genetic and noncommunicable.
Orthologous Kcnq1/Kcne1 channel biology is evolutionarily conserved in mammals. Relevant taxa include human (NCBI Taxon 9606) and laboratory mouse (NCBI Taxon 10090).
Kcnq1-null mice reproduce major disease components: deafness, vestibular dysfunction, and abnormal cardiac repolarization. Their inner ears show collapsed Reissner membrane, extensive hair-cell loss, and abnormalities of the saccule, utricle, and semicircular ducts. This provides strong mechanistic support for KCNQ1-dependent endolymph homeostasis. Limitations include species-specific cardiac electrophysiology and differences in developmental timing and arrhythmic susceptibility. (qiu2020jervellandlangenielsen pages 1-2)
Xenopus oocytes and mammalian expression systems permit voltage-clamp measurement of IKs, trafficking, assembly, and dominant-negative or recessive behavior. Such work demonstrated that KCNE1 could rescue function in complexes containing wild-type KCNQ1 for an atypical recessive variant. (oertli2021molecularmechanismof pages 1-2)
Patient-specific iPSC-derived cardiomyocytes reproduce prolonged action potentials and allow isogenic CRISPR correction, mechanistic study, and high-throughput drug testing. A 2023 review described WGS, CRISPR editing, machine learning, and iPSC cardiomyocytes as converging platforms for LQTS precision medicine. These remain research systems because iPSC cardiomyocytes are relatively immature and do not fully reproduce whole-heart autonomic, conduction, pharmacokinetic, or developmental physiology. (yu2023precisionmedicinefor pages 1-2)
The most consequential 2023–2024 developments were not new approved treatments but improvements in variant interpretation, risk-adapted management, and human disease modeling. CardiacG2P formally encoded biallelic requirement and KCNQ1 loss-of-function variant classes for scalable genomic interpretation; across its benchmark set it retained 281/285 pathogenic/likely pathogenic variants (98.6% sensitivity), although that benchmark was not JLNS1-specific. (josephs2023beyondgenediseasevalidity pages 1-2, josephs2023beyondgenediseasevalidity pages 9-10)
The 2024 pediatric synthesis of ESC guidance reinforced nonselective β-blockade, selective use of ICD and LCSD, and careful reassessment of risk after therapy. Meanwhile, iPSC/CRISPR work supports eventual genotype-specific treatment but remains preclinical. (balestra2024congenitallongqt pages 8-9, yu2023precisionmedicinefor pages 1-2)
JLNS1 should be treated as a medical emergency in genetic deafness evaluation: every child with severe congenital sensorineural hearing loss should have a careful history for syncope/seizures and consideration of ECG, especially before anesthesia. Molecular confirmation matters because KCNQ1-related JLNS has greater arrhythmic severity than KCNE1-related disease. The strongest current intervention is coordinated early care—expert β-blockade, trigger avoidance, rapid escalation to device or denervation therapy when warranted, and cochlear rehabilitation—not an experimental molecular therapy. (qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7, crotti2008congenitallongqt pages 4-5)
Reliable JLNS1-specific estimates remain unavailable for annual incidence, modern treated survival, sex ratio, individual phenotype frequencies, quantitative quality-of-life scores, carrier frequency, penetrance by variant class, validated modifier genes, epigenomic or multi-omic signatures, and naturally occurring veterinary disease. Many published outcome statistics combine JLNS1 and JLNS2 or derive from historical cohorts; database ingestion should preserve those evidence-scope qualifiers.
References
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(NCT06534671 chunk 1): Prince Joseph Kannankeril. Diltiazem in Jervell and Lange-Nielsen Syndrome. Vanderbilt University Medical Center. 2024. ClinicalTrials.gov Identifier: NCT06534671
(josephs2023beyondgenediseasevalidity pages 1-2): Katherine S. Josephs, Angharad M. Roberts, Pantazis Theotokis, Roddy Walsh, Philip J. Ostrowski, Matthew Edwards, Andrew Fleming, Courtney Thaxton, Jason D. Roberts, Melanie Care, Wojciech Zareba, Arnon Adler, Amy C. Sturm, Rafik Tadros, Valeria Novelli, Emma Owens, Lucas Bronicki, Olga Jarinova, Bert Callewaert, Stacey Peters, Tom Lumbers, Elizabeth Jordan, Babken Asatryan, Neesha Krishnan, Ray E. Hershberger, C. Anwar A. Chahal, Andrew P. Landstrom, Cynthia James, Elizabeth M. McNally, Daniel P. Judge, Peter van Tintelen, Arthur Wilde, Michael Gollob, Jodie Ingles, and James S. Ware. Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions. Genome Medicine, Oct 2023. URL: https://doi.org/10.1186/s13073-023-01246-8, doi:10.1186/s13073-023-01246-8. This article has 35 citations and is from a highest quality peer-reviewed journal.
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| References checked | 8 |
| Resolved | 8 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 8 |
| On topic | 4 |
| Off topic | 0 |
All extracted references resolved successfully.