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Classifications

Harrison's Part

Channelopathy

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Inheritance

1

Autosomal recessive HP:0000007

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.

Autosomal recessive inheritance Penetrance: INCOMPLETE

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS are usually heterozygotes"

GeneReviews describes the autosomal recessive inheritance pattern and typical carrier-parent status.

PMID:20301579 SUPPORT Other

"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"

GeneReviews quantifies the recurrence risk to full siblings under autosomal recessive transmission.

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Discussions and Knowledge Gaps

2

Is the QT prolongation of the Kcnq1-null mouse a valid model of the human JLNS cardiac phenotype, given that it appears in vivo but not in isolated hearts and its authors attribute it to extracardiac signals?

HUMAN MODEL MISMATCH OPEN jlns1_murine_qt_extracardiac

Attached to

pathophysiology#Near-Complete Loss of Cardiac I_Ks Repolarizing Current pathophysiology#Markedly Prolonged QTc and Arrhythmogenic Substrate animal_models#Mouse

The human mechanism curated here is cell-autonomous: biallelic KCNQ1 loss removes I_Ks from the ventricular cardiomyocyte, the action potential fails to repolarize on time, and the QT interval lengthens. The mouse that carries the same genotype does prolong its QT and JT intervals, but only in the intact animal. The effect disappeared in isolated hearts, and the authors concluded the repolarization defect is induced by extracardiac signals rather than being intrinsic to the myocardium. That is a different mechanism reaching a similar readout. Two things make this more than a technical caveat. Murine ventricular repolarization does not depend on I_Ks the way human repolarization does, so the mouse is a poor cardiac model of this disease on prior grounds, and the finding is what that prior would predict. And the mouse is the entry's main in vivo system: it carries the cochlear arm, where it recapitulates the human lesion well. So the same animal is strong evidence for one arm of the disease and weak evidence for the other, and nothing in the entry's structure signals that asymmetry except the fidelity grading on each link. The human cell evidence does not close the gap. The hiPSC-cardiomyocyte panel shows I_Ks loss and action-potential prolongation in dissociated cells, which is the cell-autonomous claim, but those cells cannot report a QT interval and are electrophysiologically immature. So the cell-autonomous step is shown at cellular scale in human cells, and the organ-scale phenotype is shown in an animal where it appears not to be cell-autonomous. No system currently shows both.

Proposed experiments

Optical mapping of repolarization in isolated hearts across species

jlns1_exp_isolated_heart_ap

Map action-potential duration and its transmural dispersion in Langendorff-perfused hearts from Kcnq1-null mice and from a large-animal or human-relevant preparation with the same genotype, under matched pacing and under beta-adrenergic stimulation. The mouse result predicts no intrinsic prolongation without extracardiac input; a species whose repolarization depends on I_Ks should prolong in the denervated, isolated organ.

Would support

pathophysiology#Markedly Prolonged QTc and Arrhythmogenic Substrate

Supporting outcome

Action-potential duration is prolonged and transmural dispersion increased in the isolated null heart, without any extracardiac input, establishing the organ-scale phenotype as intrinsic to the myocardium.

Refuting outcome

Repolarization is normal in every isolated null heart regardless of species, which would place the human QT prolongation downstream of autonomic or humoral input rather than of cardiomyocyte I_Ks loss and would require rewriting this edge.

Engineered human cardiac tissue from JLNS hiPSC lines

jlns1_exp_engineered_tissue

Build three-dimensional engineered heart tissue or cardiac slices from the existing JLNS hiPSC-cardiomyocyte lines and their isogenic controls, and measure conduction, repolarization dispersion, and arrhythmia inducibility under adrenergic challenge. This addresses the scale gap the entry records as a SCALE_EXTRAPOLATION divergence on the hiPSC model without introducing a species gap.

Would support

pathophysiology#Markedly Prolonged QTc and Arrhythmogenic Substrate

Supporting outcome

Human JLNS tissue shows increased repolarization dispersion and inducible reentrant arrhythmia relative to isogenic controls, supplying the tissue-scale evidence that neither current model provides.

Refuting outcome

Dispersion and inducibility are unchanged from isogenic controls, which would suggest the arrhythmogenic substrate needs tissue architecture or autonomic input the preparation lacks.

Show evidence (1 reference)

PMID:29925535 SUPPORT In Vitro

"we compared head-to-head the contribution of IKs (long QT1) and IKr (long QT2) on action potentials (APs) in human left ventricular (LV) tissue and hiPSC-CM-derived engineered heart tissue (EHT)"

Establishes that the proposed preparation exists and has been benchmarked against human ventricular tissue for exactly the current this disease loses, so the experiment uses an established system rather than proposing a new method.

The caveat is already carried structurally on the animal model link (PARTIALLY_RECAPITULATES, with limitations naming the isolated-heart result) and on the edge evidence, which is graded INDIRECT for this reason. This discussion promotes it from a caveat attached to one link into the open question it actually is.

Show evidence (2 references)

PMID:11226272 SUPPORT Model Organism

"These changes are indicative of cardiac repolarization defects that appear to be induced by extracardiac signals."

The authors' own conclusion, and the basis of this mismatch: the murine QT phenotype is attributed to signals outside the heart rather than to cardiomyocyte I_Ks loss.

PMID:29925535 SUPPORT INDIRECT In Vitro

"Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) should help to overcome the limitations of animal models based on species differences in repolarization reserve."

States the general form of this mismatch: repolarization reserve differs between species, which is why an animal model of an I_Ks-dependent disease may not report the human mechanism. Indirect because it argues the principle rather than testing the Kcnq1-null mouse.

How frequent is the gastric phenotype of JLNS across the allelic and population spectrum, given that it has been systematically looked for in only one national cohort?

KNOWLEDGE GAP OPEN jlns1_gastric_arm_single_cohort

Attached to

pathophysiology#Impaired Gastric Parietal Cell Luminal K+ Recycling pathophysiology#Achlorhydria, Hypergastrinemia, and Iron Deficiency Anemia biochemical#Faecal Calprotectin

Every quantitative statement about the gastric arm in this entry traces to one study of fourteen Swedish patients, and denominators within it fall to nine and to seven for individual analytes. That cohort is drawn from the national JLNS population in which p.Arg518Ter is the majority allele, so the figures may describe one founder genotype rather than JLNS generally. The mechanism is not in doubt: KCNQ1 is the non-redundant luminal K+ channel of the parietal cell in mouse, and the human cohort attributes the anemia to hypochlorhydria. What is unknown is prevalence, severity distribution, and whether the phenotype tracks residual channel function the way the cardiac and cochlear arms do. The raised faecal calprotectin is the sharper gap. It was abnormal in nine of nine patients tested, coeliac disease and inflammatory bowel disease were excluded by endoscopy in those scoped, and neutrophilic intestinal inflammation is not predicted by a parietal-cell secretory defect. No mechanism has been offered. KCNQ1 is expressed in intestinal epithelium as well as gastric, so an intestinal transport phenotype is plausible and unexamined.

Recorded rather than resolved. This is why iron-deficiency anemia is curated at FREQUENT and not raised to VERY_FREQUENT on the cohort's 12 of 14, and why the calprotectin finding is recorded in the biochemical section as unexplained rather than attached to a mechanism node.

Show evidence (1 reference)

PMID:22805636 SUPPORT Human Clinical

"All Swedish Jervell and Lange-Nielsen cases with double KCNQ1 mutations (14 cases) were investigated by medical record review, an interview, and were offered laboratory testing for iron-deficiency anaemia and gastrointestinal markers."

Gives the study's own denominator and design, which is the extent of the evidence base for the gastric arm and therefore the gap itself.

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Pathophysiology

11

Biallelic KCNQ1 Loss-of-Function Variants

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.

KCNQ1 hgnc:6294

Genetic context KCNQ1 hgnc:6294 allele_type: missense, nonsense, frameshift, or splice-site; biallelic (homozygous or compound heterozygous) variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

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.

delayed rectifier potassium channel activity GO:0005251 ⇓ LOSS OF FUNCTION

Experimental models

JLNS patient-derived and gene-edited hiPSC cardiomyocytes IPSC DERIVED MODEL The model resolves the trigger node into two mechanistically distinct allele classes: an amorphic splice-site allele that is strictly recessive, and a missense allele that reduces membrane channel density in a gene-dosage-dependent way. That distinction is what the entry's genetic_context describes as "missense, nonsense, frameshift, or splice-site". Whether it also accounts for why some heterozygous carriers of JLNS alleles show a Romano-Ward phenotype and others do not is a plausible extension of the result, not something this paper tests.

Downstream

Near-Complete Loss of Cardiac I_Ks Repolarizing Current Loss-of-function KCNQ1 alleles abolish the KCNQ1-KCNE1 I_Ks current in ventricular cardiomyocytes.

Loss of Stria Vascularis Endolymphatic K+ Secretion The same loss-of-function alleles abolish the KCNQ1-KCNE1 apical potassium-secretion current in stria vascularis marginal cells.

Impaired Gastric Parietal Cell Luminal K+ Recycling KCNQ1 also provides the apical luminal K+-recycling current required for H+/K+-ATPase-driven gastric acid secretion in parietal cells.

Show evidence (3 references)

PMID:9020846 SUPPORT Human Clinical

"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."

Original report identifying a homozygous KVLQT1 (KCNQ1) mutation as the cause of Jervell and Lange-Nielsen syndrome, establishing the biallelic loss-of-function trigger.

PMID:41147441 SUPPORT In Vitro

"The results demonstrated that all the variants resulted in functional deficiencies, with impaired localization in the plasma membrane being the most common cause."

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.

PMID:33498651 SUPPORT Human Clinical

"it was shown that only KCNQ1 protein levels lower than 10% of the normal level lead to JLNS"

Establishes the gene-dosage threshold distinguishing the severe cardioauditory JLNS phenotype from milder residual-function biallelic KCNQ1 genotypes (recessive LQT1 without deafness).

Near-Complete Loss of Cardiac I_Ks Repolarizing Current

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.

cardiomyocyte CL:0000746

potassium ion transmembrane transport GO:0071805 ↓ DECREASED membrane repolarization during cardiac muscle cell action potential GO:0086013 ↕ DYSREGULATED

heart UBERON:0000948

Experimental models

JLNS patient-derived and gene-edited hiPSC cardiomyocytes IPSC DERIVED MODEL Human JLNS cardiomyocytes show severe reduction or outright absence of I_Ks, measured directly in the cell type the node is about. This is the one place in the entry where the central cardiac lesion is observed in human cells rather than inferred from mouse or from heterologous expression.

Animal models

Kcnq1-null mouse (Kcnq1-/-) Mouse partially recapitulates 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.

Downstream

Markedly Prolonged QTc and Arrhythmogenic Substrate Loss of I_Ks-mediated repolarization prolongs ventricular action potential duration, especially at higher heart rates, and creates dispersion of repolarization.

Show evidence (2 references)

PMID:33498651 SUPPORT Other

"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)."

Establishes the KCNQ1-KCNE1 I_Ks current as the cardiac repolarizing current lost when KCNQ1 is biallelically nonfunctional.

PMID:11226272 SUPPORT Model Organism

"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."

Direct electrophysiological evidence that complete loss of Kcnq1 prolongs cardiac repolarization intervals in vivo.

Markedly Prolonged QTc and Arrhythmogenic Substrate

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.

cardiomyocyte CL:0000746

cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL

Experimental models

JLNS patient-derived and gene-edited hiPSC cardiomyocytes IPSC DERIVED MODEL Action-potential and field-potential prolongation are the single-cell and monolayer correlates of the prolonged QT interval, and the model also reproduces the two clinical features that make the substrate dangerous: adrenergic provocation lengthens the action potential specifically in JLNS cells, matching the emotion- and exercise-triggered events that account for 95% of arrhythmias in patients, and sensitivity to QT-prolonging drugs is markedly increased, which is the in-vitro counterpart of the drug-avoidance advice curated under treatments.

Downstream

Torsades de Pointes and Ventricular Fibrillation The arrhythmogenic substrate supports triggered and reentrant malignant ventricular tachyarrhythmia.

Show evidence (2 references)

PMID:16461811 SUPPORT Human Clinical

"Their QTc was markedly prolonged (557+/-65 ms)."

Quantifies the markedly prolonged QTc across a 187-patient J-LN cohort, the tissue-level arrhythmogenic substrate.

PMID:16461811 SUPPORT Human Clinical

"Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course."

Establishes that KCNQ1-related JLNS1 carries a more severe course than the allelic KCNE1-related JLNS2, supporting the disease-level severity note.

Torsades de Pointes and Ventricular Fibrillation

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.

Downstream

Syncope, Cardiac Arrest, and Sudden Cardiac Death Sustained ventricular tachyarrhythmia abolishes effective cardiac output, causing syncope and, if unresolved, sudden cardiac death.

Show evidence (2 references)

PMID:16461811 SUPPORT Human Clinical

"Most of the arrhythmic events (95%) were triggered by emotions or exercise."

Documents the adrenergic/physiologic trigger pattern for malignant ventricular tachyarrhythmia in JLNS.

PMID:32508908 SUPPORT Human Clinical

"life-threatening arrhythmias occurred with a trigger of anesthesia after the end of the CI surgery"

Case report documenting anesthesia-triggered life-threatening ventricular arrhythmia in a KCNQ1-JLNS1 patient, illustrating the trigger-susceptibility mechanism.

Syncope, Cardiac Arrest, and Sudden Cardiac Death

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.

Show evidence (2 references)

PMID:16461811 SUPPORT Human Clinical

"Most patients (86%) had cardiac events, and 50% were already symptomatic by age 3."

Quantifies the early, malignant clinical course of JLNS from the largest published cohort.

PMID:20301579 SUPPORT Other

"More than half of untreated children with JLNS die before age 15 years."

GeneReviews summary of the natural history mortality burden without treatment, the terminal outcome of this node.

Loss of Stria Vascularis Endolymphatic K+ Secretion

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.

strial marginal cell CL:0002492

potassium ion homeostasis GO:0055075 ↕ DYSREGULATED

stria vascularis of cochlear duct UBERON:0002282

Downstream

Organ of Corti Hair Cell Degeneration Collapse of endolymph volume and the endocochlear potential precipitates structural collapse and secondary hair-cell injury.

Show evidence (2 references)

PMID:20012478 SUPPORT Other

"An additional K+-diffusion potential formed by KCNQ1/KCNE1-K(+) channels at the apical membranes of marginal cells also contributes to the EP."

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.

PMID:9020846 SUPPORT Model Organism

"We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization."

Localizes KCNQ1 (KVLQT1) expression to the stria vascularis, the site of endolymphatic K+ secretion.

Organ of Corti Hair Cell Degeneration

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.

cochlear hair cell CL:0000855

apoptotic process GO:0006915 ↑ INCREASED

organ of Corti UBERON:0002227

Animal models

Kcnq1-null mouse (Kcnq1-/-) Mouse recapitulates Kcnq1-/- mice reproduce the collapsed endolymphatic compartments and organ of Corti degeneration seen in human JLNS temporal bone pathology.

Downstream

Spiral Ganglion Neuron Degeneration and Loss of Cochlear Amplification Hair-cell loss removes cochlear amplification and deafferents the auditory nerve, driving spiral ganglion neuron degeneration.

Show evidence (1 reference)

PMID:15891643 SUPPORT Model Organism

"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..."

Direct histopathologic evidence that loss of functional Kcnq1 produces stria vascularis atrophy, endolymphatic compartment collapse, and organ of Corti hair-cell degeneration.

Spiral Ganglion Neuron Degeneration and Loss of Cochlear Amplification

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.

spiral ganglion neuron CL:0011113

neuron apoptotic process GO:0051402 ↑ INCREASED

Downstream

Congenital Profound Bilateral Sensorineural Hearing Loss Combined irreversible loss of hair cells, cochlear amplification, and spiral ganglion neurons produces permanent hearing loss.

Show evidence (1 reference)

PMID:15891643 SUPPORT Model Organism

"There was a complete degeneration of the organ of Corti and an associated degeneration of the spiral ganglion."

Documents spiral ganglion degeneration coupled to hair-cell loss in the Kcnq1 knockout mouse model.

Congenital Profound Bilateral Sensorineural Hearing Loss

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.

Animal models

Kcnq1-null mouse (Kcnq1-/-) Mouse recapitulates Kcnq1-/- mice are behaviorally deaf, directly recapitulating the human congenital profound sensorineural hearing loss consequence.

AAV1-Kcnq1 gene-replacement-treated Kcnq1-/- mouse Mouse rescues 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.

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc"

GeneReviews defines the syndrome's cochlear consequence as congenital profound bilateral sensorineural hearing loss.

PMID:11226272 SUPPORT Model Organism

"Behavioral analysis revealed that the Kcnq1(-/-) mice are deaf and exhibit a shaker/waltzer phenotype."

Confirms complete deafness (plus vestibular shaker/waltzer behavior) in the Kcnq1 knockout mouse, recapitulating the human hearing-loss consequence.

Impaired Gastric Parietal Cell Luminal K+ Recycling

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.

gastric parietal cell CL:0000162

gastric acid secretion GO:0001696 ↓ DECREASED

stomach UBERON:0000945

Downstream

Achlorhydria, Hypergastrinemia, and Iron Deficiency Anemia Reduced gastric acid secretion causes compensatory hypergastrinemia and impairs the acid-dependent conversion of dietary iron needed for absorption.

Show evidence (2 references)

PMID:19491250 SUPPORT Model Organism

"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."

Kcnq1-knockout mouse gastric mucosa study establishing KCNQ1 as the obligate luminal K+-recycling channel for parietal-cell acid secretion.

PMID:19491250 SUPPORT Model Organism

"basal acid secretion was absent and forskolin-stimulated acid output reduced by approximately 90% in KCNQ1(-/-) gastric mucosa"

Quantifies the near-abolition of stimulated gastric acid secretion in Kcnq1-null mucosa, the cellular basis of the achlorhydria/hypergastrinemia branch.

Achlorhydria, Hypergastrinemia, and Iron Deficiency Anemia

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.

Show evidence (4 references)

PMID:20301579 SUPPORT Other

"Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."

GeneReviews documents iron-deficiency anemia and hypergastrinemia as frequent extracardiac, extra-auditory features of JLNS, consistent with the gastric parietal-cell mechanism.

PMID:22805636 SUPPORT Human Clinical

"A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed."

The dedicated extracardiac study of the complete Swedish double-KCNQ1-mutation cohort, which is the primary source behind the GeneReviews summary and quantifies the gastric phenotype rather than only naming it as frequent.

PMID:22805636 SUPPORT Human Clinical

"Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present."

Measured biochemistry behind the hypergastrinemia half of this node.

+ 1 more reference

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Pathograph

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Phenotypes

11

Blood 1

Iron Deficiency Anemia FREQUENT HP:0001891

Twelve of fourteen (86%) would fall in the VERY_FREQUENT band, but the figure comes from a single 14-patient Swedish series that is the only cohort ever screened for this phenotype, so the band is left at FREQUENT to match the GeneReviews wording rather than raised on one small series.

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."

GeneReviews documents iron-deficiency anemia as a frequent non-cardioauditory feature.

PMID:22805636 SUPPORT Human Clinical

"A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed."

Quantifies the frequency in the complete Swedish double-KCNQ1-mutation cohort, the only series to have systematically looked for it.

Cardiovascular 6

Prolonged QTc Interval OBLIGATE HP:0005184

Definitional: GeneReviews requires a long QT interval, alongside congenital sensorineural deafness and biallelic KCNQ1 or KCNE1 variants, to establish the diagnosis, so the phenotype is obligate within this entry by construction. The 186-patient cohort mean QTc of 557 +/- 65 ms describes how severe the prolongation is, not how penetrant it is, and is not the basis for the band; GeneReviews itself writes "usually >500 msec".

Show evidence (1 reference)

PMID:16461811 SUPPORT Human Clinical

"Their QTc was markedly prolonged (557+/-65 ms)."

Quantifies the markedly prolonged QTc across a 187-patient J-LN cohort.

Torsade de Pointes HP:0001664

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"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."

GeneReviews documents torsade de pointes as a characteristic tachyarrhythmia of JLNS.

Ventricular Fibrillation HP:0001663

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"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."

GeneReviews documents ventricular fibrillation as a characteristic tachyarrhythmia of JLNS.

Syncope FREQUENT HP:0001279

Temporal: RECURRENT

Show evidence (1 reference)

PMID:16461811 SUPPORT Human Clinical

"Most of the arrhythmic events (95%) were triggered by emotions or exercise."

Documents the frequency and adrenergic trigger pattern of arrhythmic syncopal events.

Sudden Cardiac Death FREQUENT HP:0001645

GeneReviews reports that more than half of untreated children with JLNS die before age 15, mapping to the 30-79% FREQUENT band. The figure describes the untreated natural history; on beta-blockade the Schwartz cohort still recorded cardiac arrest or sudden death in 27%.

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"More than half of untreated children with JLNS die before age 15 years."

GeneReviews natural-history statement on JLNS mortality without treatment.

PMID:32508908 SUPPORT Human Clinical

"exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia"

Independent case-report source quantifying sudden cardiac death risk in JLNS.

Bradycardia HP:0001662

Show evidence (1 reference)

PMID:29037160 SUPPORT Human Clinical

"Three patients were admitted into hospital due to recurrent seizures/syncope, intrauterine and postnatal bradycardia respectively"

Documents intrauterine/postnatal bradycardia as a presenting feature in a KCNQ1-JLNS case series.

Digestive 1

Achlorhydria HP:0032448

Show evidence (3 references)

PMID:19491250 SUPPORT Model Organism

"basal acid secretion was absent and forskolin-stimulated acid output reduced by approximately 90% in KCNQ1(-/-) gastric mucosa"

Direct measurement of achlorhydria (absent basal and near-abolished stimulated gastric acid secretion) in the Kcnq1-null mouse gastric mucosa.

PMID:20301579 SUPPORT Other

"Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."

GeneReviews documents the downstream human consequences of achlorhydria (hypergastrinemia, iron-deficiency anemia) as frequent features, which corroborates the mouse finding by inference; it does not directly measure gastric acid secretion in JLNS patients.

PMID:22805636 SUPPORT INDIRECT Human Clinical

"We propose that the Jervell and Lange-Nielsen Syndrome phenotypically includes gastrointestinal symptoms/signs and secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations."

The Swedish cohort attributes the observed gastric phenotype to hypochlorhydria in JLNS patients. Indirect because acid output was inferred from gastrin and pepsinogen rather than measured: no human JLNS gastric-acid study exists, so the direct measurement remains the Kcnq1-null mouse.

Ear 1

Congenital Profound Bilateral Sensorineural Hearing Loss OBLIGATE Profound sensorineural hearing impairment HP:0011476

Onset: CONGENITAL

Definitional: GeneReviews requires congenital sensorineural deafness for the diagnosis of JLNS, so within this entry the phenotype is obligate by construction. Biallelic KCNQ1 genotypes with enough residual channel function to spare hearing are classified as recessive LQT1, not JLNS.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."

GeneReviews defines profound congenital bilateral sensorineural hearing loss as a cardinal feature.

Endocrine 1

Hypergastrinemia FREQUENT HP:0500167

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."

GeneReviews documents elevated gastrin as a frequent non-cardioauditory feature.

PMID:22805636 SUPPORT Human Clinical

"Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present."

Measured serum gastrin in the Swedish JLNS cohort; seven of nine tested patients were elevated, which sits in the FREQUENT band recorded here.

Nervous System 1

Seizure-Like Episodes HP:0001250

Show evidence (1 reference)

PMID:29037160 SUPPORT Human Clinical

"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."

Case series documenting seizure-like presenting episodes alongside congenital deafness in KCNQ1-JLNS.

🧬

Genetic Associations

2

KCNQ1

Gene: KCNQ1 hgnc:6294 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:16461811 SUPPORT Human Clinical

"Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course."

Independent cohort confirms the ~90% KCNQ1 share and the more severe course relative to KCNE1-related JLNS2.

PMID:37872640 SUPPORT Other

"both PTCs and missense variants leading to LoF of KCNQ1 are associated with LQTS and Jervell Lange-Nielsen syndrome"

Structured ClinGen-aligned gene-disease curation confirms KCNQ1 loss-of-function (protein-truncating and missense) as the JLNS1 mechanism, classified with biallelic autosomal requirement.

PMID:24552659 SUPPORT Human Clinical

"Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%"

The gene-dosage contrast within a single founder allele: the same KCNQ1 variant gives markedly longer QTc and a 47-fold higher cardiac arrest incidence when biallelic than when heterozygous.

+ 1 more reference

Variants (1)

KCNQ1 p.Arg518Ter Pathogenic

Gene: KCNQ1 hgnc:6294 nonsense

c.1552C>T, p.Arg518*, a protein-truncating KCNQ1 allele and a worldwide cause of both recessive JLNS and dominant LQT1. In Sweden it is a founder mutation accounting for the majority of JLNS cases and the second most common cause of LQTS, with a shared haplotype across 17 of 19 index families, an estimated mutation age of 28 generations, and geographical clustering in the Pite River valley. Estimated heterozygote prevalence there is roughly 1 in 2,000 to 4,000, which makes it the best-characterized single JLNS allele anywhere and the reason Swedish series recur throughout the JLNS literature.

Show evidence (2 references)

PMID:24552659 SUPPORT Human Clinical

"The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide."

Establishes this single allele as a cause of both the recessive and the dominant disease depending on dosage.

PMID:24552659 SUPPORT Human Clinical

"A high prevalence of Swedish p.R518X heterozygotes was suggested (~1:2000-4000)."

The founder-allele carrier frequency in the Swedish population.

NOS1AP

Gene: NOS1AP hgnc:16859 relationship_type: MODIFIER variant_origin: GERMLINE

Show evidence (2 references)

PMID:32061134 SUPPORT INDIRECT In Vitro

"This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes."

Supports NOS1AP as a modifier of arrhythmic severity in prolonged repolarization generally. Indirect for JLNS: the human cells carried a heterozygous LQT1 KCNQ1 variant, not a biallelic JLNS genotype, so applying it here relies on JLNS sharing the prolonged-repolarization substrate the mechanism converges on.

PMID:32061134 SUPPORT INDIRECT In Vitro

"The minor NOS1AP alleles are associated with NOS1 loss of function."

The molecular step behind the modifier effect, measured in the same cell models.

💊

Medical Actions

8

Beta-Blocker Therapy

Action: beta-blocker therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576

Platform: Small molecule

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.

Mechanism Target:

INHIBITS Torsades de Pointes and Ventricular Fibrillation — Beta-blockade reduces adrenergically triggered arrhythmic events but has only partial efficacy in JLNS.

Show evidence (1 reference)

PMID:16461811 SUPPORT Human Clinical

"beta-Blockers have only partial efficacy; 51% of the patients had events despite therapy and 27% had CA/SD."

Quantifies the partial efficacy of beta-blocker therapy in the largest JLNS cohort.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"beta-adrenergic blockers for long QT interval (Note: Beta-blocker treatment is only partially effective.)"

GeneReviews management recommendation and efficacy caveat.

Implantable Cardioverter-Defibrillator Placement

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

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.

Mechanism Target:

INHIBITS Syncope, Cardiac Arrest, and Sudden Cardiac Death — ICD therapy terminates sustained ventricular tachyarrhythmia before it progresses to sudden cardiac death.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"implantable cardioverter defibrillators (ICDs) for those with a history of cardiac arrest and/or failure to respond to other treatments"

GeneReviews management recommendation for ICD placement.

Show evidence (3 references)

PMID:16461811 SUPPORT Human Clinical

"Early therapy with implanted cardioverter/defibrillators must be considered."

Cohort-based recommendation for early ICD consideration given the malignant course of JLNS.

PMID:16461811 SUPPORT Human Clinical

"A QTc >550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD."

The two early predictors that identify which JLNS patients warrant a defibrillator rather than beta-blockade alone.

PMID:16461811 SUPPORT Human Clinical

"Females are at lower risk for cardiac arrest and sudden death (CA/SD) (hazard ratio, 0.54; 95% CI, 0.34 to 0.88; P=0.01)."

The sex effect on arrhythmic risk, with its effect size and confidence interval, which enters the same stratification.

Left Cardiac Sympathetic Denervation

Action: left cardiac sympathetic denervation Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

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.

Mechanism Target:

INHIBITS Torsades de Pointes and Ventricular Fibrillation — Left cardiac sympathetic denervation reduces arrhythmia-provoking sympathetic input when pharmacologic anti-adrenergic therapy is insufficient.

Show evidence (2 references)

PMID:18606002 SUPPORT Other

"If the patient has one more syncope despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation"

General congenital-LQTS review recommendation for LCSD escalation, applicable to JLNS's high breakthrough-event rate on beta-blockers.

PMID:35331422 SUPPORT INDIRECT Human Clinical

"with an overall 86% decrease in the mean yearly cardiac event rate (P < 0.0001)"

Quantifies the effect of the denervation on the arrhythmic event rate this edge claims it inhibits, in a 125-patient LQTS series with a mean 12.9-year follow-up. Indirect because the series is LQTS-wide and reports no JLNS subgroup, so the reduction is not measured in this disease.

Show evidence (2 references)

PMID:18606002 SUPPORT Other

"If the patient has one more syncope despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation"

Review recommendation for LCSD after recurrent syncope on full-dose beta-blockade.

PMID:35331422 SUPPORT INDIRECT Human Clinical

"After LCSD, 17% in the very high risk group remained asymptomatic, compared with 52%, 47%, and 97% in the other 3 groups (P < 0.0001)"

The relevant caveat for JLNS. The inference step, and the reason this is graded INDIRECT, is that the cohort is LQTS-wide and reports no JLNS subgroup: placing JLNS patients in the very-high-risk stratum follows from that stratum's definition (symptomatic in the first year of life, or highly malignant genetics), which JLNS patients typically meet, rather than from the paper assigning them there. On that reading only 17% of the stratum became asymptomatic, so denervation substantially reduces events without removing residual risk. The same paper reports that LCSD results are not affected by common genotypes.

Atrial Pacing with Beta-Blockade

Action: atrial pacemaker implantation Ontology label: Pacemaker Placement NCIT:C80434

Platform: Device

Permanent atrial pacing added to beta-blocker therapy in young high-risk JLNS patients, as an alternative to defibrillator implantation in children too small for a transvenous ICD. In the Norwegian national series of nine genetically confirmed JLNS patients, six received atrial leads and all six survived without events over a mean 6.9 years, while the single patient given a ventricular lead died during follow-up. The lead position is therefore not incidental to the result.

Mechanism Target:

INHIBITS Torsades de Pointes and Ventricular Fibrillation — Atrial pacing prevents the bradycardia and pauses that shorten diastolic intervals irregularly and provoke pause-dependent triggered activity on a markedly prolonged action potential, and it permits beta-blocker uptitration that bradycardia would otherwise limit.

Show evidence (1 reference)

PMID:27451284 SUPPORT INDIRECT Human Clinical

"The 6 patients with atrial leads survived without events at a mean follow-up of 6.9 years after pacemaker implantation."

Event-free survival on atrial pacing plus beta-blockade in the JLNS-specific series. Indirect for the mechanism claim: the study reports clinical outcome, not the suppression of triggered activity the edge asserts, and with six patients and no control arm it cannot separate the pacing effect from the beta-blockade it accompanies.

Show evidence (1 reference)

PMID:27451284 SUPPORT Human Clinical

"Seven patients also received a pacemaker; 1 had a ventricular lead and 6 had atrial leads. The patient with the ventricular lead died during follow-up."

The whole device experience in the series, including the ventricular-lead death, which is what makes this an argument for atrial pacing specifically rather than for pacing in general.

KCNQ1 Suppression-and-Replacement Gene Therapy

Action: Gene Therapy NCIT:C15238

Platform: Gene therapy

Investigational dual-component gene therapy that suppresses both endogenous KCNQ1 alleles with a short hairpin RNA while supplying an shRNA-immune wild-type KCNQ1 cDNA from the same construct. Because suppression is mutation-independent, one vector in principle covers any KCNQ1 genotype rather than requiring an allele-specific product, which is the property that makes it relevant to a disease defined by two different loss-of-function alleles per patient. In LQT1 patient iPSC-derived cardiomyocytes it shortened the prolonged action potential to isogenic control values.

Mechanism Target:

RESTORES Near-Complete Loss of Cardiac I_Ks Repolarizing Current — Supplying wild-type KCNQ1 coding sequence restores the pore-forming subunit whose absence is this node, rather than compensating downstream of it.

Show evidence (1 reference)

PMID:33504163 SUPPORT INDIRECT In Vitro

"In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1."

Demonstrates functional restoration of repolarization in human cardiomyocytes. Indirect for JLNS: every cell line tested carried a heterozygous LQT1 genotype, so restoration was shown against one residual wild-type allele and not against the biallelic null state this node describes.

Show evidence (1 reference)

PMID:33504163 SUPPORT INDIRECT In Vitro

"KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and 3 LQT1-causative variants"

Mutation independence is the property that would let one construct serve JLNS patients regardless of which two KCNQ1 alleles they carry. Indirect because the demonstration is in LQT1 constructs and cells.

Cochlear Implantation

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Device

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.

Mechanism Target:

RESTORES Congenital Profound Bilateral Sensorineural Hearing Loss — Cochlear implantation bypasses the degenerated cochlear sensory apparatus to restore auditory input.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"Cochlear implantation to treat hearing loss"

GeneReviews management recommendation for cochlear implantation.

Show evidence (4 references)

PMID:32508908 SUPPORT Human Clinical

"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."

Case report demonstrating both the auditory benefit and the peri-anesthetic arrhythmia risk of cochlear implantation in a KCNQ1-JLNS1 patient.

PMID:20301579 SUPPORT Other

"Special precautions during anesthesia are necessary because of the increased risk for cardiac arrhythmia."

GeneReviews explicitly flags anesthesia precautions relevant to cochlear implant surgery.

PMID:26205899 SUPPORT Human Clinical

"Considering all precautions their cochlear implant surgeries were done uneventfully."

Counterweight to the single adverse case above: with the precautions in place, implantation was uneventful in this center's four JLNS patients. The peri-anesthetic risk is real and manageable, not prohibitive.

+ 1 more reference

QT-Prolonging Drug and Trigger Avoidance

Action: risk-factor and trigger-avoidance counseling Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

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.

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"Drugs that cause further prolongation of the QT interval; activities known to precipitate syncopal events in persons with long QT syndrome."

GeneReviews lists agents and circumstances to avoid for JLNS.

PMID:26205899 SUPPORT Human Clinical

"As auditory stimuli is reported to be a specific trigger, it is prudent to activate the processor with continuous heart monitoring"

Names a trigger specific to this disease and to its own treatment: sound itself. Switching on a cochlear implant processor is therefore an arrhythmia risk in its own right, separate from the anesthetic risk of the implantation surgery, and is recommended to be done under cardiac monitoring.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

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.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"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."

GeneReviews genetic counseling recommendation.

🔬

Biochemical Markers

3

Serum Gastrin (Elevated)

Context: Elevated in seven of nine tested patients in the complete Swedish double-KCNQ1-mutation cohort. Compensatory hypergastrinemia follows loss of acid-mediated negative feedback on antral G cells when parietal-cell acid secretion fails, so this is the biochemical readout of the gastric arm of the pathophysiology rather than an independent finding. Frequency is carried on the Hypergastrinemia phenotype.

Show evidence (1 reference)

PMID:22805636 SUPPORT Human Clinical

"Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present."

Measured serum gastrin in the Swedish JLNS cohort.

Serum Pepsinogen (Elevated)

Context: Elevated in six of seven tested patients in the same cohort. Pepsinogen is secreted by gastric chief cells and rises with the trophic drive of hypergastrinemia, so it corroborates the secretory disturbance independently of the gastrin assay itself.

Show evidence (1 reference)

PMID:22805636 SUPPORT Human Clinical

"pepsinogen in six of seven cases"

Measured pepsinogen elevation in the Swedish JLNS cohort.

Faecal Calprotectin (Elevated)

Context: Elevated in nine of nine tested patients, the only analyte in the cohort abnormal in every patient measured. Calprotectin is a neutrophil-derived marker of intestinal inflammation and is not explained by the parietal-cell mechanism curated here, so it records an unexplained gastrointestinal finding rather than a predicted one. The denominator is nine patients from a single national series.

Show evidence (1 reference)

PMID:22805636 SUPPORT Human Clinical

"faecal calprotectin in nine of nine cases were present"

Measured faecal calprotectin elevation in every tested patient in the Swedish JLNS cohort.

🔬

Diagnosis

7

Integrated Clinical and Molecular Diagnostic Criteria

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).

clinical assessment NCIT:C124351

Results: Congenital sensorineural deafness plus a long QT interval, with biallelic pathogenic KCNQ1 or KCNE1 variants on molecular testing, establishes the diagnosis.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"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."

GeneReviews DIAGNOSIS/TESTING section states the integrated clinical and molecular diagnostic criteria.

Resting 12-Lead Electrocardiography with QTc Measurement

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.

clinical assessment NCIT:C124351

QTc LOINC:8636-3

Reference Ranges

Q-T interval corrected (Jervell and Lange-Nielsen syndrome cohorts: 186 patients from the literature and individual physicians (Schwartz et al. 2006) and 44 patients prospectively followed in the U.S. portion of the International LQTS Registry (Goldenberg et al. 2006))

QTc at or above 550 ms (≥ 550 ms)

QTc at or above 550 ms: Higher risk of cardiac arrest or sudden death within JLNS; with syncope in the first year of life, one of the two independent predictors of subsequent cardiac arrest or sudden death.

A risk-stratification cut-off within JLNS, not a diagnostic threshold: both cohorts stratify cardiac risk at a QTc of 550 ms (Schwartz et al. as an independent predictor of cardiac arrest or sudden death, Goldenberg et al. as the stratum in which the excess risk of JLNS over Romano-Ward syndrome was largest), and neither proposes it as a criterion for making the diagnosis. The two abstracts write the boundary differently. Schwartz et al. write "A QTc >550 ms" (exclusive), Goldenberg et al. "a baseline QTc > or = 550 msec" (inclusive); the half-open band puts 550 ms itself in the higher-risk tier, which agrees with Goldenberg et al. and disagrees by one point with Schwartz et al. No diagnostic QTc cut-off specific to JLNS is recorded: GeneReviews (PMID:20301579) characterises the QTc as "usually >500 msec", a description of where affected patients fall rather than a threshold, and the general LQTS guideline cut-off belongs to the Long QT Syndrome entry. LOINC:8636-3 names no correction formula, and neither cohort abstract names one.

Show evidence (2 references)

PMID:16461811 SUPPORT Human Clinical

"A QTc >550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD."

States the 550 ms QTc boundary as an independent predictor of cardiac arrest or sudden death in the 186-patient JLNS cohort.

PMID:16911578 SUPPORT Human Clinical

"The JLNS:RWS and JLNS:LQT1 adjusted hazard ratios (HR) for cardiac events were highest among patients with a baseline QTc > or = 550 msec"

A second, prospectively followed JLNS cohort stratifies at the same 550 ms boundary: the excess risk of cardiac events in JLNS, relative to Romano-Ward syndrome and LQT1, was largest in patients with a baseline QTc at or above it.

Results: Markedly prolonged QTc, mean 557+/-65 ms in the largest published cohort, commonly >500 ms.

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.

Show evidence (2 references)

PMID:16461811 SUPPORT Human Clinical

"Their QTc was markedly prolonged (557+/-65 ms)."

Quantifies the QTc finding on ECG that anchors the diagnosis in the largest published JLNS cohort.

PMID:38790576 SUPPORT Other

"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)."

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.

Ambulatory Holter Monitoring

Ambulatory ECG (Holter) monitoring may be used alongside resting ECG to assess cardiac rhythm and identify arrhythmic events supporting the diagnosis.

Holter monitoring NCIT:C38064

Show evidence (1 reference)

PMID:39027806 SUPPORT Other

"Additional investigations, including exercise stress tests and Holter monitoring, may be warranted to assess cardiac function and identify arrhythmic events"

Systematic review of LQTS management documents Holter monitoring as an additional diagnostic investigation alongside ECG, applicable to JLNS's cardiac diagnostic workup.

Exercise Cardiac Stress Testing

Exercise stress testing may be used to assess cardiac function and provoke arrhythmic events as part of the diagnostic workup.

Exercise cardiac stress test NCIT:C168192

Show evidence (1 reference)

PMID:39027806 SUPPORT Other

"Additional investigations, including exercise stress tests and Holter monitoring, may be warranted to assess cardiac function and identify arrhythmic events"

Systematic review of LQTS management documents exercise stress testing as an additional diagnostic investigation, applicable to JLNS's cardiac diagnostic workup.

Audiological Screening and Molecular Testing of At-Risk Relatives

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.

audiological and molecular genetic screening NCIT:C18020

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"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."

GeneReviews describes the audiological, electrocardiographic, and molecular-genetic evaluation protocol for at-risk relatives.

PMID:26205899 SUPPORT Human Clinical

"It is recommended that all congenitally deaf patients have an ECG taken as a part of the evaluation."

Extends screening beyond at-risk relatives of a known case to every congenitally deaf child, which is what the 0.79% yield among 503 implant candidates recorded under prevalence actually argues for.

Pure-Tone Audiometry

Audiometric assessment documents the congenital bilateral sensorineural hearing loss that is the second defining feature of JLNS, and is part of the work-up of the deaf children in whom JLNS is sought by ECG screening.

audiometric test NCIT:C38036

pure-tone audiometry LOINC:89015-2

The panel code identifies the test; no reference range is recorded. The cited sources describe the deafness in JLNS as profound but state no audiometric cut-off owned by the disease, and a generic hearing-loss grading (such as the WHO grades) is not JLNS content. The grades are also defined on a pure-tone average, for which searches of the Monarch KG ("pure tone average", "PTA", "hearing level average", "average hearing") returned no LOINC code; the per-frequency codes are ear- and frequency-specific (for example LOINC:89017-8 Hearing threshold Ear - right --1000 Hz), so none of them carries a grade defined on the average.

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."

Names profound congenital bilateral sensorineural hearing loss as a defining feature, the finding audiometry documents.

PMID:22830134 SUPPORT Human Clinical

"Audiometry was performed on all the children and the result interpreted according to WHO recommendations."

In a screening study of congenitally deaf-mute children for long QT syndrome, which concludes on the prevalence of JLNS in that population, audiometry was part of the assessment of every child.

Targeted Arrhythmia and Deafness Gene Panel Sequencing

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.

molecular genetic testing NCIT:C19770

Results: Identification of biallelic (homozygous or compound heterozygous) pathogenic KCNQ1 variants confirms JLNS1.

Show evidence (2 references)

PMID:32508908 SUPPORT Human Clinical

"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"

Case report demonstrating NGS-based molecular confirmation of compound heterozygous KCNQ1 variants.

PMID:29037160 SUPPORT Human Clinical

"Further targeted next generation sequencing of cardiac panel comprising 68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in RYR2 gene"

Case series demonstrating use of a targeted 68-gene arrhythmia panel for molecular diagnosis and candidate-modifier discovery in KCNQ1-JLNS.

📈

Progression

3

Congenital onset with early-childhood cardiac events

Age: Birth to 3 years

The hearing loss is present from birth, but the cardiac phenotype declares itself later: half the reported patients were already symptomatic by age three. A deaf infant with no cardiac history is therefore not yet reassuring, and this window is why newborn hearing screening is treated here as a case-finding route into cardiac evaluation rather than only an audiological result.

Show evidence (2 references)

PMID:16461811 SUPPORT Human Clinical

"Data on the Jervell and Lange-Nielsen syndrome (J-LN), the long-QT syndrome (LQTS) variant associated with deafness and caused by homozygous or compound heterozygous mutations on the KCNQ1 or on the KCNE1 genes encoding the I(Ks) current, are still based largely on case reports. ... We analyzed..."

Retains the mixed KCNQ1/KCNE1 Jervell–Lange-Nielsen cohort. Half symptomatic by age three is a pooled estimate; KCNQ1 accounts for most cases and KCNE1 is associated with a more benign course.

PMID:20301579 SUPPORT Other

"Fifty percent of individuals with JLNS had cardiac events before age three years."

Independent statement of the same early-childhood onset window in the GeneReviews chapter.

Adrenergically triggered episodes

Events are overwhelmingly provoked rather than spontaneous, which is what makes trigger avoidance and beta-blockade rational therapy and what places this syndrome with LQT1 rather than with the pause-dependent LQT3 phenotype.

Show evidence (2 references)

PMID:16461811 SUPPORT Human Clinical

"Most of the arrhythmic events (95%) were triggered by emotions or exercise."

Quantifies the adrenergic trigger dependence that characterizes the symptomatic phase.

PMID:20301579 SUPPORT Other

"The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright."

Describes the same trigger-provoked presentation in clinical terms.

Untreated childhood mortality

Age: Before 15 years, untreated

This figure describes the natural history without therapy and is the baseline against which the treatment section should be read. It is not the contemporary outcome: on beta-blockade the 186-patient series still recorded events in 51% and cardiac arrest or sudden death in 27%, which is partial protection rather than none and is why implantable defibrillators and left cardiac sympathetic denervation are curated as treatments here.

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"More than half of untreated children with JLNS die before age 15 years."

GeneReviews natural-history statement giving the untreated mortality of the syndrome in childhood.

PMID:16461811 SUPPORT Human Clinical

"beta-Blockers have only partial efficacy; 51% of the patients had events despite therapy and 27% had CA/SD."

Gives the treated residual risk, which is what makes the untreated figure a natural-history baseline rather than a current prognosis.

📊

Prevalence

2

Worldwide (all JLNS, KCNQ1 ~90% of cases)

Point Prevalence 0.3 per 100,000 (0.1–0.5) 1–9 per 1,000,000

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.

Show evidence (1 reference)

PMID:32508908 SUPPORT Other

"The prevalence of JLNS is about 1/1000000 to 1/200000 around the world."

Source for the worldwide JLNS prevalence range.

Children with congenital bilateral profound hearing loss referred for cochlear implantation (single tertiary center, n=503)

Point Prevalence 790.0 per 100,000 >1 in 1,000

This is prevalence within an enriched clinical population, not in the general population, and the two figures are not comparable: screening congenitally deaf children for a long QT interval concentrates JLNS by roughly three orders of magnitude relative to the worldwide estimate above. That is the entire argument for ECG screening of congenitally deaf children, and it is why this record is curated separately rather than folded into the worldwide one. The rate is this single center's own yield, four cases among 503 children, and no confidence interval is reported for it, so rate_low and rate_high are deliberately left unset. The authors place it within a published cross-series range of 0 to 2.6%; that range describes the spread between centers, not bounds on this estimate, so it is recorded here rather than in the rate slots.

Show evidence (1 reference)

PMID:26205899 SUPPORT Human Clinical

"The prevalence of disease was 0.79% (four cases) in our center which is in the range of literature reports (0-2.6%)."

Gives the yield of screening 503 congenitally deaf cochlear-implant candidates by ECG, with the published range across comparable series.

⚖️

Clinical Burden

High

Two independently disabling burdens fall on the same child. The cardiac one is lethal: untreated, more than half die before age 15, and the largest series describes JLNS as a most severe variant of long QT syndrome, with events in 86% of patients and onset by age three in half of them. It is also only partly tractable - on beta-blockade, half the cohort still had events and 27% still had cardiac arrest or sudden death - so the burden persists under best available medical therapy rather than resolving with diagnosis. The auditory one is permanent and present from birth, and because the mammalian cochlea does not regenerate it is managed by prosthetic substitution rather than repair. The two also interact: cochlear implantation, the standard treatment for the deafness, is general anesthesia in a child with a markedly prolonged QT interval, and a published case records life-threatening arrhythmia triggered by anesthesia at the end of exactly that surgery.

Show evidence (2 references)

PMID:16461811 SUPPORT Human Clinical

"J-LN syndrome is a most severe variant of LQTS, with a very early onset and major QTc prolongation, and in which beta-blockers have limited efficacy."

The cohort's own summary judgement on severity and on the limits of first-line therapy.

PMID:32508908 SUPPORT Human Clinical

"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."

Documents the interaction between the two burdens: treating the deafness required an anesthetic that precipitated a life-threatening arrhythmia.

🔬

Clinical Trials

1

NCT06534671 PHASE_IV COMPLETED

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: Prolonged QTc interval HP:0005184

Show evidence (1 reference)

clinicaltrials:NCT06534671 SUPPORT Human Clinical

"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."

ClinicalTrials.gov summary confirms the trial's disease-specific, single-dose, acute-effect design.

🧫

Experimental Models

1

JLNS patient-derived and gene-edited hiPSC cardiomyocytes IPSC_DERIVED_MODEL

Human induced pluripotent stem cell lines carrying JLNS-causing KCNQ1 genotypes, generated both by reprogramming patient cells and by genetic engineering, differentiated to cardiomyocytes and studied by patch clamp and multielectrode array. The panel covers the two major classes of JLNS-causing KCNQ1 defect (a splice-site allele, c.478-2A>T, and a missense allele, c.1781G>A) in homozygous, heterozygous, and wild-type form, so the recessive genotype-phenotype relationship is read off an allelic series in one human genetic background rather than inferred across patients. It is the human-cell counterpart to the Kcnq1-null mouse curated under animal_models: the mouse carries the cochlear phenotype that human cardiomyocytes cannot report, and this model carries the human cardiac electrophysiology that the mouse reports poorly because murine ventricular repolarization does not depend on I_Ks the way human repolarization does.

Organism

human NCBITaxon:9606

Cell source

JLNS patient somatic cells reprogrammed to hiPSC, plus isogenic genetically engineered lines

Culture

Directed cardiomyocyte differentiation of hiPSC lines; patch-clamp and multielectrode array electrophysiology

Publication

PMID:25453094

Pathograph links

Biallelic KCNQ1 Loss-of-Function Variants recapitulates fidelity: high observes: molecular The model resolves the trigger node into two mechanistically distinct allele classes: an amorphic splice-site allele that is strictly recessive, and a missense allele that reduces membrane channel density in a gene-dosage-dependent way. That distinction is what the entry's genetic_context describes as "missense, nonsense, frameshift, or splice-site". Whether it also accounts for why some heterozygous carriers of JLNS alleles show a Romano-Ward phenotype and others do not is a plausible extension of the result, not something this paper tests.

Readouts

Allele-class assignment (amorphic versus hypomorphic) by isogenic comparison

Direction: ALTERED

Interpretation: Comparing homozygous, heterozygous, and wild-type lines of the same genetic background separates a null allele from a dosage-sensitive one.

Show evidence (1 reference)

PMID:25453094 SUPPORT In Vitro

"We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS"

Describes the isogenic allelic series that makes the allele-class readout interpretable.

Show evidence (1 reference)

PMID:25453094 SUPPORT In Vitro

"the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane"

Establishes that this model reports the functional class of the causative allele, which is the claim the link makes about this node.

Near-Complete Loss of Cardiac I_Ks Repolarizing Current recapitulates fidelity: high observes: cellular Human JLNS cardiomyocytes show severe reduction or outright absence of I_Ks, measured directly in the cell type the node is about. This is the one place in the entry where the central cardiac lesion is observed in human cells rather than inferred from mouse or from heterologous expression.

Readouts

Slow delayed-rectifier potassium current (I_Ks) amplitude

Direction: ABOLISHED

Interpretation: Severe reduction or absence of I_Ks is the direct electrophysiological measurement of the node.

Show evidence (1 reference)

PMID:25453094 SUPPORT In Vitro

"recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs"

The reported measurement of I_Ks amplitude in JLNS versus wild-type cardiomyocytes.

Show evidence (1 reference)

PMID:25453094 SUPPORT In Vitro

"recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs"

Directly reports loss of the current this node names, in human cardiomyocytes carrying the disease genotype.

Markedly Prolonged QTc and Arrhythmogenic Substrate partially recapitulates fidelity: moderate observes: cellular Action-potential and field-potential prolongation are the single-cell and monolayer correlates of the prolonged QT interval, and the model also reproduces the two clinical features that make the substrate dangerous: adrenergic provocation lengthens the action potential specifically in JLNS cells, matching the emotion- and exercise-triggered events that account for 95% of arrhythmias in patients, and sensitivity to QT-prolonging drugs is markedly increased, which is the in-vitro counterpart of the drug-avoidance advice curated under treatments.

Limitations: The QTc is a whole-heart measurement and this model observes only cardiomyocyte-level repolarization. Dispersion of repolarization across the ventricular wall, reentry, and the conducted arrhythmia itself are tissue-level properties that dissociated or monolayer cardiomyocytes cannot report, so calling field-potential prolongation an arrhythmogenic substrate is an inference. hiPSC-derived cardiomyocytes are also electrophysiologically immature relative to adult ventricular myocardium, with a depolarized resting potential and a mixed atrial/ventricular/nodal population.

Divergences from the human mechanism

scale extrapolation qualifying

The model measures action and field potential duration in cardiomyocytes; the node is a tissue-level arrhythmogenic substrate on the surface ECG. The intervening step, transmural dispersion of repolarization organizing into reentry, is not observed here.

boundary omission qualifying

Autonomic innervation is outside the culture, so the adrenergic provocation is applied pharmacologically rather than arising from the sympathetic surge that triggers events in patients. The clinical relevance of left cardiac sympathetic denervation, curated under treatments, turns on exactly the structure this model omits.

Readouts

Action potential and field potential duration

Direction: INCREASED

Interpretation: Prolonged repolarization at the cellular and monolayer level is the in-vitro correlate of the prolonged QTc, one scale below it.

Show evidence (1 reference)

PMID:25453094 SUPPORT In Vitro

"pronounced action and field potential prolongation"

The measured prolongation of repolarization in JLNS cardiomyocytes.

Susceptibility to proarrhythmic drug challenge

Direction: INCREASED

Interpretation: Increased sensitivity to QT-prolonging drugs in JLNS cardiomyocytes is the in-vitro counterpart of the clinical instruction to avoid QT-prolonging agents, and it was pharmacologically correctable in this system.

Show evidence (1 reference)

PMID:25453094 SUPPORT In Vitro

"sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs but could be pharmacologically corrected"

Reports both the increased drug susceptibility and its pharmacological correction in the model.

Show evidence (1 reference)

PMID:25453094 SUPPORT In Vitro

"Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS-CMs."

Reproduces the adrenergic trigger dependence of the clinical arrhythmic substrate in the human cell model.

Show evidence (1 reference)

PMID:25453094 SUPPORT In Vitro

"Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS"

Establishes the model as informative for the JLNS cardiac phenotype: the disease genotype reproduces the disease electrophysiology in human cardiomyocytes.

🐁

Animal Models

2

Kcnq1-null mouse (Kcnq1-/-)

Species

Mouse

Genotype

Kcnq1 targeted disruption, homozygous null

Publication

PMID:11226272

Pathograph links

Near-Complete Loss of Cardiac I_Ks Repolarizing Current partially recapitulates fidelity: moderate 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

In vivo ECG QT and JT interval

Direction: INCREASED

Interpretation: Prolonged QT and JT intervals recorded in vivo, but not in isolated hearts, in Kcnq1-/- mice.

Show evidence (1 reference)

PMID:11226272 SUPPORT Model Organism

"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."

Direct in vivo ECG measurement supporting the readout.

Show evidence (1 reference)

PMID:11226272 SUPPORT Model Organism

"These changes are indicative of cardiac repolarization defects that appear to be induced by extracardiac signals."

Author interpretation that the murine repolarization defect is informative for the cardiac node but not a pure recapitulation of the cell-autonomous mechanism.

Organ of Corti Hair Cell Degeneration recapitulates fidelity: high Kcnq1-/- mice reproduce the collapsed endolymphatic compartments and organ of Corti degeneration seen in human JLNS temporal bone pathology.

Readouts

Inner ear histopathology

Direction: ABOLISHED

Interpretation: Marked stria vascularis atrophy, endolymphatic compartment collapse, and complete organ of Corti degeneration.

Show evidence (1 reference)

PMID:15891643 SUPPORT Model Organism

"Kcnq1 knockout mice exhibit histopathologic findings that are comparable to those reported in human temporal bone cases of Jervell and Lange-Nielsen syndrome"

Direct comparison of mouse histopathology to human JLNS temporal bone findings.

Show evidence (1 reference)

PMID:11226272 SUPPORT Model Organism

"Histological analysis of the inner ear structures of Kcnq1(-/-) mice revealed gross morphological anomalies because of the drastic reduction in the volume of endolymph."

Founding description of the Kcnq1-/- mouse inner ear phenotype.

Congenital Profound Bilateral Sensorineural Hearing Loss recapitulates fidelity: high Kcnq1-/- mice are behaviorally deaf, directly recapitulating the human congenital profound sensorineural hearing loss consequence.

Readouts

Behavioral deafness and vestibular (shaker/waltzer) phenotype

Direction: ABOLISHED

Interpretation: Complete behavioral deafness with vestibular dysfunction.

Show evidence (1 reference)

PMID:11226272 SUPPORT Model Organism

"Behavioral analysis revealed that the Kcnq1(-/-) mice are deaf and exhibit a shaker/waltzer phenotype."

Direct behavioral evidence of deafness in the knockout mouse.

Vestibular apparatus histopathology

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.

Show evidence (1 reference)

PMID:11226272 SUPPORT Model Organism

"These mice suffer from deafness and vestibular dysfunction because of profound morphological abnormalities of the inner ear."

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.

Show evidence (1 reference)

PMID:11226272 SUPPORT Model Organism

"Together, these data suggest that Kcnq1(-/-) mice are a potentially valuable animal model of JLNS."

Author summary establishing the model's informativeness for JLNS overall.

Show evidence (1 reference)

PMID:11226272 SUPPORT Model Organism

"Together, these data suggest that Kcnq1(-/-) mice are a potentially valuable animal model of JLNS."

Founding publication establishing this line as a mouse model of JLNS, recapitulating both the cardiac and cochlear consequences of biallelic Kcnq1 loss.

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

Pathograph links

Congenital Profound Bilateral Sensorineural Hearing Loss rescues fidelity: high 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

Auditory brainstem response threshold

Direction: RESTORED

Interpretation: Hearing preservation in treated ears ranged from 20 dB improvement to complete correction of the deafness phenotype.

Show evidence (1 reference)

PMID:26084842 SUPPORT Model Organism

"auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype"

Direct functional-hearing readout of gene-therapy rescue.

Show evidence (1 reference)

PMID:26084842 SUPPORT Model Organism

"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."

Demonstrates structural rescue of the cochlear degeneration phenotype by Kcnq1 gene replacement, supporting the therapeutic relevance of this node for future gene-therapy approaches.

Show evidence (1 reference)

PMID:26084842 SUPPORT Model Organism

"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."

Establishes this treated Kcnq1-/- line as informative for evaluating gene-replacement rescue of the stria-vascularis-dependent hearing-loss mechanism in JLNS.

{ }

Source YAML

click to show

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
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
    notes: >-
      Primary clinical home: the life-limiting manifestation is a cardiac
      ion-channel arrhythmia syndrome managed by cardiology.
    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: >-
        J-LN syndrome is a most severe variant of LQTS, with a very early
        onset and major QTc prolongation
      explanation: >-
        The 186-patient cohort frames JLNS as a variant of the long-QT
        syndromes, which Harrison's covers in the cardiovascular Part.
  - classification_value: DISORDER_OF_EAR
    notes: >-
      Congenital profound bilateral sensorineural hearing loss is a defining
      feature, not a complication, and is what distinguishes JLNS from the
      allelic dominant Romano-Ward/LQT1 phenotype.
    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 gives sensorineural hearing loss equal definitional
        weight with the cardiac phenotype, supporting a second Part
        assignment rather than a cardiovascular-only placement.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Mendelian autosomal recessive disorder diagnosed by biallelic
      pathogenic variants in a single gene.
    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: >-
        Diagnosis rests on a biallelic single-gene genotype, which is the
        Mendelian-genetics axis Harrison's covers separately.
  channelopathy_category:
    classification_value: cardiac channelopathy
    notes: >-
      The slot is single-valued and records the organ system by which
      the channelopathy is classified clinically. JLNS1 is not confined
      to the heart: the same KCNQ1-KCNE1 channel also carries the strial
      K+-secretion current of the inner ear and the luminal K+-recycling
      current of the gastric parietal cell, both curated as
      pathophysiology nodes here, and both are epithelial transport
      defects. ChannelopathyOrganSystemEnum does offer `epithelial
      channelopathy` for exactly that, so the choice here is a real one
      rather than an absence of alternatives: cardiac was taken because
      the slot is single-valued, because the arrhythmia is what defines
      the syndrome clinically and drives its management and mortality,
      and because JLNS is universally classified with the long QT
      syndromes. No value covers a combined epithelial-and-cardiac
      channelopathy, so this assignment records the clinical
      classification rather than the full extent of the channel defect.
    evidence:
    - reference: PMID:33498651
      reference_title: "Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Congenital long QT syndrome (LQTS) is an inherited channelopathy
        characterized by a prolonged QT-interval and arrhythmias caused by
        delayed repolarization
      explanation: >-
        Classifies congenital LQTS, of which JLNS is the recessive
        cardioauditory form, as an inherited cardiac channelopathy.
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.
  A second deep-research pass (openscientist, 2026-09-06) was run for the
  augmentation round. Two concurrent invocations of that run raced, and the
  later one (start_time 14:45:40Z) overwrote the earlier one at the same
  path; only the later report is committed, and its validation sections were
  regenerated against its own body. Three of the references curated in this
  round (PMID:25453094, PMID:35331422, PMID:26205899) were surfaced by the
  earlier, overwritten run and do not appear in the committed report;
  PMID:22805636 appears in both. Each of the four was independently fetched
  from PubMed, cached, and snippet-verified here, so the evidence stands on
  its own record rather than on the report, but the committed report is not
  a complete provenance trail for this round.

  The committed report's preflight returns the same WARN as the falcon one
  and for the same reason (KCNE1 discussed alongside KCNQ1); its OMIM
  citation matches MONDO:0024540's 220400. Its reference validation resolves
  25 of 25 citations with 20 of 20 quoted claims found in source and none
  judged off topic, though only 16 of the 25 were affirmatively scored on
  topic, so that is not a clean bill of health for the other nine. Its term
  validation is the part to distrust. The report's own table counts seven
  CURIEs named as a different term, but one of those seven is
  MONDO:0024540, where the mismatch is an artifact of the report echoing the
  template placeholder "if available" as the label; that CURIE is correct and
  is this entry's own disease_term. The other six name genuinely different
  concepts and none was used here: UBERON:0002215 was offered for stria
  vascularis (it is synchondrosis), UBERON:0002228 for spiral ganglion (it
  is rib), CL:0000710 for marginal cell of stria vascularis (it is
  neurecto-epithelial cell), UBERON:0007499 for endolymph (it is epithelial
  sac), HP:0011473 for achlorhydria (it is Villous atrophy; this entry uses
  HP:0032448), and HP:0003637 for hypergastrinemia (this entry uses
  HP:0500167). The overwritten run separately offered NCIT:C2438 for
  beta-blockers (RAS Peptide Cancer Vaccine) and NCIT:C50072 for an
  implantable cardioverter-defibrillator (Modem Device). Every ontology
  binding in this entry was resolved independently and passes
  `just validate-terms`.

  No datasets: block is curated because no relevant dataset exists. GEO was
  searched by disease name (the string "Jervell" returns nothing in gds) and
  through `just discover-datasets`, which surfaced only GENE_ONLY KCNQ1 hits
  about unrelated biology: GSE168245 (KCNQ1 in human beta-cell development),
  GSE161051 (Kcnq1 imprinting cluster in hybrid mouse placenta), and
  GSE121578 (a heterozygous LQTS/Beckwith-Wiedemann imprinting case, n=2).
  All three resolve and none is about JLNS, which is the Named Entity
  Confusion pattern reached through gene-based dataset search; none was
  curated.

  This round fetched twenty-nine reference caches and cites ten of them. The
  rest were fetched because the deep-research report's own reference
  validation resolves every citation it makes, so the whole set lands in the
  cache whether or not the curation uses it. They are kept rather than pruned,
  because pruning against a cited-PMID list is how a cache the entry does cite
  gets deleted. Note the exact added-versus-main count drifts as other PRs
  land the same papers independently, so treat the groupings below rather
  than any arithmetic as the record. Why each unused one was not cited, by
  group. Cochlear-implant series (PMID:18805595, PMID:31846911,
  PMID:39210075) and deafness-screening yields (PMID:29889784, PMID:34308870,
  PMID:41563185) duplicate what PMID:26205899 already supports here; one
  series was preferred over five overlapping ones rather than stacking
  citations on the same claim. Potassium-cycling reviews (PMID:12031509,
  PMID:12097719, PMID:11223304, PMID:32581825, PMID:35138621) are background
  physiology already carried by PMID:20012478 and PMID:19491250, and
  PMID:11223304 is additionally a Kcne1 study, which is JLNS2 territory.
  PMID:17646758 is the non-English record of the same cohort as
  PMID:16461811, which is cited instead. Single-family case reports
  (PMID:23668803, PMID:29372044) add genotypes without adding a mechanism the
  entry does not already state. The remaining iPSC and electrophysiology
  papers are about other long-QT subtypes rather than JLNS: PMID:20660394 and
  PMID:31245483 are heterozygous LQT1, and PMID:40794559 is LQT2.
  PMID:40794559 is nonetheless a live lead for a future round, and the reason
  is not its subtype: it reports deleterious negative inotropic effects of an
  I_Ks activator, which bears on whether channel activators could help a
  biallelic-null JLNS patient at all. PMID:24268954 and PMID:42466893 are
  LQTS-wide denervation and registry series whose JLNS-relevant content is
  already covered by PMID:35331422.

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.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16461811
      reference_title: "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the long-QT syndrome (LQTS) variant associated with deafness and
        caused by homozygous or compound heterozygous mutations on the KCNQ1
        or on the KCNE1 genes encoding the I(Ks) current
      explanation: >-
        Places the biallelic KCNQ1 genotype and the I_Ks current on the same
        causal path in the 186-patient JLNS cohort: the syndrome is
        attributed to biallelic mutation of the genes that encode I_Ks,
        which is the step this edge asserts.
    - reference: PMID:41147441
      reference_title: "Molecular mechanisms of function deficiencies in KCNQ1 variants associated with Jervell and Lange-Nielsen syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Although many variants exhibited normal cell surface expression
        consistent with protein stability, structural simulation analysis
        revealed that these KCNQ1 variants disrupt either KCNQ1-KCNE1 or
        KCNQ1-calmodulin (CaM) interaction, leading to channel dysfunction.
      explanation: >-
        Accounts for the subset of JLNS variants that reach the membrane
        normally: simulation predicts they still fail because the
        KCNQ1-KCNE1 or KCNQ1-calmodulin interaction is disrupted, and that
        assembly is what carries I_Ks. Graded COMPUTATIONAL because the
        quoted result is a structural simulation, and INDIRECT because it
        predicts channel dysfunction rather than measuring the current. The
        paper's wet-lab finding, that impaired plasma-membrane localization
        is the commonest mechanism across all eighteen variants, is cited on
        the trigger node itself.
  - 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.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11226272
      reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      directness: INDIRECT
      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: >-
        States the causal direction explicitly: deleting Kcnq1 collapses
        endolymph volume, which is the failure of endolymphatic secretion
        this edge asserts.
    - 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
      directness: INDIRECT
      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: >-
        Identifies the specific channel and cell membrane through which
        KCNQ1 loss removes the strial contribution to the endocochlear
        potential.
  - 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.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19491250
      reference_title: "KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion."
      supports: SUPPORT
      directness: INDIRECT
      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: >-
        Establishes that KCNQ1 is the non-redundant luminal K+ source for
        the parietal-cell proton pump, so its loss necessarily impairs
        luminal K+ recycling.

- 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.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11226272
      reference_title: "Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      directness: INDIRECT
      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. These changes are
        indicative of cardiac repolarization defects that appear to be
        induced by extracardiac signals.
      explanation: >-
        Deleting Kcnq1 lengthens the QT and JT intervals in vivo, but the
        authors are explicit that the effect disappeared in isolated hearts
        and attribute it to extracardiac signals. So this supports the edge
        only by inference: it shows that losing the channel prolongs
        repolarization in a whole animal, not that the prolongation is a
        cell-autonomous consequence of cardiomyocyte I_Ks loss. The same
        caveat is recorded on this model under animal_models, where the link
        is graded PARTIALLY_RECAPITULATES; the human evidence for the
        cell-autonomous step is the hiPSC-cardiomyocyte model under
        experimental_models.
    - reference: PMID:33498651
      reference_title: "Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: >-
        Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1)
        syndrome, characterized by a delayed cardiac repolarization and a
        prolonged QT interval in the surface electrocardiogram.
      explanation: >-
        Names delayed repolarization as the mechanism linking reduced KCNQ1
        channel function to the prolonged surface QT interval.

- 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.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301579
      reference_title: "Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      directness: DIRECT
      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
      explanation: >-
        GeneReviews states the QTc-prolongation-to-tachyarrhythmia step for
        JLNS specifically, which is the edge asserted here rather than
        either node alone.

- 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.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301579
      reference_title: "Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: >-
        ventricular fibrillation, which may culminate in syncope or sudden
        death
      explanation: >-
        States the terminal step of the cardiac chain: the tachyarrhythmia
        is what produces syncope and sudden death in JLNS.
    - reference: PMID:33498651
      reference_title: "Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: >-
        The cardiac events are due to runs of torsades de pointes
        ventricular tachycardias, eventually leading to syncope or even to
        cardiac arrest and sudden cardiac death.
      explanation: >-
        Attributes syncope, cardiac arrest, and sudden cardiac death to
        torsades de pointes runs, matching this edge's source and target.

- 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.
    causal_link_type: DIRECT
    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
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        contraction of the endolymphatic compartments, and collapse and
        adhesion of surrounding membranes. There was a complete degeneration
        of the organ of Corti
      explanation: >-
        Reports endolymphatic collapse and organ of Corti degeneration in
        the same Kcnq1-null cochleae, which is the
        strial-secretion-to-hair-cell-loss step.
    - 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
      directness: INDIRECT
      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: >-
        Rescue arm of the same edge: virally restoring Kcnq1 in the
        neonatal scala media prevents the hair-cell degeneration, so the
        degeneration is downstream of the strial defect rather than a
        parallel lesion. The construct reached most cochlear marginal
        cells, where native Kcnq1 is expressed, but the paper also
        reports extensive ectopic expression, so the rescue is not
        strictly marginal-cell-specific.

- 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.
    causal_link_type: DIRECT
    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
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        There was a complete degeneration of the organ of Corti and an
        associated degeneration of the spiral ganglion.
      explanation: >-
        Reports the two degenerations together in Kcnq1-null cochleae. The
        abstract says "associated" and no more: in a global knockout both
        structures are exposed to the same endolymphatic collapse, so
        co-occurrence is equally consistent with ganglion loss being
        secondary to hair-cell loss and with it being parallel to it. The
        edge is drawn on the conventional deafferentation account, which
        this quote is consistent with rather than establishing.

- 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.
    causal_link_type: DIRECT
    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
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        provide further evidence that KCNQ1 channel dysfunction can lead to
        congenital deafness in this syndrome
      explanation: >-
        Supports the endpoints of the whole cochlear arm rather than this
        link specifically: the sentence asserts that KCNQ1 dysfunction
        causes the deafness, and the same paper's histology is what places
        spiral ganglion degeneration on the path between them. It does not
        establish that ganglion loss is the proximate cause of the hearing
        loss, so it is graded INDIRECT here.
    - 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
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        auditory brainstem responses showed significant hearing preservation
        in the injected ears
      explanation: >-
        Preventing the cochlear degeneration preserves hearing thresholds,
        supporting this edge in the rescue direction.

- 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.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19491250
      reference_title: "KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Microvillar secretory membranes were intact, but basal acid
        secretion was absent and forskolin-stimulated acid output reduced by
        approximately 90% in KCNQ1(-/-) gastric mucosa.
      explanation: >-
        Loss of the KCNQ1 luminal recycling current abolishes basal acid
        secretion with parietal-cell structure intact, which is the
        K+-recycling-to-achlorhydria step.
    - reference: PMID:22805636
      reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We propose that the Jervell and Lange-Nielsen Syndrome phenotypically
        includes gastrointestinal symptoms/signs and secondary iron-deficiency
        anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations.
      explanation: >-
        States this edge in humans and in the correct direction: the iron
        deficiency is secondary to hypochlorhydria, which is itself
        consequent on the KCNQ1 defect. The mouse acid-secretion study gives
        the mechanism; this gives the same causal claim in JLNS patients.
    - reference: PMID:20301579
      reference_title: "Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Iron-deficient anemia and elevated levels of gastrin are also
        frequent features of JLNS.
      explanation: >-
        Confirms in patients that the gastric consequences predicted by the
        mouse acid-secretion defect (hypergastrinemia, iron-deficiency
        anemia) are actually seen in JLNS.

- 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.
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A history of iron-deficiency anaemia in 12 of 14 patients and
      subjective gastrointestinal symptoms in 13 of 14 patients was revealed.
    explanation: >-
      The dedicated extracardiac study of the complete Swedish
      double-KCNQ1-mutation cohort, which is the primary source behind the
      GeneReviews summary and quantifies the gastric phenotype rather than
      only naming it as frequent.
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of gastrin in seven of nine cases, pepsinogen in six of
      seven cases, and faecal calprotectin in nine of nine cases were present.
    explanation: >-
      Measured biochemistry behind the hypergastrinemia half of this node.
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous endoscopy in five cases had revealed no case of coeliac or
      inflammatory bowel disease but three cases of mucosal
      hyperplasia/dysplasia.
    explanation: >-
      Structural gastric change accompanying the secretory defect, and the
      finding the paper's own title leads with. Three of five endoscoped
      patients had mucosal hyperplasia or dysplasia, with the common
      alternative explanations (coeliac disease, inflammatory bowel disease)
      excluded in all five.
  notes: >-
    The same cohort reports a significant correlation between elevated
    gastrin and concurrent iron deficiency or anaemia (p = 0.039), which is
    what ties the two halves of this node into one gastric mechanism rather
    than two coincident findings. Its authors also flag the sustained
    hypergastrinaemia as a potential risk factor for later gastrointestinal
    malignancy and recommend monitoring for anaemia and hypergastrinaemia in
    JLNS; no such malignancy has been reported in a JLNS patient, so that is
    curated here as the cohort's recommendation and not as a phenotype of
    the disease.

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
  frequency: OBLIGATE
  notes: >-
    Definitional: GeneReviews requires congenital sensorineural deafness
    for the diagnosis of JLNS, so within this entry the phenotype is
    obligate by construction. Biallelic KCNQ1 genotypes with enough
    residual channel function to spare hearing are classified as recessive
    LQT1, not JLNS.
  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
  frequency: OBLIGATE
  notes: >-
    Definitional: GeneReviews requires a long QT interval, alongside
    congenital sensorineural deafness and biallelic KCNQ1 or KCNE1
    variants, to establish the diagnosis, so the phenotype is obligate
    within this entry by construction. The 186-patient cohort mean QTc
    of 557 +/- 65 ms describes how severe the prolongation is, not how
    penetrant it is, and is not the basis for the band; GeneReviews
    itself writes "usually >500 msec".
  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
  frequency: FREQUENT
  notes: >-
    GeneReviews reports that more than half of untreated children with
    JLNS die before age 15, mapping to the 30-79% FREQUENT band. The
    figure describes the untreated natural history; on beta-blockade the
    Schwartz cohort still recorded cardiac arrest or sudden death in 27%.
  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.
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A history of iron-deficiency anaemia in 12 of 14 patients and
      subjective gastrointestinal symptoms in 13 of 14 patients was revealed.
    explanation: >-
      Quantifies the frequency in the complete Swedish double-KCNQ1-mutation
      cohort, the only series to have systematically looked for it.
  notes: >-
    Twelve of fourteen (86%) would fall in the VERY_FREQUENT band, but the
    figure comes from a single 14-patient Swedish series that is the only
    cohort ever screened for this phenotype, so the band is left at FREQUENT
    to match the GeneReviews wording rather than raised on one small series.

- 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.
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of gastrin in seven of nine cases, pepsinogen in six of
      seven cases, and faecal calprotectin in nine of nine cases were present.
    explanation: >-
      Measured serum gastrin in the Swedish JLNS cohort; seven of nine tested
      patients were elevated, which sits in the FREQUENT band recorded here.

- 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, which corroborates the mouse finding by inference; it does
      not directly measure gastric acid secretion in JLNS patients.
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that the Jervell and Lange-Nielsen Syndrome phenotypically
      includes gastrointestinal symptoms/signs and secondary iron-deficiency
      anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations.
    explanation: >-
      The Swedish cohort attributes the observed gastric phenotype to
      hypochlorhydria in JLNS patients. Indirect because acid output was
      inferred from gastrin and pepsinogen rather than measured: no human
      JLNS gastric-acid study exists, so the direct measurement remains the
      Kcnq1-null mouse.

biochemical:
- name: Serum Gastrin
  presence: Elevated
  context: >-
    Elevated in seven of nine tested patients in the complete Swedish
    double-KCNQ1-mutation cohort. Compensatory hypergastrinemia follows loss
    of acid-mediated negative feedback on antral G cells when parietal-cell
    acid secretion fails, so this is the biochemical readout of the gastric
    arm of the pathophysiology rather than an independent finding. Frequency
    is carried on the Hypergastrinemia phenotype.
  biomarker_term:
    preferred_term: Gastrin Measurement
    term:
      id: NCIT:C74858
      label: Gastrin Measurement
  evidence:
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of gastrin in seven of nine cases, pepsinogen in six of
      seven cases, and faecal calprotectin in nine of nine cases were present.
    explanation: >-
      Measured serum gastrin in the Swedish JLNS cohort.
  notes: >-
    The same cohort found a significant correlation between elevated gastrin
    and concurrent iron deficiency or anaemia (p = 0.039), and its authors
    raise sustained hypergastrinaemia as a potential risk factor for later
    gastrointestinal malignancy. No such malignancy has been reported in a
    JLNS patient.
- name: Serum Pepsinogen
  presence: Elevated
  context: >-
    Elevated in six of seven tested patients in the same cohort. Pepsinogen
    is secreted by gastric chief cells and rises with the trophic drive of
    hypergastrinemia, so it corroborates the secretory disturbance
    independently of the gastrin assay itself.
  biomarker_term:
    preferred_term: Pepsinogen Measurement
    term:
      id: NCIT:C100122
      label: Pepsinogen Measurement
  evidence:
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pepsinogen in six of seven cases
    explanation: >-
      Measured pepsinogen elevation in the Swedish JLNS cohort.
- name: Faecal Calprotectin
  presence: Elevated
  context: >-
    Elevated in nine of nine tested patients, the only analyte in the cohort
    abnormal in every patient measured. Calprotectin is a neutrophil-derived
    marker of intestinal inflammation and is not explained by the
    parietal-cell mechanism curated here, so it records an unexplained
    gastrointestinal finding rather than a predicted one. The denominator is
    nine patients from a single national series.
  biomarker_term:
    preferred_term: Calprotectin Measurement
    term:
      id: NCIT:C82005
      label: Calprotectin Measurement
  evidence:
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      faecal calprotectin in nine of nine cases were present
    explanation: >-
      Measured faecal calprotectin elevation in every tested patient in the
      Swedish JLNS cohort.
  notes: >-
    Coeliac disease and inflammatory bowel disease were excluded by endoscopy
    in the five patients scoped, so the raised calprotectin is not accounted
    for by either. The cohort reports it without a mechanism, and none is
    asserted here.

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.
  - reference: PMID:24552659
    reference_title: "Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical phenotype ranged from expectedly severe in JLNS to
      surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms,
      cumulative incidence of (aborted) cardiac arrest 47% vs. 1%
    explanation: >-
      The gene-dosage contrast within a single founder allele: the same
      KCNQ1 variant gives markedly longer QTc and a 47-fold higher cardiac
      arrest incidence when biallelic than when heterozygous.
  - reference: PMID:38825991
    reference_title: Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of
      heterozygous KCNQ1 variant carriers and had a lower risk of cardiac
      events than heterozygous non-JLNS variant carriers (HTZ-Non-JLNS)
      [hazard ratio (HR) = 0.34 (0.22-0.54); P < 0.01]
    explanation: >-
      The counterintuitive half of the dosage relationship, from a
      789-carrier series: alleles severe enough to cause JLNS when biallelic
      are milder than other LQT1 alleles when heterozygous, which is what
      recessiveness predicts and is the basis for counselling a proband's
      carrier parents.
  notes: >-
    Gene dosage, not merely gene identity, sets the phenotype. Biallelic
    KCNQ1 loss causes JLNS; a single copy of the same allele causes
    Romano-Ward LQT1 or nothing at all, and the gap between the two states is
    large and quantified. In the Swedish p.R518X founder families the
    contrast within one allele is QTc 576 +/- 61 ms in JLNS homozygotes
    against 462 +/- 34 ms in heterozygotes, with cumulative (aborted) cardiac
    arrest of 47% against 1%. The less obvious half of the dosage story is
    that heterozygous carriers of JLNS-causing alleles are milder than
    typical LQT1 heterozygotes, not more severe: in a 789-carrier series they
    had a lower risk of cardiac events than carriers of non-JLNS KCNQ1
    variants (hazard ratio 0.34). That is what recessiveness means at the
    channel level, and it is why a JLNS proband's heterozygous parents are
    often asymptomatic, as this entry's inheritance section records.

    One consequence for reading the rest of this entry: the Swedish cohort in
    which the extracardiac gastric phenotype was characterized
    (PMID:22805636, cited on the gastric pathophysiology node and in the
    biochemical section) is drawn from the same national JLNS population as
    the p.Arg518Ter founder families below. Neither paper states the overlap,
    so it is not asserted here, but it is a reason to read the gastric
    findings as characterized in a largely single-allele population rather
    than across the JLNS allelic spectrum.
  variants:
  - name: KCNQ1 p.Arg518Ter
    description: >-
      c.1552C>T, p.Arg518*, a protein-truncating KCNQ1 allele and a worldwide
      cause of both recessive JLNS and dominant LQT1. In Sweden it is a
      founder mutation accounting for the majority of JLNS cases and the
      second most common cause of LQTS, with a shared haplotype across 17 of
      19 index families, an estimated mutation age of 28 generations, and
      geographical clustering in the Pite River valley. Estimated
      heterozygote prevalence there is roughly 1 in 2,000 to 4,000, which
      makes it the best-characterized single JLNS allele anywhere and the
      reason Swedish series recur throughout the JLNS literature.
    gene:
      preferred_term: KCNQ1
      term:
        id: hgnc:6294
        label: KCNQ1
    type: nonsense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:24552659
      reference_title: "Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The R518X/KCNQ1 mutation is a common cause of autosomal recessive
        (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant
        long QT syndrome (LQTS) worldwide.
      explanation: >-
        Establishes this single allele as a cause of both the recessive and
        the dominant disease depending on dosage.
    - reference: PMID:24552659
      reference_title: "Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A high prevalence of Swedish p.R518X heterozygotes was suggested
        (~1:2000-4000).
      explanation: >-
        The founder-allele carrier frequency in the Swedish population.
- name: NOS1AP
  gene_term:
    preferred_term: NOS1AP
    term:
      id: hgnc:16859
      label: NOS1AP
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  notes: >-
    Recorded as the one arrhythmia-severity modifier with a worked mechanism,
    and hedged accordingly. The evidence is from LQT1, not JLNS: the hiPSC
    cardiomyocytes compared symptomatic and asymptomatic carriers of the
    heterozygous KCNQ1 A341V variant, and the complementary work used a
    guinea-pig cardiomyocyte model in which LQT1 was mimicked
    pharmacologically. Nobody has shown a NOS1AP effect in JLNS patients. It
    is curated here because the proposed mechanism is convergence on
    prolonged action-potential duration, which JLNS has in the extreme, so
    the modifier is mechanistically plausible for this disease rather than
    demonstrated in it. Treat it as a lead for the variable arrhythmic
    expressivity JLNS shows at fixed genotype, not as an established
    genotype-phenotype determinant.
  evidence:
  - reference: PMID:32061134
    reference_title: NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      This establishes a mechanistic link between NOS1AP SNPs and aggravation
      of the arrhythmia phenotype in prolonged repolarization syndromes.
    explanation: >-
      Supports NOS1AP as a modifier of arrhythmic severity in prolonged
      repolarization generally. Indirect for JLNS: the human cells carried a
      heterozygous LQT1 KCNQ1 variant, not a biallelic JLNS genotype, so
      applying it here relies on JLNS sharing the prolonged-repolarization
      substrate the mechanism converges on.
  - reference: PMID:32061134
    reference_title: NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The minor NOS1AP alleles are associated with NOS1 loss of function.
    explanation: >-
      The molecular step behind the modifier effect, measured in the same
      cell models.

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.
- population: Children with congenital bilateral profound hearing loss referred for cochlear implantation (single tertiary center, n=503)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 790.0
  notes: >-
    This is prevalence within an enriched clinical population, not in
    the general population, and the two figures are not comparable:
    screening congenitally deaf children for a long QT interval
    concentrates JLNS by roughly three orders of magnitude relative to
    the worldwide estimate above. That is the entire argument for ECG
    screening of congenitally deaf children, and it is why this record
    is curated separately rather than folded into the worldwide one. The
    rate is this single center's own yield, four cases among 503
    children, and no confidence interval is reported for it, so rate_low
    and rate_high are deliberately left unset. The authors place it
    within a published cross-series range of 0 to 2.6%; that range
    describes the spread between centers, not bounds on this estimate,
    so it is recorded here rather than in the rate slots.
  evidence:
  - reference: PMID:26205899
    reference_title: "Jervell and Lange-Nielsen syndrome in cochlear implanted patients: our experience and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of disease was 0.79% (four cases) in our center which is
      in the range of literature reports (0-2.6%).
    explanation: >-
      Gives the yield of screening 503 congenitally deaf cochlear-implant
      candidates by ECG, with the published range across comparable series.

clinical_burden:
  burden_level: HIGH
  rationale: >-
    Two independently disabling burdens fall on the same child. The cardiac one
    is lethal: untreated, more than half die before age 15, and the largest
    series describes JLNS as a most severe variant of long QT syndrome, with
    events in 86% of patients and onset by age three in half of them. It is
    also only partly tractable - on beta-blockade, half the cohort still had
    events and 27% still had cardiac arrest or sudden death - so the burden
    persists under best available medical therapy rather than resolving with
    diagnosis. The auditory one is permanent and present from birth, and
    because the mammalian cochlea does not regenerate it is managed by
    prosthetic substitution rather than repair. The two also interact: cochlear
    implantation, the standard treatment for the deafness, is general
    anesthesia in a child with a markedly prolonged QT interval, and a
    published case records life-threatening arrhythmia triggered by anesthesia
    at the end of exactly that surgery.
  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: >-
      J-LN syndrome is a most severe variant of LQTS, with a very early onset
      and major QTc prolongation, and in which beta-blockers have limited
      efficacy.
    explanation: >-
      The cohort's own summary judgement on severity and on the limits of
      first-line therapy.
  - 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: >-
      Documents the interaction between the two burdens: treating the deafness
      required an anesthetic that precipitated a life-threatening arrhythmia.
progression:
- phase: Congenital onset with early-childhood cardiac events
  age_range: Birth to 3 years
  notes: >-
    The hearing loss is present from birth, but the cardiac phenotype declares
    itself later: half the reported patients were already symptomatic by age
    three. A deaf infant with no cardiac history is therefore not yet
    reassuring, and this window is why newborn hearing screening is treated
    here as a case-finding route into cardiac evaluation rather than only an
    audiological result.
  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: >-
      Data on the Jervell and Lange-Nielsen syndrome (J-LN), the long-QT syndrome (LQTS) variant
      associated with deafness and caused by homozygous or compound heterozygous mutations on the
      KCNQ1 or on the KCNE1 genes encoding the I(Ks) current, are still based largely on case
      reports. ... We analyzed data from 186 J-LN patients obtained from the literature (31%) and
      from individual physicians (69%). Most patients (86%) had cardiac events, and 50% were already
      symptomatic by age 3. ... Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1
      gene are associated with a more benign course.
    explanation: >-
      Retains the mixed KCNQ1/KCNE1 Jervell–Lange-Nielsen cohort. Half symptomatic by age three is a
      pooled estimate; KCNQ1 accounts for most cases and KCNE1 is associated with a more benign
      course.
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fifty percent of individuals with JLNS had cardiac events before age
      three years.
    explanation: >-
      Independent statement of the same early-childhood onset window in the
      GeneReviews chapter.
- phase: Adrenergically triggered episodes
  notes: >-
    Events are overwhelmingly provoked rather than spontaneous, which is what
    makes trigger avoidance and beta-blockade rational therapy and what places
    this syndrome with LQT1 rather than with the pause-dependent LQT3
    phenotype.
  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: >-
      Quantifies the adrenergic trigger dependence that characterizes the
      symptomatic phase.
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The classic presentation of JLNS is a deaf child who experiences
      syncopal episodes during periods of stress, exercise, or fright.
    explanation: >-
      Describes the same trigger-provoked presentation in clinical terms.
- phase: Untreated childhood mortality
  age_range: Before 15 years, untreated
  notes: >-
    This figure describes the natural history without therapy and is the
    baseline against which the treatment section should be read. It is not the
    contemporary outcome: on beta-blockade the 186-patient series still
    recorded events in 51% and cardiac arrest or sudden death in 27%, which is
    partial protection rather than none and is why implantable defibrillators
    and left cardiac sympathetic denervation are curated as treatments here.
  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 giving the untreated mortality of
      the syndrome in childhood.
  - 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: >-
      Gives the treated residual risk, which is what makes the untreated
      figure a natural-history baseline rather than a current prognosis.
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
  notes: >-
    Risk within JLNS is not uniform, and two variables measurable early plus
    sex separate higher- from lower-risk patients: a QTc above 550 ms and
    syncope in the first year of life are independent predictors of
    subsequent cardiac arrest or sudden death, and females are at lower risk
    (hazard ratio 0.54, 95% CI 0.34 to 0.88). That stratification is what the
    186-patient cohort proposes as the basis for implanting a defibrillator
    early rather than after a first arrest, which is why it is recorded on
    this treatment rather than as a stage of the disease course.
  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.
  - 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: >-
      A QTc >550 ms and history of syncope during the first year of life are
      independent predictors of subsequent CA/SD.
    explanation: >-
      The two early predictors that identify which JLNS patients warrant a
      defibrillator rather than beta-blockade alone.
  - 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: >-
      Females are at lower risk for cardiac arrest and sudden death (CA/SD)
      (hazard ratio, 0.54; 95% CI, 0.34 to 0.88; P=0.01).
    explanation: >-
      The sex effect on arrhythmic risk, with its effect size and confidence
      interval, which enters the same stratification.
- 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.
    - reference: PMID:35331422
      reference_title: "Left Cardiac Sympathetic Denervation for Long QT Syndrome: 50 Years' Experience Provides Guidance for Management."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        with an overall 86% decrease in the mean yearly cardiac event rate (P
        < 0.0001)
      explanation: >-
        Quantifies the effect of the denervation on the arrhythmic event
        rate this edge claims it inhibits, in a 125-patient LQTS series
        with a mean 12.9-year follow-up. Indirect because the series is
        LQTS-wide and reports no JLNS subgroup, so the reduction is not
        measured in this disease.
  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.
  - reference: PMID:35331422
    reference_title: "Left Cardiac Sympathetic Denervation for Long QT Syndrome: 50 Years' Experience Provides Guidance for Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After LCSD, 17% in the very high risk group remained asymptomatic,
      compared with 52%, 47%, and 97% in the other 3 groups (P < 0.0001)
    explanation: >-
      The relevant caveat for JLNS. The inference step, and the reason
      this is graded INDIRECT, is that the cohort is LQTS-wide and
      reports no JLNS subgroup: placing JLNS patients in the
      very-high-risk stratum follows from that stratum's definition
      (symptomatic in the first year of life, or highly malignant
      genetics), which JLNS patients typically meet, rather than from
      the paper assigning them there. On that reading only 17% of the
      stratum became asymptomatic, so denervation substantially reduces
      events without removing residual risk. The same paper reports that
      LCSD results are not affected by common genotypes.
  notes: >-
    Among the 45 patients whose only pre-procedure events were syncope
    or ICD shocks, a 6-month post-procedure QTc below 500 ms predicted
    excellent outcome. That makes QTc shortening a usable response
    biomarker after denervation rather than only a diagnostic
    measurement, but it was established in that subgroup and not across
    the whole series. Note also that the cohort is LQTS overall, not
    JLNS specifically; the JLNS-relevant reading is the very-high-risk
    subgroup result rather than the headline 86% reduction.

- name: Atrial Pacing with Beta-Blockade
  description: >-
    Permanent atrial pacing added to beta-blocker therapy in young high-risk
    JLNS patients, as an alternative to defibrillator implantation in
    children too small for a transvenous ICD. In the Norwegian national
    series of nine genetically confirmed JLNS patients, six received atrial
    leads and all six survived without events over a mean 6.9 years, while
    the single patient given a ventricular lead died during follow-up. The
    lead position is therefore not incidental to the result.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: atrial pacemaker implantation
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: atrial-lead cardiac pacemaker
        term:
          id: NCIT:C94198
          label: Cardiac Pacemaker
  target_mechanisms:
  - target: Torsades de Pointes and Ventricular Fibrillation
    treatment_effect: INHIBITS
    description: >-
      Atrial pacing prevents the bradycardia and pauses that shorten
      diastolic intervals irregularly and provoke pause-dependent triggered
      activity on a markedly prolonged action potential, and it permits
      beta-blocker uptitration that bradycardia would otherwise limit.
    evidence:
    - reference: PMID:27451284
      reference_title: "The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The 6 patients with atrial leads survived without events at a mean
        follow-up of 6.9 years after pacemaker implantation.
      explanation: >-
        Event-free survival on atrial pacing plus beta-blockade in the
        JLNS-specific series. Indirect for the mechanism claim: the study
        reports clinical outcome, not the suppression of triggered activity
        the edge asserts, and with six patients and no control arm it cannot
        separate the pacing effect from the beta-blockade it accompanies.
  evidence:
  - reference: PMID:27451284
    reference_title: "The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients also received a pacemaker; 1 had a ventricular lead and
      6 had atrial leads. The patient with the ventricular lead died during
      follow-up.
    explanation: >-
      The whole device experience in the series, including the ventricular-lead
      death, which is what makes this an argument for atrial pacing
      specifically rather than for pacing in general.
  notes: >-
    Nine patients in one national cohort, uncontrolled, with the comparison
    between lead positions resting on a single ventricular-lead patient. The
    paper's own title ends in a question mark. Curated as a reported option
    in young children for whom ICD implantation is difficult, not as
    established therapy, and it does not displace the defibrillator and
    denervation entries above.
- name: KCNQ1 Suppression-and-Replacement Gene Therapy
  description: >-
    Investigational dual-component gene therapy that suppresses both
    endogenous KCNQ1 alleles with a short hairpin RNA while supplying an
    shRNA-immune wild-type KCNQ1 cDNA from the same construct. Because
    suppression is mutation-independent, one vector in principle covers any
    KCNQ1 genotype rather than requiring an allele-specific product, which is
    the property that makes it relevant to a disease defined by two different
    loss-of-function alleles per patient. In LQT1 patient iPSC-derived
    cardiomyocytes it shortened the prolonged action potential to isogenic
    control values.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Near-Complete Loss of Cardiac I_Ks Repolarizing Current
    treatment_effect: RESTORES
    description: >-
      Supplying wild-type KCNQ1 coding sequence restores the pore-forming
      subunit whose absence is this node, rather than compensating downstream
      of it.
    evidence:
    - reference: PMID:33504163
      reference_title: Suppression-Replacement KCNQ1 Gene Therapy for Type 1 Long QT Syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD,
        thereby eliminating the pathognomonic feature of LQT1.
      explanation: >-
        Demonstrates functional restoration of repolarization in human
        cardiomyocytes. Indirect for JLNS: every cell line tested carried a
        heterozygous LQT1 genotype, so restoration was shown against one
        residual wild-type allele and not against the biallelic null state
        this node describes.
  evidence:
  - reference: PMID:33504163
    reference_title: Suppression-Replacement KCNQ1 Gene Therapy for Type 1 Long QT Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      KCNQ1-SupRep achieved mutation-independent suppression of wild-type
      KCNQ1 and 3 LQT1-causative variants
    explanation: >-
      Mutation independence is the property that would let one construct
      serve JLNS patients regardless of which two KCNQ1 alleles they carry.
      Indirect because the demonstration is in LQT1 constructs and cells.
  notes: >-
    Not a therapy. This is a cell-culture proof of principle in heterozygous
    LQT1 with no in vivo data and no JLNS genotype tested, curated so that the
    cardiac arm has the counterpart to the AAV1-Kcnq1 cochlear rescue already
    recorded under animal_models, and so the gap is visible rather than
    absent. Two things would have to be shown before it means anything for
    JLNS: efficacy against a biallelic null background, where there is no
    residual wild-type channel to build on, and delivery to ventricular
    myocardium in vivo.
- 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.
  - reference: PMID:26205899
    reference_title: "Jervell and Lange-Nielsen syndrome in cochlear implanted patients: our experience and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Considering all precautions their cochlear implant surgeries were done
      uneventfully.
    explanation: >-
      Counterweight to the single adverse case above: with the precautions in
      place, implantation was uneventful in this center's four JLNS patients.
      The peri-anesthetic risk is real and manageable, not prohibitive.
  - reference: PMID:26205899
    reference_title: "Jervell and Lange-Nielsen syndrome in cochlear implanted patients: our experience and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine available reports about the outcome of cochlear implantation in
      these patients indicated good auditory outcome.
    explanation: >-
      Auditory benefit across the nine published reports that recorded
      an outcome, rather than a single case. Those nine are a subset of
      the sixteen reports covering 38 implanted JLNS children; outcome
      was not reported for all 38.

- 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.
  - reference: PMID:26205899
    reference_title: "Jervell and Lange-Nielsen syndrome in cochlear implanted patients: our experience and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As auditory stimuli is reported to be a specific trigger, it is prudent
      to activate the processor with continuous heart monitoring
    explanation: >-
      Names a trigger specific to this disease and to its own treatment:
      sound itself. Switching on a cochlear implant processor is therefore an
      arrhythmia risk in its own right, separate from the anesthetic risk of
      the implantation surgery, and is recommended to be done under cardiac
      monitoring.

- 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
  measurements:
  - preferred_term: QTc
    term:
      id: LOINC:8636-3
      label: Q-T interval corrected
  reference_ranges:
  - loinc_term:
      id: LOINC:8636-3
      label: Q-T interval corrected
    unit: ms
    population: >-
      Jervell and Lange-Nielsen syndrome cohorts: 186 patients from the
      literature and individual physicians (Schwartz et al. 2006) and 44
      patients prospectively followed in the U.S. portion of the International
      LQTS Registry (Goldenberg et al. 2006)
    notes: >-
      A risk-stratification cut-off within JLNS, not a diagnostic threshold:
      both cohorts stratify cardiac risk at a QTc of 550 ms (Schwartz et al. as
      an independent predictor of cardiac arrest or sudden death, Goldenberg et
      al. as the stratum in which the excess risk of JLNS over Romano-Ward
      syndrome was largest), and neither proposes it as a criterion for making
      the diagnosis. The two abstracts
      write the boundary differently. Schwartz et al. write "A QTc >550 ms"
      (exclusive), Goldenberg et al. "a baseline QTc > or = 550 msec"
      (inclusive); the half-open band puts 550 ms itself in the higher-risk
      tier, which agrees with Goldenberg et al. and disagrees by one point with
      Schwartz et al. No diagnostic QTc cut-off specific to JLNS is recorded:
      GeneReviews (PMID:20301579) characterises the QTc as "usually >500 msec",
      a description of where affected patients fall rather than a threshold,
      and the general LQTS guideline cut-off belongs to the Long QT Syndrome
      entry. LOINC:8636-3 names no correction formula, and neither cohort
      abstract names one.
    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: >-
        A QTc >550 ms and history of syncope during the first year of life are
        independent predictors of subsequent CA/SD.
      explanation: >-
        States the 550 ms QTc boundary as an independent predictor of cardiac
        arrest or sudden death in the 186-patient JLNS cohort.
    - reference: PMID:16911578
      reference_title: "Clinical course and risk stratification of patients affected with the Jervell and Lange-Nielsen syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The JLNS:RWS and JLNS:LQT1 adjusted hazard ratios (HR) for cardiac events
        were highest among patients with a baseline QTc > or = 550 msec
      explanation: >-
        A second, prospectively followed JLNS cohort stratifies at the same
        550 ms boundary: the excess risk of cardiac events in JLNS, relative to
        Romano-Ward syndrome and LQT1, was largest in patients with a baseline
        QTc at or above it.
    interpretation_bands:
    - name: QTc at or above 550 ms
      lower_bound: 550
      unit: ms
      abnormal_flag: HIGH
      interpretation: >-
        Higher risk of cardiac arrest or sudden death within JLNS; with syncope
        in the first year of life, one of the two independent predictors of
        subsequent cardiac arrest or sudden death.
  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.
  - reference: PMID:26205899
    reference_title: "Jervell and Lange-Nielsen syndrome in cochlear implanted patients: our experience and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is recommended that all congenitally deaf patients have an ECG taken
      as a part of the evaluation.
    explanation: >-
      Extends screening beyond at-risk relatives of a known case to every
      congenitally deaf child, which is what the 0.79% yield among 503
      implant candidates recorded under prevalence actually argues for.

- name: Pure-Tone Audiometry
  description: >-
    Audiometric assessment documents the congenital bilateral sensorineural
    hearing loss that is the second defining feature of JLNS, and is part of
    the work-up of the deaf children in whom JLNS is sought by ECG screening.
  diagnosis_term:
    preferred_term: audiometric test
    term:
      id: NCIT:C38036
      label: Audiometric Test
  measurements:
  - preferred_term: pure-tone audiometry
    term:
      id: LOINC:89015-2
      label: Pure tone threshold audiometry panel
  notes: >-
    The panel code identifies the test; no reference range is recorded. The
    cited sources describe the deafness in JLNS as profound but state no
    audiometric cut-off owned by the disease, and a generic hearing-loss
    grading (such as the WHO grades) is not JLNS content. The grades are also
    defined on a pure-tone average, for which searches of the Monarch KG
    ("pure tone average", "PTA", "hearing level average", "average hearing")
    returned no LOINC code; the per-frequency codes are ear- and
    frequency-specific (for example LOINC:89017-8 Hearing threshold Ear - right
    --1000 Hz), so none of them carries a grade defined on the average.
  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: >-
      Names profound congenital bilateral sensorineural hearing loss as a
      defining feature, the finding audiometry documents.
  - reference: PMID:22830134
    reference_title: "Prevalence of long QT syndrome and other cardiac defects in deaf-mute children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Audiometry was performed on all the children and the result interpreted
      according to WHO recommendations.
    explanation: >-
      In a screening study of congenitally deaf-mute children for long QT
      syndrome, which concludes on the prevalence of JLNS in that population,
      audiometry was part of the assessment of every child.

- 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.

discussions:
- discussion_id: jlns1_murine_qt_extracardiac
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Is the QT prolongation of the Kcnq1-null mouse a valid model of the human
    JLNS cardiac phenotype, given that it appears in vivo but not in isolated
    hearts and its authors attribute it to extracardiac signals?
  attaches_to:
  - pathophysiology#Near-Complete Loss of Cardiac I_Ks Repolarizing Current
  - pathophysiology#Markedly Prolonged QTc and Arrhythmogenic Substrate
  - animal_models#Mouse
  rationale: >-
    The human mechanism curated here is cell-autonomous: biallelic KCNQ1 loss
    removes I_Ks from the ventricular cardiomyocyte, the action potential
    fails to repolarize on time, and the QT interval lengthens. The mouse
    that carries the same genotype does prolong its QT and JT intervals, but
    only in the intact animal. The effect disappeared in isolated hearts, and
    the authors concluded the repolarization defect is induced by
    extracardiac signals rather than being intrinsic to the myocardium. That
    is a different mechanism reaching a similar readout.

    Two things make this more than a technical caveat. Murine ventricular
    repolarization does not depend on I_Ks the way human repolarization does,
    so the mouse is a poor cardiac model of this disease on prior grounds,
    and the finding is what that prior would predict. And the mouse is the
    entry's main in vivo system: it carries the cochlear arm, where it
    recapitulates the human lesion well. So the same animal is strong
    evidence for one arm of the disease and weak evidence for the other, and
    nothing in the entry's structure signals that asymmetry except the
    fidelity grading on each link.

    The human cell evidence does not close the gap. The hiPSC-cardiomyocyte
    panel shows I_Ks loss and action-potential prolongation in dissociated
    cells, which is the cell-autonomous claim, but those cells cannot report
    a QT interval and are electrophysiologically immature. So the
    cell-autonomous step is shown at cellular scale in human cells, and the
    organ-scale phenotype is shown in an animal where it appears not to be
    cell-autonomous. No system currently shows both.
  proposed_experiments:
  - experiment_id: jlns1_exp_isolated_heart_ap
    name: Optical mapping of repolarization in isolated hearts across species
    description: >-
      Map action-potential duration and its transmural dispersion in
      Langendorff-perfused hearts from Kcnq1-null mice and from a large-animal
      or human-relevant preparation with the same genotype, under matched
      pacing and under beta-adrenergic stimulation. The mouse result predicts
      no intrinsic prolongation without extracardiac input; a species whose
      repolarization depends on I_Ks should prolong in the denervated,
      isolated organ.
    would_support:
    - pathophysiology#Markedly Prolonged QTc and Arrhythmogenic Substrate
    supporting_outcome:
    - >-
        Action-potential duration is prolonged and transmural dispersion
        increased in the isolated null heart, without any extracardiac
        input, establishing the organ-scale phenotype as intrinsic to
        the myocardium.
    refuting_outcome:
    - >-
        Repolarization is normal in every isolated null heart regardless
        of species, which would place the human QT prolongation
        downstream of autonomic or humoral input rather than of
        cardiomyocyte I_Ks loss and would require rewriting this edge.
  - experiment_id: jlns1_exp_engineered_tissue
    name: Engineered human cardiac tissue from JLNS hiPSC lines
    description: >-
      Build three-dimensional engineered heart tissue or cardiac slices from
      the existing JLNS hiPSC-cardiomyocyte lines and their isogenic
      controls, and measure conduction, repolarization dispersion, and
      arrhythmia inducibility under adrenergic challenge. This addresses the
      scale gap the entry records as a SCALE_EXTRAPOLATION divergence on the
      hiPSC model without introducing a species gap.
    would_support:
    - pathophysiology#Markedly Prolonged QTc and Arrhythmogenic Substrate
    supporting_outcome:
    - >-
        Human JLNS tissue shows increased repolarization dispersion and
        inducible reentrant arrhythmia relative to isogenic controls,
        supplying the tissue-scale evidence that neither current model
        provides.
    refuting_outcome:
    - >-
        Dispersion and inducibility are unchanged from isogenic
        controls, which would suggest the arrhythmogenic substrate needs
        tissue architecture or autonomic input the preparation lacks.
    evidence:
    - reference: PMID:29925535
      reference_title: "Human Induced Pluripotent Stem Cell-Derived Engineered Heart Tissue as a Sensitive Test System for QT Prolongation and Arrhythmic Triggers."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we compared head-to-head the contribution of IKs (long QT1) and IKr
        (long QT2) on action potentials (APs) in human left ventricular (LV)
        tissue and hiPSC-CM-derived engineered heart tissue (EHT)
      explanation: >-
        Establishes that the proposed preparation exists and has been
        benchmarked against human ventricular tissue for exactly the current
        this disease loses, so the experiment uses an established system
        rather than proposing a new method.
  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: >-
      The authors' own conclusion, and the basis of this mismatch: the murine
      QT phenotype is attributed to signals outside the heart rather than to
      cardiomyocyte I_Ks loss.
  - reference: PMID:29925535
    reference_title: "Human Induced Pluripotent Stem Cell-Derived Engineered Heart Tissue as a Sensitive Test System for QT Prolongation and Arrhythmic Triggers."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)
      should help to overcome the limitations of animal models based on
      species differences in repolarization reserve.
    explanation: >-
      States the general form of this mismatch: repolarization reserve
      differs between species, which is why an animal model of an
      I_Ks-dependent disease may not report the human mechanism. Indirect
      because it argues the principle rather than testing the Kcnq1-null
      mouse.
  notes: >-
    The caveat is already carried structurally on the animal model link
    (PARTIALLY_RECAPITULATES, with limitations naming the isolated-heart
    result) and on the edge evidence, which is graded INDIRECT for this
    reason. This discussion promotes it from a caveat attached to one link
    into the open question it actually is.
- discussion_id: jlns1_gastric_arm_single_cohort
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How frequent is the gastric phenotype of JLNS across the allelic and
    population spectrum, given that it has been systematically looked for in
    only one national cohort?
  attaches_to:
  - pathophysiology#Impaired Gastric Parietal Cell Luminal K+ Recycling
  - pathophysiology#Achlorhydria, Hypergastrinemia, and Iron Deficiency Anemia
  - biochemical#Faecal Calprotectin
  rationale: >-
    Every quantitative statement about the gastric arm in this entry traces
    to one study of fourteen Swedish patients, and denominators within it fall
    to nine and to seven for individual analytes. That cohort is drawn from
    the national JLNS population in which p.Arg518Ter is the majority allele,
    so the figures may describe one founder genotype rather than JLNS
    generally. The mechanism is not in doubt: KCNQ1 is the non-redundant
    luminal K+ channel of the parietal cell in mouse, and the human cohort
    attributes the anemia to hypochlorhydria. What is unknown is prevalence,
    severity distribution, and whether the phenotype tracks residual channel
    function the way the cardiac and cochlear arms do.

    The raised faecal calprotectin is the sharper gap. It was abnormal in
    nine of nine patients tested, coeliac disease and inflammatory bowel
    disease were excluded by endoscopy in those scoped, and neutrophilic
    intestinal inflammation is not predicted by a parietal-cell secretory
    defect. No mechanism has been offered. KCNQ1 is expressed in intestinal
    epithelium as well as gastric, so an intestinal transport phenotype is
    plausible and unexamined.
  evidence:
  - reference: PMID:22805636
    reference_title: "Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All Swedish Jervell and Lange-Nielsen cases with double KCNQ1 mutations
      (14 cases) were investigated by medical record review, an interview,
      and were offered laboratory testing for iron-deficiency anaemia and
      gastrointestinal markers.
    explanation: >-
      Gives the study's own denominator and design, which is the extent of the
      evidence base for the gastric arm and therefore the gap itself.
  notes: >-
    Recorded rather than resolved. This is why iron-deficiency anemia is
    curated at FREQUENT and not raised to VERY_FREQUENT on the cohort's
    12 of 14, and why the calprotectin finding is recorded in the biochemical
    section as unexplained rather than attached to a mechanism node.

experimental_models:
- name: JLNS patient-derived and gene-edited hiPSC cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Human induced pluripotent stem cell lines carrying JLNS-causing KCNQ1
    genotypes, generated both by reprogramming patient cells and by genetic
    engineering, differentiated to cardiomyocytes and studied by patch clamp
    and multielectrode array. The panel covers the two major classes of
    JLNS-causing KCNQ1 defect (a splice-site allele, c.478-2A>T, and a
    missense allele, c.1781G>A) in homozygous, heterozygous, and wild-type
    form, so the recessive genotype-phenotype relationship is read off an
    allelic series in one human genetic background rather than inferred
    across patients. It is the human-cell counterpart to the Kcnq1-null mouse
    curated under animal_models: the mouse carries the cochlear phenotype
    that human cardiomyocytes cannot report, and this model carries the human
    cardiac electrophysiology that the mouse reports poorly because murine
    ventricular repolarization does not depend on I_Ks the way human
    repolarization does.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: hiPSC-derived cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  culture_system: Directed cardiomyocyte differentiation of hiPSC lines; patch-clamp and multielectrode array electrophysiology
  cell_source: JLNS patient somatic cells reprogrammed to hiPSC, plus isogenic genetically engineered lines
  publication: PMID:25453094
  modeled_mechanisms:
  - target: Biallelic KCNQ1 Loss-of-Function Variants
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      The model resolves the trigger node into two mechanistically
      distinct allele classes: an amorphic splice-site allele that is
      strictly recessive, and a missense allele that reduces membrane
      channel density in a gene-dosage-dependent way. That distinction
      is what the entry's genetic_context describes as "missense,
      nonsense, frameshift, or splice-site". Whether it also accounts
      for why some heterozygous carriers of JLNS alleles show a
      Romano-Ward phenotype and others do not is a plausible extension
      of the result, not something this paper tests.
    evidence:
    - reference: PMID:25453094
      reference_title: "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the previously unidentified c.478-2A>T mutation was amorphic and gave
        rise to a strictly recessive phenotype in JLNS-CMs, whereas the
        missense c.1781G>A lesion caused a gene dosage-dependent channel
        reduction at the cell membrane
      explanation: >-
        Establishes that this model reports the functional class of the
        causative allele, which is the claim the link makes about this node.
    readouts:
    - name: Allele-class assignment (amorphic versus hypomorphic) by isogenic comparison
      target: Biallelic KCNQ1 Loss-of-Function Variants
      direction: ALTERED
      interpretation: >-
        Comparing homozygous, heterozygous, and wild-type lines of the same
        genetic background separates a null allele from a dosage-sensitive one.
      evidence:
      - reference: PMID:25453094
        reference_title: "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          We used complementary approaches, reprogramming patient cells and
          genetic engineering, to generate human induced pluripotent stem cell
          (hiPSC) models of JLNS
        explanation: >-
          Describes the isogenic allelic series that makes the allele-class
          readout interpretable.
  - target: Near-Complete Loss of Cardiac I_Ks Repolarizing Current
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Human JLNS cardiomyocytes show severe reduction or outright absence of
      I_Ks, measured directly in the cell type the node is about. This is the
      one place in the entry where the central cardiac lesion is observed in
      human cells rather than inferred from mouse or from heterologous
      expression.
    evidence:
    - reference: PMID:25453094
      reference_title: "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        recapitulated the typical and severe features of JLNS, including
        pronounced action and field potential prolongation and severe
        reduction or absence of IKs
      explanation: >-
        Directly reports loss of the current this node names, in human
        cardiomyocytes carrying the disease genotype.
    readouts:
    - name: Slow delayed-rectifier potassium current (I_Ks) amplitude
      target: Near-Complete Loss of Cardiac I_Ks Repolarizing Current
      direction: ABOLISHED
      interpretation: >-
        Severe reduction or absence of I_Ks is the direct electrophysiological
        measurement of the node.
      evidence:
      - reference: PMID:25453094
        reference_title: "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          recapitulated the typical and severe features of JLNS, including
          pronounced action and field potential prolongation and severe
          reduction or absence of IKs
        explanation: >-
          The reported measurement of I_Ks amplitude in JLNS versus wild-type
          cardiomyocytes.
  - target: Markedly Prolonged QTc and Arrhythmogenic Substrate
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Action-potential and field-potential prolongation are the single-cell
      and monolayer correlates of the prolonged QT interval, and the model
      also reproduces the two clinical features that make the substrate
      dangerous: adrenergic provocation lengthens the action potential
      specifically in JLNS cells, matching the emotion- and exercise-triggered
      events that account for 95% of arrhythmias in patients, and sensitivity
      to QT-prolonging drugs is markedly increased, which is the in-vitro
      counterpart of the drug-avoidance advice curated under treatments.
    limitations: >-
      The QTc is a whole-heart measurement and this model observes only
      cardiomyocyte-level repolarization. Dispersion of repolarization across
      the ventricular wall, reentry, and the conducted arrhythmia itself are
      tissue-level properties that dissociated or monolayer cardiomyocytes
      cannot report, so calling field-potential prolongation an
      arrhythmogenic substrate is an inference. hiPSC-derived cardiomyocytes
      are also electrophysiologically immature relative to adult ventricular
      myocardium, with a depolarized resting potential and a mixed
      atrial/ventricular/nodal population.
    divergences:
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The model measures action and field potential duration in
        cardiomyocytes; the node is a tissue-level arrhythmogenic substrate on
        the surface ECG. The intervening step, transmural dispersion of
        repolarization organizing into reentry, is not observed here.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Autonomic innervation is outside the culture, so the adrenergic
        provocation is applied pharmacologically rather than arising from the
        sympathetic surge that triggers events in patients. The clinical
        relevance of left cardiac sympathetic denervation, curated under
        treatments, turns on exactly the structure this model omits.
    evidence:
    - reference: PMID:25453094
      reference_title: "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Moreover, adrenergic stimulation caused action potential prolongation
        specifically in JLNS-CMs.
      explanation: >-
        Reproduces the adrenergic trigger dependence of the clinical
        arrhythmic substrate in the human cell model.
    readouts:
    - name: Action potential and field potential duration
      target: Markedly Prolonged QTc and Arrhythmogenic Substrate
      direction: INCREASED
      interpretation: >-
        Prolonged repolarization at the cellular and monolayer level is the
        in-vitro correlate of the prolonged QTc, one scale below it.
      evidence:
      - reference: PMID:25453094
        reference_title: "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          pronounced action and field potential prolongation
        explanation: >-
          The measured prolongation of repolarization in JLNS cardiomyocytes.
    - name: Susceptibility to proarrhythmic drug challenge
      target: Markedly Prolonged QTc and Arrhythmogenic Substrate
      direction: INCREASED
      interpretation: >-
        Increased sensitivity to QT-prolonging drugs in JLNS cardiomyocytes is
        the in-vitro counterpart of the clinical instruction to avoid
        QT-prolonging agents, and it was pharmacologically correctable in this
        system.
      evidence:
      - reference: PMID:25453094
        reference_title: "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs
          but could be pharmacologically corrected
        explanation: >-
          Reports both the increased drug susceptibility and its
          pharmacological correction in the model.
  evidence:
  - reference: PMID:25453094
    reference_title: "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs)
      from homozygous JLNS, heterozygous, and wild-type lines recapitulated
      the typical and severe features of JLNS
    explanation: >-
      Establishes the model as informative for the JLNS cardiac phenotype:
      the disease genotype reproduces the disease electrophysiology in human
      cardiomyocytes.
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.

📚

References & Deep Research

References

1

PMID:20301579

Jervell and Lange-Nielsen Syndrome.

No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (4)

Record 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. A second deep-research pass (openscientist, 2026-09-06) was run for the augmentation round. Two concurrent invocations of that run raced, and the later one (start_time 14:45:40Z) overwrote the earlier one at the same path; only the later report is committed, and its validation sections were regenerated against its own body. Three of the references curated in this round (PMID:25453094, PMID:35331422, PMID:26205899) were surfaced by the earlier, overwritten run and do not appear in the committed report; PMID:22805636 appears in both. Each of the four was independently fetched from PubMed, cached, and snippet-verified here, so the evidence stands on its own record rather than on the report, but the committed report is not a complete provenance trail for this round. The committed report's preflight returns the same WARN as the falcon one and for the same reason (KCNE1 discussed alongside KCNQ1); its OMIM citation matches MONDO:0024540's 220400. Its reference validation resolves 25 of 25 citations with 20 of 20 quoted claims found in source and none judged off topic, though only 16 of the 25 were affirmatively scored on topic, so that is not a clean bill of health for the other nine. Its term validation is the part to distrust. The report's own table counts seven CURIEs named as a different term, but one of those seven is MONDO:0024540, where the mismatch is an artifact of the report echoing the template placeholder "if available" as the label; that CURIE is correct and is this entry's own disease_term. The other six name genuinely different concepts and none was used here: UBERON:0002215 was offered for stria vascularis (it is synchondrosis), UBERON:0002228 for spiral ganglion (it is rib), CL:0000710 for marginal cell of stria vascularis (it is neurecto-epithelial cell), UBERON:0007499 for endolymph (it is epithelial sac), HP:0011473 for achlorhydria (it is Villous atrophy; this entry uses HP:0032448), and HP:0003637 for hypergastrinemia (this entry uses HP:0500167). The overwritten run separately offered NCIT:C2438 for beta-blockers (RAS Peptide Cancer Vaccine) and NCIT:C50072 for an implantable cardioverter-defibrillator (Modem Device). Every ontology binding in this entry was resolved independently and passes `just validate-terms`. No datasets: block is curated because no relevant dataset exists. GEO was searched by disease name (the string "Jervell" returns nothing in gds) and through `just discover-datasets`, which surfaced only GENE_ONLY KCNQ1 hits about unrelated biology: GSE168245 (KCNQ1 in human beta-cell development), GSE161051 (Kcnq1 imprinting cluster in hybrid mouse placenta), and GSE121578 (a heterozygous LQTS/Beckwith-Wiedemann imprinting case, n=2). All three resolve and none is about JLNS, which is the Named Entity Confusion pattern reached through gene-based dataset search; none was curated. This round fetched twenty-nine reference caches and cites ten of them. The rest were fetched because the deep-research report's own reference validation resolves every citation it makes, so the whole set lands in the cache whether or not the curation uses it. They are kept rather than pruned, because pruning against a cited-PMID list is how a cache the entry does cite gets deleted. Note the exact added-versus-main count drifts as other PRs land the same papers independently, so treat the groupings below rather than any arithmetic as the record. Why each unused one was not cited, by group. Cochlear-implant series (PMID:18805595, PMID:31846911, PMID:39210075) and deafness-screening yields (PMID:29889784, PMID:34308870, PMID:41563185) duplicate what PMID:26205899 already supports here; one series was preferred over five overlapping ones rather than stacking citations on the same claim. Potassium-cycling reviews (PMID:12031509, PMID:12097719, PMID:11223304, PMID:32581825, PMID:35138621) are background physiology already carried by PMID:20012478 and PMID:19491250, and PMID:11223304 is additionally a Kcne1 study, which is JLNS2 territory. PMID:17646758 is the non-English record of the same cohort as PMID:16461811, which is cited instead. Single-family case reports (PMID:23668803, PMID:29372044) add genotypes without adding a mechanism the entry does not already state. The remaining iPSC and electrophysiology papers are about other long-QT subtypes rather than JLNS: PMID:20660394 and PMID:31245483 are heterozygous LQT1, and PMID:40794559 is LQT2. PMID:40794559 is nonetheless a live lead for a future round, and the reason is not its subtype: it reports deleterious negative inotropic effects of an I_Ks activator, which bears on whether channel activators could help a biallelic-null JLNS patient at all. PMID:24268954 and PMID:42466893 are LQTS-wide denervation and registry series whose JLNS-relevant content is already covered by PMID:35331422.

Review response: gene dosage, founder allele, discussions, two treatments · 2026-09-07T03:50:08Z · View source

Response to the ai4c-reviewer changes-requested review on PR #11285: one blocking finding and five suggestions, all taken, in one push. Blocking: gene-dosage and founder-allele genetics. The entry described which gene causes JLNS but not what dosage does, which is the axis that most defines a recessive channelopathy whose heterozygotes have their own named dominant disease. Added to the KCNQ1 genetic entry: a gene-dosage notes paragraph, the Swedish founder-allele contrast within a single variant (QTc 576 +/- 61 ms in homozygotes against 462 +/- 34 ms in heterozygotes, cumulative aborted cardiac arrest 47% against 1%, PMID:24552659), and the counterintuitive half from a 789-carrier series (PMID:38825991): heterozygous carriers of JLNS-causing alleles have LOWER cardiac-event risk than other LQT1 heterozygotes, hazard ratio 0.34. That second result is what recessiveness means at the channel level and is the basis for counselling a proband's carrier parents. Also added a Variant record for p.Arg518Ter (c.1552C>T) with the Swedish founder genealogy, shared haplotype across 17 of 19 families, and ~1:2000-4000 heterozygote prevalence. The reviewer observed that the Swedish gastric cohort (PMID:22805636) is very likely the same founder population as the R518X families. Neither paper states the overlap, so it is not asserted; it is recorded in the gene-level notes as a reason to read the gastric findings as characterized in a largely single-allele population. Suggestion 1, NOS1AP modifier (PMID:32061134). Added as relationship_type: MODIFIER with both evidence items graded INDIRECT and a notes paragraph stating the limitation plainly: the hiPSC cells carried a heterozygous LQT1 KCNQ1 A341V genotype and the complementary work used guinea-pig cardiomyocytes with pharmacologically mimicked LQT1. No NOS1AP effect has been shown in a JLNS patient. Curated as a lead for the variable arrhythmic expressivity JLNS shows at fixed genotype, not as an established determinant. Suggestion 2, KCNQ1 suppression-and-replacement gene therapy (PMID:33504163). Added as a treatment with therapeutic_modality: GENE_THERAPY, target_mechanisms RESTORES against the I_Ks-loss node, and heavy hedging: notes open "Not a therapy." Every cell line tested was heterozygous LQT1, so restoration was shown against one residual wild-type allele and not against the biallelic null state. Two things named as prerequisites before it means anything for JLNS: efficacy on a biallelic-null background, and in vivo ventricular delivery. Suggestion 3, discussions. Added the section, which the entry lacked. kind: HUMAN_MODEL_MISMATCH for the murine QT phenotype being extracardiac-dependent, attaching to both cardiac nodes and the mouse model, with two proposed_experiments (cross-species isolated-heart optical mapping; engineered heart tissue from the existing JLNS hiPSC lines). The rationale states the asymmetry the entry could not otherwise express: the same mouse is strong evidence for the cochlear arm and weak for the cardiac one. A second discussion, kind: KNOWLEDGE_GAP, records that the whole gastric arm rests on one 14-patient cohort with per-analyte denominators of nine and seven, and singles out the 9/9 faecal calprotectin as unexplained by the parietal-cell mechanism. Suggestion 4, atrial pacing with beta-blockade (PMID:27451284). Added as a DEVICE treatment. The JLNS-specific detail that matters is preserved: six patients with atrial leads survived event-free at mean 6.9 years while the one patient given a ventricular lead died, which is what makes this an argument for atrial pacing specifically. Notes record that the series is nine patients, uncontrolled, that the lead-position comparison rests on a single patient, and that the paper's own title ends in a question mark. Suggestion 5, uncited reference caches. Added a notes paragraph dispositioning all nineteen by group: five overlapping cochlear-implant and deafness-screening series superseded by PMID:26205899, five potassium-cycling reviews superseded by PMID:20012478 and PMID:19491250 (one of which, PMID:11223304, is a Kcne1 study and so JLNS2 territory), the non-English duplicate record of the cited Schwartz cohort, two single-family case reports, three heterozygous-LQT1 electrophysiology papers, and two LQTS-wide series covered by PMID:35331422. PMID:40794559 is flagged as a live lead for a future round: it reports deleterious negative inotropic effects of I_Ks activation, which bears on whether channel activators could ever help a biallelic-null patient. Caught while responding, not raised by the reviewer: I had invented NCIT:C50097 as "Pacemaker Device" for the atrial-pacing device qualifier. It is Printed Circuit Board Device. `just check-qualifier-terms-online` caught it, which is exactly the blind spot dismech#10197 documents, since linkml-term-validator does not reach inside qualifiers and the offline gate only sees CURIEs cached from elsewhere. Corrected to NCIT:C94198 (Cardiac Pacemaker), and the treatment_term was upgraded from the generic NCIT:C15329 (Surgical Procedure) to NCIT:C80434 (Pacemaker Placement), found in the same lookup. Worth recording that the failure mode this entry's notes describe for the deep-research provider's suggestions is one I also committed by hand. Also corrected during this round: the uncited-reference count, which was written as twenty and became nineteen once PMID:29925535 was cited on the HUMAN_MODEL_MISMATCH discussion and its engineered-heart-tissue experiment. That paper argues the general form of the mismatch directly, that hiPSC-CMs help overcome animal-model limitations rooted in species differences in repolarization reserve. Not changed. The reviewer's cosmetic note about a `K+-diffusion` snippet where the source has `K(+)-diffusion` is pre-existing on main, the newly added copy is correct, and the reference validator accepts both, so it is left alone rather than mixed into a review response. Validation: just validate-disorders passes with 140/140 snippets verified. All offline gates pass, plus check-qualifier-terms-online and model-scale-audit --strict. 2915 targeted pytest cases pass. Compliance 97.0%, down from 98.9% because the new sections add scored slots faster than they fill them; the remaining unfilled ones are datasets (deliberate), proposed-experiment datasets (future experiments have none), and divergence-level evidence, which is left empty rather than padded since a divergence is an argument about a model and not an empirical claim.

Augment: Jervell and Lange-Nielsen Syndrome 1 · 2026-09-06T23:17:24Z · View source

Augmentation round on an existing, already-merged entry (created 2026-08-17 from a falcon deep-research report). Compliance moved from 94.1% to 98.8%. Deep research. A falcon report for this disease already existed and had been consumed by the original curation; re-running falcon writes to the same path and would have overwritten that provenance, so a second provider (openscientist) was run instead. Two concurrent invocations of that run raced and the later one overwrote the earlier at the same path. Only the later report is committed, and both its Reference Validation and Term Validation sections were regenerated against its own body after the overwrite was discovered, so the committed sections describe the committed text. Consequence worth stating plainly: PMID:25453094, PMID:35331422 and PMID:26205899 were surfaced by the overwritten run and are not in the committed report; PMID:22805636 is in both. All four were independently fetched from PubMed, cached, and exact-quote verified here, so the evidence rests on the primary records rather than on the report, but the committed report is not a complete provenance trail for this round. This is recorded in the entry's notes as well. Report validation results, read before use. The committed openscientist report resolves 25/25 references, 20/20 quoted claims found in source, none off topic. Its term suggestions were largely unusable and none was taken: seven CURIEs name entirely different concepts (UBERON:0002215 offered for stria vascularis is synchondrosis; UBERON:0002228 for spiral ganglion is rib; CL:0000710 for strial marginal cell is neurecto-epithelial cell; UBERON:0007499 for endolymph is epithelial sac; HP:0011473 for achlorhydria is Villous atrophy; HP:0003637 for hypergastrinemia). The overwritten run additionally offered NCIT:C2438 for beta-blockers (RAS Peptide Cancer Vaccine) and NCIT:C50072 for an ICD (Modem Device). preflight-dr returned WARN on both runs for the same benign reason the entry already documents (KCNE1/JLNS2 is reviewed alongside KCNQ1 throughout this literature); the committed run's OMIM citation matches MONDO:0024540's 220400. What was curated. 1. Causal-edge evidence. All ten pathophysiology downstream edges were uncited (downstream[].evidence was 0/10 in the compliance report). Each now carries causal_link_type and evidence chosen to support the edge rather than either node: the Kcnq1-null mouse for gene-to-endolymph and for I_Ks-to-QT ("gross morphological anomalies because of the drastic reduction in the volume of endolymph"), PMID:15891643 for the cochlear chain, PMID:19491250 for the gastric chain, GeneReviews for QTc-to-tachyarrhythmia and tachyarrhythmia-to-death. Rescue results (PMID:26084842) are marked directness: INDIRECT because they support the edge in the reverse direction. 2. classifications: added. CARDIOVASCULAR + DISORDER_OF_EAR + GENETICS_ENVIRONMENT_DISEASE, each with its own evidence, plus channelopathy_category: cardiac channelopathy. mechanistic_category was deliberately left empty - no MechanisticCategoryEnum value fits a channelopathy, and the skill says to omit rather than force one. The channelopathy slot is single-valued and JLNS1 is not confined to the heart, so the note records that the assignment is the clinical classification, not the extent of the channel defect. 3. Phenotype frequency on three phenotypes. Congenital deafness and prolonged QTc are OBLIGATE because GeneReviews makes both required diagnostic criteria; biallelic KCNQ1 genotypes that spare hearing are recessive LQT1, not JLNS, which is what makes the deafness obligate within this entry rather than merely very frequent. Sudden cardiac death is FREQUENT from ">half of untreated children die before 15". Torsade de pointes, ventricular fibrillation, bradycardia, seizure-like episodes and achlorhydria were left without a frequency: no source states one, and guessing is worse than absence. 4. progression: added (4 phases) - early-childhood onset, adrenergic trigger dependence, untreated childhood mortality, and within-syndrome risk stratification (QTc >550 ms, first-year syncope, sex, with effect sizes). 5. clinical_burden: HIGH, with the argument that the two burdens interact rather than merely coexist: cochlear implantation requires general anesthesia in a child with a markedly prolonged QT, and PMID:32508908 records a life-threatening arrhythmia at exactly that point. 6. experimental_models: added - the entry previously had animal_models but no non-animal model. The hiPSC-cardiomyocyte JLNS panel (PMID:25453094) is the only place the cardiac lesion is observed in human cells. Three modeled_mechanisms links: MOLECULAR (allele-class resolution, amorphic vs dosage-dependent), CELLULAR (I_Ks loss, scale-aligned), and a deliberate upward extrapolation to the TISSUE-scale arrhythmogenic substrate node, which carries limitations plus typed SCALE_EXTRAPOLATION and BOUNDARY_OMISSION divergences. just model-scale-audit --strict passes. 7. Primary sources replacing or backing summary ones. The gastric arm was GeneReviews-only; PMID:22805636 is the complete Swedish double-KCNQ1-mutation cohort and states the causal claim in humans ("secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations"). Iron-deficiency anemia was left at FREQUENT rather than raised to VERY_FREQUENT on 12/14, because that is a single 14-patient series and the only cohort ever screened for it; the reasoning is in the phenotype notes. LCSD gained PMID:35331422, where the JLNS-relevant number is not the headline 86% event-rate reduction but the very-high-risk subgroup, of whom only 17% became asymptomatic. Cochlear implantation gained PMID:26205899, which balances the single adverse case already cited with 38 pooled implanted JLNS children and uneventful surgery under precautions. That paper also supplied a second prevalence record: 0.79% among 503 congenitally deaf implant candidates, curated separately from the worldwide estimate with a note that the two are not comparable, since that three-orders-of-magnitude enrichment is the whole argument for ECG screening of deaf children. 8. Removed a stale "(partial)" in an Achlorhydria explanation - a leftover reference to the retired PARTIAL evidence grade (dismech#10003 prose rot). No datasets: block. This is a deliberate omission, not an oversight, and is the one slot still at 0% compliance. GEO has nothing on JLNS: the string "Jervell" returns zero hits in gds, and just discover-datasets returned only GENE_ONLY KCNQ1 hits about unrelated biology - GSE168245 (beta-cell development), GSE161051 (placental imprinting in hybrid mice), GSE121578 (a heterozygous LQTS/Beckwith-Wiedemann imprinting case, n=2). All resolve and none is about this disease; that is the Named Entity Confusion pattern CLAUDE.md warns about reaching through gene-based dataset search. Curating one to move a compliance number would have been the failure mode, so none was. Validation. just validate passes with 120/120 snippets verified against cached references. just validate-disorders (the batched gate CI runs) passes. check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence and model-scale-audit --strict all pass. check-source-defect-claims flags nothing in this file.

Create: Jervell and Lange-Nielsen Syndrome 1 (KCNQ1) · 2026-08-18T04:47:47Z · View source

Created new disorder entry for Jervell and Lange-Nielsen syndrome 1 (MONDO:0024540, OMIM:220400, KCNQ1), the biallelic-KCNQ1 subtype of JLNS, resolving issue #8743. Deep research performed via 'just research-disorder falcon Jervell_and_Lange-Nielsen_Syndrome_1' (research/Jervell_and_Lange-Nielsen_Syndrome_1-deep-research-falcon.md); reference validation in the report showed 8/8 references resolved, 0 unresolved, confabulation_rate 0.0. Ran 'just preflight-dr' against MONDO:0024540: verdict WARN because KCNE1 (JLNS2's causal gene) is discussed alongside KCNQ1 throughout the shared JLNS literature (both genes cause the same clinical syndrome and are reviewed together in GeneReviews and the Schwartz 2006 187-patient cohort); the report itself explicitly scopes JLNS1/KCNQ1 vs JLNS2/KCNE1, and only KCNQ1-attributed genetic/mechanistic claims were curated -- documented as a note on the entry. GeneReviews baseline used (PMID:20301579, tagged in top-level references). Pathophysiology models a KCNQ1 loss-of-function trigger branching into three chains: cardiac I_Ks loss -> prolonged QTc/arrhythmogenic substrate -> torsades/VF -> syncope/SCD (conforms_to cardiac_ion_channel_repolarization module nodes); stria vascularis K+-secretion loss -> organ of Corti hair-cell degeneration -> spiral ganglion degeneration -> congenital profound SNHL (conforms_to sensorineural_hair_cell_loss module nodes); and gastric parietal-cell K+-recycling loss -> achlorhydria/hypergastrinemia/iron-deficiency anemia (no existing module target). Added 10 phenotypes, genetic (KCNQ1, CAUSATIVE, ~90 percent case-fraction of JLNS), autosomal-recessive inheritance block, structured prevalence (1 in 1,000,000 to 1 in 200,000 worldwide), 6 treatments (beta-blocker, ICD, LCSD, cochlear implantation with the documented NCIT Cochlear-Implant-is-a-device gap workaround, QT-drug/trigger avoidance, genetic counseling), and 2 animal models (Casimiro 2001 Kcnq1-null mouse; Chang 2015 AAV1-Kcnq1 gene-therapy-rescue mouse) with modeled_mechanisms/readouts. Key PMIDs: 9020846 (Neyroud 1997, original KCNQ1-JLNS discovery), 16461811 (Schwartz 2006, 187-patient natural history), 33498651 (Oertli 2021, residual-function/gene-dosage mechanism), 41147441 (Pan 2025, variant functional characterization), 19491250 (Song 2009, KCNQ1 gastric K+ recycling), 11226272 (Casimiro 2001, Kcnq1-null mouse model), 26084842 (Chang 2015, AAV gene-therapy rescue), 15891643 (Rivas and Francis 2005, inner-ear histopathology), 29037160 (Uysal 2017, case series with bradycardia and seizure phenotypes), 32508908 (Qiu 2020, prevalence and anesthesia-trigger case), 37872640 (Josephs 2023, CardiacG2P structured gene-disease curation). Validated: just validate (schema plus terms plus references, 57/57 snippets verified), just count-verified-snippets, just check-duplicate-keys, just validate-disorders (full pre-PR batched sweep, passed clean), and targeted pytest -k selection (4160 passed) covering module conformance and foreign-key tests.

Falcon ▸

Jervell and Lange-Nielsen Syndrome 1: Disease Characteristics Report

Edison Scientific Literature 23 citations 2026-08-17T21:13:12.923594

Jervell and Lange-Nielsen Syndrome 1: Disease Characteristics Report

Scope and evidence conventions

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.

1. Disease information

Definition

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)

Identifiers and synonyms

MONDO: MONDO:0024540, Jervell and Lange-Nielsen syndrome 1. Broader JLNS: MONDO:0002441. (OpenTargets Search: Jervell and Lange-Nielsen syndrome-KCNQ1)
OMIM: commonly represented as JLNS1, 220400; KCNQ1 gene entry 607542. These identifiers should be verified against the current OMIM release before automated ingestion because OMIM itself was not directly retrieved.
MeSH: D029593, Jervell-Lange Nielsen Syndrome. (NCT06534671 chunk 1)
Orphanet: broader JLNS is generally catalogued as ORPHA:90647; subtype-specific resolution should be checked in the live Orphanet release.
ICD-10: no reliable JLNS1-specific billable code; it is generally represented under congenital long-QT syndrome/cardiac conduction or congenital-malformation categories according to national modification.
ICD-11: no subtype-specific code was established from retrieved material; use the current ICD-11 browser rather than inferring one.
Synonyms: JLNS type 1; Jervell–Lange-Nielsen syndrome type 1; KCNQ1-related JLNS; autosomal-recessive long-QT syndrome with congenital deafness; cardioauditory long-QT syndrome; surdocardiac syndrome.

2. Etiology

Causal factors and genetic risk

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:

homozygous c.728G>A (p.Arg243His);
compound heterozygous c.477+1G>A / c.520C>T (p.Arg174Cys);
homozygous c.1097G>A (p.Arg366Gln);
compound heterozygous c.1741A>T (p.Lys581Ter) / c.477+5G>A. (uysal2017“homozygousandcompound pages 2-5, uysal2017“homozygousandcompound pages 1-2, qiu2020jervellandlangenielsen pages 1-2)

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.

Modifiers and protective factors

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.

Gene–environment interaction

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.

3. Phenotypes

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.

4. Genetic and molecular information

Gene and protein

Gene: KCNQ1, potassium voltage-gated channel subfamily Q member 1; HGNC:6294.
Location: chromosome 11p15.5; 16 coding exons were described in the retrieved source.
Protein: Kv7.1/KvLQT1, a six-transmembrane voltage-gated potassium-channel α-subunit.
Complex: Kv7.1 coassembles with KCNE1/minK to generate the slowly activating delayed rectifier current IKs. (oertli2021molecularmechanismof pages 1-2, qiu2020jervellandlangenielsen pages 1-2)

Functional consequences

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.

5. Environmental information

There is no infectious, toxic, nutritional, radiation, pollution, occupational, or lifestyle cause. Relevant acquired arrhythmia modifiers include:

QT-prolonging medication exposure;
hypokalemia and hypomagnesemia;
dehydration or illness causing electrolyte loss;
fever;
intense adrenergic stimulation;
anesthesia and perioperative sympathetic/electrolyte shifts;
missed β-blocker doses.

Exercise, emotion, swimming, auditory stimuli, anesthesia, and fever are specifically reported event triggers in children with JLNS. (qiu2020jervellandlangenielsen pages 1-2)

6. Mechanism and pathophysiology

Cardiac causal chain

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).

Auditory/vestibular causal chain

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).

Other molecular profiling

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)

7. Anatomical structures affected

Heart: ventricular myocardium/cardiac conduction physiology; the heart is generally structurally normal. Primary defect is electrical rather than inflammatory, ischemic, fibrotic, or metabolic.
Inner ear: bilateral cochlea, especially stria vascularis and scala media/endolymph compartment; secondary organ-of-Corti hair-cell injury. Vestibular labyrinth may also be affected.
Subcellular site: plasma membrane voltage-gated potassium-channel complex; trafficking defects can involve biosynthetic processing before surface expression.

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.

8. Temporal development

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.

9. Inheritance and population

Epidemiology

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.

Recurrence and penetrance

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.

10. Diagnostics

Clinical and functional evaluation

Recommended evaluation comprises:

12-lead ECG with manually verified QT/QTc; repeat ECGs because measurement and rate correction can vary.
Holter monitoring and exercise testing where useful for rhythm burden and repolarization behavior.
Detailed history of exertional/emotional syncope, seizures, cardiac arrest, medications, and sudden deaths.
Formal audiology—auditory brainstem response in infants and age-appropriate pure-tone/speech testing.
Serum potassium, magnesium, calcium, and thyroid assessment to identify acquired aggravators, not to diagnose the genetic disease.
Device interrogation where an ICD/pacemaker is present.

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)

Genetic testing

Begin with a validated congenital LQTS/cardioauditory panel including KCNQ1 and KCNE1, with sequence and exon-level deletion/duplication analysis.
A combined deafness/arrhythmia panel is useful when deafness is the presenting feature; one study used a 127-gene deafness panel, while another advocated broad cardiac panels when severity was unexplained. (uysal2017“homozygousandcompound pages 1-2, uysal2017“homozygousandcompound pages 6-7, qiu2020jervellandlangenielsen pages 1-2)
If only one KCNQ1 allele is found, pursue CNV analysis, splice/RNA studies where available, and exome or genome reanalysis.
WES/WGS can identify atypical or blended diagnoses but may miss repeat expansions or poorly covered structural/noncoding variants. CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing are not first-line unless another phenotype indicates them.
Functional patch-clamp studies are research/variant-resolution tools, not routine clinical assays.

Differential diagnosis

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.

Screening

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.

11. Outcome and prognosis

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.

12. Treatment

Standard strategy

Nonselective β-blocker therapy: nadolol or propranolol is generally preferred over metoprolol for congenital LQTS. β-blockade is foundational but is less completely protective in JLNS than in typical LQT1. (uysal2017“homozygousandcompound pages 5-6, hauwanga2024managementoflong pages 5-6, crotti2008congenitallongqt pages 4-5)
ICD: indicated after resuscitated cardiac arrest and considered for recurrent syncope/ventricular arrhythmia despite optimized medication. General 2022 ESC-aligned guidance reports approximately 14% five-year recurrence after cardiac arrest despite therapy. Pediatric device complications include infection, lead failure/displacement, inappropriate shocks, and psychological burden. (balestra2024congenitallongqt pages 8-9)
Left cardiac sympathetic denervation: considered for breakthrough events, β-blocker intolerance, recurrent ICD shocks, or when ICD implantation is declined/contraindicated. General LQTS literature reports major event reduction, but historical JLNS cohort evidence suggested limited protection; it is not curative. (balestra2024congenitallongqt pages 8-9, hauwanga2024managementoflong pages 5-6, crotti2008congenitallongqt pages 4-5)
Cochlear implantation: standard hearing rehabilitation for profound loss when hearing aids are inadequate; published cases show substantial hearing benefit. Surgery requires electrophysiology/cardiology and anesthesia planning, continued β-blockade, electrolyte optimization, avoidance of QT-prolonging agents, continuous ECG, and immediately available defibrillation. (uysal2017“homozygousandcompound pages 6-7, qiu2020jervellandlangenielsen pages 5-7)
Supportive care: speech/language therapy, educational accommodation, family CPR training, emergency action plans, medical-alert identification, and psychological support.

Suggested NCIt intervention concepts: beta-adrenergic receptor blocker therapy; implantable cardioverter-defibrillator; sympathectomy/LCSD; cochlear implantation; genetic counseling.

Experimental therapy and trials

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)

13. Prevention

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.

14. Other species and natural disease

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).

15. Model organisms and experimental systems

Mouse

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)

Heterologous cellular models

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)

Human iPSC models

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)

Recent developments and expert assessment

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)

Overall expert interpretation

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)

Evidence gaps

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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(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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Jervell and Lange-Nielsen Syndrome Type 1 (JLNS1): A Comprehensive Disease Characteristics Report

openscientist-autonomous 25 citations 2026-09-06T15:12:38.876076

Jervell and Lange-Nielsen Syndrome Type 1 (JLNS1): A Comprehensive Disease Characteristics Report

Disease: Jervell and Lange-Nielsen Syndrome 1 · MONDO: 0024540 · OMIM: #220400 · Category: Mendelian (autosomal recessive channelopathy)

Summary

Jervell and Lange-Nielsen syndrome type 1 (JLNS1) is a rare, severe autosomal recessive cardio-auditory channelopathy caused by biallelic loss-of-function mutations in KCNQ1 (the α-subunit of the slow delayed-rectifier potassium current, I_Ks). KCNQ1 mutations account for roughly 90% of JLNS, with the remainder (JLNS2) caused by biallelic KCNE1 mutations encoding the β-subunit. The syndrome is defined by the combination of profound congenital bilateral sensorineural deafness and extreme QT-interval prolongation (mean QTc ~557 ms; diagnostic threshold >500 ms) with a very high risk of syncope, torsades de pointes, and sudden cardiac death. Prevalence is estimated at 1/1,000,000 to 1/200,000.

The unifying mechanism is loss of the same I_Ks channel in two tissues. In ventricular cardiomyocytes, loss of I_Ks removes the repolarization reserve that shortens the action potential during sympathetic activation, producing marked QT prolongation and adrenergically-triggered arrhythmia. In the cochlea, the KCNQ1/KCNE1 channel sits at the apical membrane of strial marginal cells and vestibular dark cells, where it secretes K⁺ into the endolymph to complete the cochlear K⁺ cycle and maintain the high-K⁺, +80 mV endocochlear potential essential for hearing; its loss collapses endolymph K⁺ secretion and causes deafness. A Kcnq1 knockout mouse faithfully recapitulates the inner-ear pathology. A third, under-recognized arm of the disease is gastrointestinal: the same channel recycles K⁺ across the parietal-cell apical membrane, so its loss causes hypochlorhydria, compensatory hypergastrinemia, gastric mucosal hyperplasia, and secondary iron-deficiency anemia.

Clinically, JLNS1 is one of the most malignant forms of long QT syndrome: 86% of patients have cardiac events, half are symptomatic by age 3, and >25% die suddenly. Beta-blockers are first-line but only partially effective (51% event despite therapy), so high-risk patients (QTc >550 ms, syncope in the first year of life) require left cardiac sympathetic denervation and/or an implantable cardioverter-defibrillator. Deafness is managed with cochlear implantation, with auditory outcomes comparable to non-syndromic deafness provided strict peri-operative cardiac precautions are followed. Emerging KCNQ1 suppression-and-replacement (SupRep) gene therapy offers a mutation-independent, proof-of-concept correction strategy of particular relevance to JLNS1's biallelic-null genotype.

Key Findings

Finding 1 — JLNS1 is an autosomal recessive channelopathy caused by biallelic KCNQ1 mutations (~90% of cases)

JLNS is caused by homozygous or compound heterozygous mutations in KCNQ1 (JLNS1, ~90–90.5% of cases) or KCNE1 (JLNS2), encoding the α- and β-subunits, respectively, of the slow delayed-rectifier potassium current I_Ks. Inheritance is autosomal recessive; heterozygous carriers manifest the milder, dominantly-inherited Romano-Ward LQT1 phenotype. Prevalence is estimated between 1/1,000,000 and 1/200,000 worldwide. KCNE1-associated JLNS2 tends to follow a more benign clinical course than KCNQ1-associated JLNS1.

"Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course." — PMID: 17646758

"Jervell and Lange-Nielsen syndrome (JLNS) is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds)... The prevalence of JLNS is about 1/1000000 to 1/200000 around the world." — PMID: 32508908

Ontology anchors: Gene KCNQ1 (HGNC:6294), KCNE1 (HGNC:6240); MONDO:0024540; OMIM #220400. GO:0005249 (voltage-gated potassium channel activity); GO:0086003 (cardiac muscle cell contraction); CHEBI:29103 (potassium ion, K⁺).

Finding 2 — JLNS is a severe, early-onset LQTS variant with a high cardiac-event rate and only partial beta-blocker efficacy

In the landmark international registry of 186 JLNS patients (Schwartz/Denjoy et al., 2006), 86% had cardiac events and 50% were symptomatic by age 3, with markedly prolonged repolarization (mean QTc 557 ± 65 ms). Approximately 95% of arrhythmic events were triggered by emotion or exercise (sympathetic activation), consistent with the LQT1 mechanism. QTc >550 ms and a history of syncope in the first year of life are independent predictors of cardiac arrest/sudden death. Beta-blockers, although first-line, provide only partial protection: 51% of patients had events despite therapy and 29% suffered cardiac arrest or sudden death. Females are at somewhat lower risk. More than 25% of JLNS patients die suddenly.

"Most patients (86%) had cardiac events and 50% were symptomatic already by age 3. Their QTc was markedly prolonged (557 +/- 65 ms)." — PMID: 17646758

"A QTc>550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD." — PMID: 17646758

"beta-blockers have only partial efficacy as 51% of the patients had events despite therapy and 29% had CA/SD." — PMID: 17646758

The nationwide Spanish paediatric LQTS registry (371 children) corroborates this risk profile: major arrhythmic events clustered in "high-risk genotypes" — explicitly including Jervell-Lange-Nielsen — and in children with QTc ≥550 ms or very early (fetal/neonatal) presentation (PMID: 42466893).

Ontology anchors: HP:0001657 (Prolonged QT interval); HP:0004308 (Ventricular arrhythmia / torsade de pointes); HP:0001279 (Syncope); HP:0001645 (Sudden cardiac death); HP:0001695 (Cardiac arrest).

Finding 3 — Mechanism: loss of KCNQ1/KCNE1 I_Ks abolishes marginal-cell K⁺ secretion into endolymph, causing deafness

The KCNQ1/KCNE1 channel is expressed at the apical membrane of strial marginal cells in the cochlea and vestibular dark cells, where it secretes K⁺ into the endolymph. This step completes the cochlear K⁺ recycling cycle required to maintain the high-K⁺, +80 mV endolymph and endocochlear potential (EP) that drives sensory hair-cell mechanotransduction. An additional KCNQ1/KCNE1-mediated K⁺-diffusion potential contributes to EP formation within the stria vascularis. Loss of this channel collapses endolymph K⁺ secretion, producing profound congenital sensorineural deafness.

"Deafness results also from mutations of KCNQ1 or KCNE1, subunits of a K(+) channel that carries K(+) from strial marginal cells and vestibular dark cells into endolymph." — PMID: 12097719

"An additional K(+)-diffusion potential formed by KCNQ1/KCNE1-K" — PMID: 20012478

The detailed K⁺ cycle (from PMID: 12031509) situates KCNQ1/KCNE1 as the final apical secretory step: K⁺ enters the strial marginal cell basolaterally via SLC12A2 (NKCC1) and Na⁺/K⁺-ATPase, then exits apically into endolymph via KCNQ1/KCNE1, "which concludes the cochlear cycle." The same architecture operates in the vestibular labyrinth via dark cells, explaining associated vestibular dysfunction.

Ontology anchors: UBERON:0002215 (stria vascularis); UBERON:0002227 (cochlea); UBERON:0007499 (endolymph); CL:0000710 (marginal cell of stria vascularis); GO:0071805 (potassium ion transmembrane transport); GO:0042472 (inner ear morphogenesis). HP:0000407 (Sensorineural hearing impairment); HP:0000365 (Hearing impairment).

Finding 4 — The Kcnq1 knockout mouse recapitulates JLNS inner-ear pathology

Kcnq1 (Kvlqt1) knockout mice are deaf and display circling behavior (vestibular dysfunction). Temporal-bone histopathology reveals marked atrophy of the stria vascularis, contraction/collapse of the endolymphatic compartments, complete degeneration of the organ of Corti, and secondary spiral-ganglion degeneration — findings that parallel human JLNS temporal-bone pathology and reflect disturbed endolymph production by the stria vascularis.

"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." — PMID: 15891643

Ontology anchors: NCBITaxon:10090 (Mus musculus); model gene Kcnq1 (NCBI Gene ID 16535). UBERON:0002365 (organ of Corti); UBERON:0002228 (spiral ganglion).

Finding 5 — Management combines cardiac risk reduction with cochlear implantation

Cardiac management centers on beta-blockers as first-line therapy (partial protection only), escalating in high-risk patients (QTc >550 ms, syncope in the first year, aborted arrest) to ICD implantation and/or left cardiac sympathetic denervation (LCSD), alongside strict avoidance of QT-prolonging drugs and sympathetic triggers. Atrial pacing combined with beta-blockade has been proposed for selected young high-risk patients (PMID: 27451284). Cochlear implantation is the standard hearing rehabilitation and yields auditory/language outcomes not worse than in non-syndromic sensorineural deafness, provided cardiac events are controlled and strict peri-operative precautions are used (beta-blockade, avoidance of sympathetic stimulation and QT-prolonging drugs, defibrillator standby, magnesium). Importantly, LQTS/JLNS syncope can be misdiagnosed as epilepsy, delaying correct therapy.

"Fatal Arrhythmias were encountered intra-operatively in five patients which was treated with cardiac pacing." — PMID: 31846911

"The auditory and language outcome after cochlear implantation in this syndrome is not worse than those in patients with non-syndromic sensorineural deafness." — PMID: 18805595

"Current treatment strategies include high doses of beta-blocker medication, left cardiac sympathetic denervation, and ICD placement, which is challenging in young children." — PMID: 27451284

Ontology anchors (NCIT): Beta-adrenergic blocker therapy (propranolol, nadolol); Implantable cardioverter-defibrillator; Left cardiac sympathetic denervation (sympathectomy); Cochlear implantation.

Finding 6 — Heterozygous carriers have milder LQT1; a common founder allele (R518X) exists

Heterozygous carriers of JLNS-causing KCNQ1 variants show a substantially milder phenotype than homozygous JLNS patients, illustrating a gene-dosage effect. In a genotype-stratified cohort, mean QTc was 551 ± 54 ms in JLNS homozygotes vs 441 ± 32 ms in heterozygous-JLNS carriers and 467 ± 36 ms in heterozygous non-JLNS carriers. The recessive JLNS phenotype (deafness + long QTc + ~47% cumulative aborted cardiac arrest) contrasts starkly with the benign dominant LQT1 phenotype of heterozygotes (QTc ~462 ms, ~1% arrest). The nonsense variant p.R518X (c.1552C>T) in KCNQ1 is a common founder allele that causes JLNS when biallelic and LQT1 when heterozygous; in Sweden it is an old founder mutation (~28 generations) with heterozygote prevalence ~1:2,000–4,000, clustering geographically. Consanguinity contributes to JLNS in inbred families.

"the mean QTc was 551 ± 54 ms for JLNS, 441 ± 32 ms for HTZ-JLNS, and 467 ± 36 ms for HTZ-Non-JLNS" — PMID: 38825991

"The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide." — PMID: 24552659

"Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%" — PMID: 24552659

Variant nomenclature: KCNQ1 p.Arg518* (R518X), c.1552C>T — nonsense (loss-of-function), Pathogenic. At least one highly inbred family displayed apparent pseudo-dominant transmission with a milder phenotype and hearing/QT severity correlating (PMID: 23668803).

Finding 7 — JLNS has an extra-cardiac gastrointestinal phenotype: hypochlorhydria, hypergastrinemia, and iron-deficiency anemia

In a Swedish cohort of 14 patients with biallelic KCNQ1 mutations, a history of iron-deficiency anemia was present in 12/14 and subjective GI symptoms in 13/14. Objective findings included elevated gastrin (7/9), elevated pepsinogen (6/7), elevated fecal calprotectin (9/9), and gastric mucosal hyperplasia/dysplasia (3/5 endoscoped). Elevated gastrin correlated significantly with iron deficiency/anemia (p = 0.039). KCNQ1 is essential for gastric acid secretion, recycling K⁺ across the parietal-cell apical membrane to supply the H⁺/K⁺-ATPase; its loss causes hypochlorhydria → impaired dietary iron absorption → iron-deficiency anemia, with compensatory hypergastrinemia that constitutes a potential long-term gastric-cancer risk factor.

"A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed." — PMID: 22805636

"We propose that the Jervell and Lange-Nielsen Syndrome phenotypically includes gastrointestinal symptoms/signs and secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations. The resultant elevated gastrin level is a potential risk factor for later gastrointestinal cancer." — PMID: 22805636

Ontology anchors: HP:0001891 (Iron deficiency anemia); HP:0011473 (Achlorhydria); HP:0003637 (Hypergastrinemia); UBERON:0000945 (stomach); CL:0000162 (parietal cell); GO:0030007 (intracellular potassium ion homeostasis); CHEBI:29103 (potassium ion). Body system: digestive/gastrointestinal (UBERON:0001007).

Finding 8 — I_Ks is a multi-subunit regulated complex; patient iPSC-cardiomyocytes recapitulate LQT1 and reveal therapeutic limits for null-I_Ks JLNS

The I_Ks channel complex is built from Kv7.1 (KCNQ1) co-assembled with the β-subunit KCNE1, plus accessory regulators PIP2, calmodulin, and yotiao (AKAP9). This regulatory flexibility lets one channel serve both cardiac repolarization and endolymph K⁺ maintenance. Patient-derived iPSC-cardiomyocytes from LQT1/KCNQ1 carriers reproduce the disease: markedly prolonged action-potential duration (APD) due to reduced KCNQ1-mediated I_Ks, with some mutations (e.g., R190Q, M437V) acting via dominant-negative trafficking defects. The NOS1AP modifier locus interacts with prolonged repolarization to modulate arrhythmia risk and penetrance. Critically, I_Ks-activator compounds shorten APD in LQT2 but not LQT1, because LQT1/JLNS I_Ks is intrinsically impaired — implying that channel-activator strategies have limited utility when I_Ks is biallelically null, as in JLNS1.

"The IKs channel complex is formed by the co-assembly of Kv7.1 (KCNQ1), a voltage-gated potassium channel, with its β-subunit, KCNE1 and the association of numerous accessory regulatory molecules such as PIP2, calmodulin, and yotiao." — PMID: 32581825

"The duration of the action potential was markedly prolonged in 'ventricular' and 'atrial' cells derived from patients with long-QT syndrome type 1, as compared with cells from control subjects." — PMID: 20660394

"DHA-gly shortened APD in vitro and QT interval ex vivo in WT and LQT2 rabbits, but not in LQT1" — PMID: 40794559

Additional supporting model data: iPSC-CM from an M437V KCNQ1 patient exhibited APD prolongation from reduced I_Ks (PMID: 31245483); human iPSC-CM engineered heart tissue has a low repolarization reserve making it a sensitive QT/arrhythmia test system (PMID: 29925535); NOS1AP minor alleles associate with NOS1 loss-of-function that aggravates the arrhythmia phenotype in prolonged-repolarization syndromes (PMID: 32061134).

Ontology anchors: GO:0086089 (voltage-gated potassium channel activity involved in cardiac repolarization); GO:1990573 (potassium ion import across plasma membrane); regulators AKAP9/yotiao, CALM1 (calmodulin); PIP2 (phosphatidylinositol 4,5-bisphosphate). Model: hiPSC-cardiomyocyte.

Finding 9 — KCNQ1 suppression-and-replacement (SupRep) gene therapy is a mutation-independent proof-of-concept for LQT1/JLNS1

A dual-component KCNQ1 "suppression-and-replacement" (SupRep) gene therapy achieves mutation-independent suppression of endogenous KCNQ1 (via shRNA) combined with delivery of an shRNA-immune replacement KCNQ1 cDNA. In TSA201 cells and LQT1 patient iPSC-cardiomyocytes, it corrected the prolonged action-potential/QT phenotype — the first proof-of-principle gene therapy for complete correction of long QT syndrome type 1. Because it is mutation-independent, a single construct could in principle treat any KCNQ1 genotype, including the biallelic null alleles of JLNS1 — an important conceptual advance, since channel-activator drugs cannot rescue a null channel.

"This study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome." — PMID: 33504163

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic loss-of-function mutation in KCNQ1 (e.g., R518X; homozygous/compound het)
│  leads to
▼
Absent or non-functional Kv7.1 α-subunit → failure to form functional KCNQ1/KCNE1 IKs channel
│  results in
▼
Loss of the slow delayed-rectifier K+ current (IKs) in multiple K+-transporting epithelia/myocytes
│
├──[CARDIAC BRANCH]──────────────────────────────────────────────┐
│  Loss of IKs removes repolarization reserve in ventricular      │
│  cardiomyocytes → prolonged action-potential duration →         │
│  QT prolongation (QTc ~557 ms). Under sympathetic activation    │
│  (emotion/exercise, ~95% of triggers), inadequate IKs upregulation
│  → early afterdepolarizations → torsades de pointes →           │
│  syncope / cardiac arrest / sudden death (>25%).                │
│                                                                 │
├──[COCHLEAR BRANCH]─────────────────────────────────────────────┤
│  Loss of apical KCNQ1/KCNE1 in strial marginal cells &          │
│  vestibular dark cells → failure of K+ secretion into endolymph │
│  → collapse of K+-rich endolymph & +80 mV endocochlear potential│
│  → loss of hair-cell mechanotransduction driving force →        │
│  (developmentally) strial atrophy, endolymphatic collapse,      │
│  organ of Corti degeneration → profound congenital deafness     │
│  (+ vestibular dysfunction).                                    │
│                                                                 │
└──[GASTRIC BRANCH]──────────────────────────────────────────────┘
   Loss of parietal-cell apical KCNQ1 K+ recycling → impaired
   H+/K+-ATPase-driven acid secretion → hypochlorhydria →
   (a) impaired iron absorption → iron-deficiency anemia
   (b) compensatory hypergastrinemia → gastric mucosal
       hyperplasia/dysplasia → potential long-term cancer risk.

The elegance of JLNS1's pathophysiology is that a single molecular lesion — loss of one K⁺ channel — produces a multi-organ syndrome because KCNQ1/KCNE1 performs the same biophysical job (K⁺ efflux/recycling) in three different epithelia. Upstream is the genetic lesion and channel loss; downstream are the tissue-specific consequences. The cardiac and cochlear arms are the classic defining dyad; the gastric arm is a more recently characterized, under-recognized systemic extension. The cardiac arm is specifically an adrenergic/gene–environment phenotype: I_Ks is the current the healthy heart recruits (via β-adrenergic/PKA signaling anchored by yotiao/AKAP9) to shorten repolarization during sympathetic drive; without it, sympathetic stress becomes dangerous, which is why ~95% of events are triggered by emotion or exercise.

Comparison of phenotypic arms

Tissue / cell type	Normal KCNQ1/KCNE1 role	Consequence of loss	Clinical manifestation
Ventricular cardiomyocyte	I_Ks repolarization reserve, esp. under β-adrenergic drive	Prolonged APD/QT, EADs	QTc ~557 ms, torsades, syncope, SCD
Strial marginal cell (UBERON:0002215) / vestibular dark cell	Apical K⁺ secretion into endolymph; EP maintenance	Endolymph K⁺ / EP collapse; strial atrophy	Profound congenital sensorineural deafness; vestibular dysfunction
Gastric parietal cell (CL:0000162)	Apical K⁺ recycling for H⁺/K⁺-ATPase	Hypochlorhydria; hypergastrinemia	Iron-deficiency anemia; gastric hyperplasia

Genotype–phenotype and dosage

Genotype	Representative QTc	Deafness	Cardiac-arrest risk
Biallelic KCNQ1 LOF (JLNS1)	~551–576 ms	Profound, congenital	~47% cumulative
Heterozygous JLNS-allele carrier	~441 ms	Normal hearing	~1%
Heterozygous non-JLNS LQT1 allele	~467 ms	Normal hearing	Low
Biallelic KCNE1 (JLNS2)	Prolonged	Present	More benign than JLNS1

Section-by-Section Reference Compilation

1. Disease Information

JLNS1 is an autosomal recessive cardio-auditory syndrome (deafness + long QT). Identifiers: MONDO:0024540; OMIM #220400; Orphanet ORPHA:90647; ICD-10 I45.81 (long QT syndrome); MeSH D029593 (Jervell-Lange Nielsen Syndrome). Synonyms: Jervell and Lange-Nielsen syndrome; cardioauditory syndrome of Jervell and Lange-Nielsen; surdo-cardiac syndrome; long QT syndrome with deafness. Information is derived predominantly from aggregated disease-level resources (international LQTS registries, OMIM, Orphanet) and case series rather than individual EHR.

2. Etiology

Primary cause is genetic — biallelic LOF mutations in KCNQ1 (JLNS1) or KCNE1 (JLNS2) (Findings 1, 6). No infectious or purely environmental cause. Genetic risk factors: the causal variants; founder alleles (R518X) and consanguinity increase incidence in specific populations. Modifiers: NOS1AP polymorphisms interact with prolonged repolarization to modulate arrhythmia penetrance (PMID: 32061134). Acquired arrhythmia multipliers (triggers, not disease cause): QT-prolonging drugs, sympathetic activation (emotion, exercise, sudden auditory stimuli), electrolyte disturbance. Protective factors: female sex confers lower cardiac risk; strict trigger avoidance and beta-blockade reduce events. Gene–environment interaction: the phenotype is fundamentally adrenergic — I_Ks loss becomes clinically dangerous under sympathetic stress (95% of events triggered by emotion/exercise).

3. Phenotypes

Core phenotypes: profound bilateral congenital sensorineural deafness (HP:0000407; essentially fully penetrant, congenital, stable, severe) and prolonged QT interval / torsades / syncope / sudden death (HP:0001657, HP:0004308, HP:0001279, HP:0001645; onset neonatal–early childhood, 50% symptomatic by age 3, severe, episodic-triggered). Extra-cardiac: iron-deficiency anemia (HP:0001891, ~85%), hypochlorhydria/hypergastrinemia, GI symptoms; vestibular dysfunction (delayed motor milestones from balance impairment). Quality-of-life impact is substantial: lifelong deafness plus activity restriction (avoidance of competitive sport/emotional stress), device dependence (ICD/cochlear implant), and the psychological burden of sudden-death risk.

4. Genetic / Molecular Information

Causal genes: KCNQ1 (11p15.5–15.4; OMIM 607542; HGNC:6294) — ~90%; KCNE1 (21q22.12; OMIM 176261; HGNC:6240) — JLNS2. Variant types: nonsense (e.g., R518X), missense, frameshift, splice-site — predominantly loss-of-function; JLNS requires biallelic hits. Functional consequence: loss of function / loss of I_Ks; some heterozygous LQT1 alleles act dominant-negative (trafficking defects, e.g., R190Q, M437V). Origin: germline. Allele frequency: individual pathogenic alleles are rare in gnomAD; founder alleles are regionally enriched. Modifier: NOS1AP. Epigenetic/chromosomal contributions: none established.

5. Environmental Information

No toxin, radiation, pollution, occupational, or infectious cause. Relevant acquired arrhythmia modifiers: QT-prolonging medications, hypokalemia/hypomagnesemia, sympathetic triggers. Lifestyle: avoidance of strenuous/competitive exercise and emotional stressors is recommended.

6. Mechanism / Pathophysiology

See the ordered causal chain and Mechanistic Model above (Findings 3, 4, 7, 8). Molecular pathway: β-adrenergic (PKA/cAMP) → yotiao/AKAP9-anchored phosphorylation normally augments I_Ks; channel loss removes this adaptive repolarization response. Cellular processes: ion transport, membrane repolarization, endolymph homeostasis, acid secretion. Protein dysfunction: loss/trafficking failure of Kv7.1. Cell types: ventricular cardiomyocytes, strial marginal cells, vestibular dark cells, gastric parietal cells.

7. Anatomical Structures Affected

Primary organs: heart (ventricular myocardium/conduction — UBERON:0000948, UBERON:0002349) and inner ear (cochlea/stria vascularis UBERON:0002227/0002215; vestibular labyrinth). Secondary: stomach (UBERON:0000945), hematologic system (secondary anemia), brain (secondary hypoxic-ischemic injury from arrests). Body systems: cardiovascular, nervous/sensory (auditory + vestibular), digestive. Subcellular: apical plasma membrane of epithelial cells (GO:0016324); cardiomyocyte sarcolemma. Lateralization: bilateral (hearing) and systemic (cardiac).

8. Temporal Development

Onset: deafness is congenital; cardiac events begin in infancy/early childhood (50% symptomatic by age 3; fetal/neonatal bradycardia can be a harbinger of malignant genotype). Course: deafness is stable/non-progressive; the cardiac phenotype is lifelong and episodic, with arrhythmic events triggered by adrenergic stress. Critical period: first year of life — syncope then is a strong predictor of subsequent cardiac arrest/sudden death. Untreated natural history carries very high early mortality.

9. Inheritance and Population

Autosomal recessive. Prevalence 1/1,000,000–1/200,000. Penetrance of deafness essentially complete in biallelic patients; cardiac severity variable/expressivity variable. Founder effects (R518X in Sweden, ~28 generations, carrier ~1:2,000–4,000) and consanguinity raise regional incidence. School-based ECG screening of deaf children found JLNS in ~0.9% (PMID: 34308870). Sex ratio ~equal for the syndrome, but females have lower cardiac-event risk.

10. Diagnostics

ECG (Bazett QTc; diagnostic >500 ms, often >550) with exercise stress testing; audiometry (profound bilateral SNHL). Genetic testing is confirmatory: single-gene KCNQ1/KCNE1 testing, LQTS/hearing-loss gene panels, or WES/WGS. Genetic testing is essential to distinguish true JLNS from the coincidental co-occurrence of independent deafness (e.g., PCDH15) and LQT genes (PMID: 41563185). Supportive: elevated gastrin/pepsinogen/calprotectin and iron studies for the GI arm. Differential diagnosis: Romano-Ward LQTS with unrelated deafness, Pendred syndrome (deafness+goiter), Usher/Waardenburg (deafness without LQT), other LQTS genotypes; seizure disorders (syncope misdiagnosed as epilepsy).

11. Outcome / Prognosis

Malignant without treatment: >25% sudden death; 86% cardiac-event rate; 29% cardiac arrest/SD even on beta-blockers. Prognostic factors: QTc >550 ms, syncope in first year, aborted arrest, male sex, high-risk genotype = worse; female sex, controlled triggers, LCSD/ICD = better. Deafness causes permanent disability mitigated by cochlear implantation. With comprehensive management (beta-blockers + LCSD/ICD + implant), survival and function improve substantially.

12. Treatment

Pharmacotherapy: beta-blockers (propranolol, nadolol) first-line (NCIT: beta-adrenergic blocker therapy); mexiletine adjunct in some LQTS. Device/interventional: ICD; left cardiac sympathetic denervation (thoracoscopic — 73% arrhythmia reduction in ventricular-arrhythmia cohorts, PMID: 24268954); atrial pacing + beta-blockade in selected young patients; catheter ablation of triggering PVCs in refractory storm (PMID: 33040543). Deafness: cochlear implantation. Supportive: iron supplementation for the anemia arm. Experimental/advanced: KCNQ1 SupRep gene therapy (mutation-independent proof-of-concept, PMID: 33504163); note I_Ks-activator drugs fail in LQT1/null-I_Ks (PMID: 40794559).

13. Prevention

No primary prevention of the genetic disease. Genetic counseling and carrier/cascade screening in affected families; prenatal/preimplantation testing feasible. Secondary prevention: ECG screening of congenitally deaf children detects unrecognized JLNS (PMID: 34308870). Tertiary prevention: trigger avoidance (QT-prolonging drugs, competitive sport, sudden loud stimuli), beta-blockade, device therapy, and peri-operative arrhythmia precautions during cochlear implantation.

14. Other Species / Natural Disease

Orthologous gene Kcnq1 in mouse (NCBI Gene 16535, NCBITaxon:10090) and rat. No prominent naturally-occurring companion-animal JLNS equivalent is established; the disease is studied primarily via engineered rodent models. The mechanism (KCNQ1-dependent endolymph K⁺ secretion and cardiac repolarization) is evolutionarily conserved across mammals.

15. Model Organisms

Mouse Kcnq1 knockout — the key model, reproducing deafness, circling/vestibular dysfunction, strial atrophy, and organ-of-Corti degeneration (Finding 4; PMID: 15891643); species differences in ventricular repolarization reserve limit full recapitulation of the human QT phenotype. Human iPSC-derived cardiomyocytes / engineered heart tissue from LQT1/KCNQ1 patients recapitulate APD/QT prolongation and serve as platforms for mechanism and therapy testing (Findings 8, 9; PMID: 20660394, PMID: 31245483, PMID: 29925535). Guinea-pig cardiomyocyte pharmacological LQT1 models are used for modifier (NOS1AP) studies (PMID: 32061134). Rabbit LQT1 models test I_Ks-activator pharmacology (PMID: 40794559).

Evidence Base

PMID	Role in this report	Evidence type
17646758	Natural history: 90.5% KCNQ1, QTc 557 ms, 86% events, partial beta-blocker efficacy, risk predictors	Human registry (186 pts)
32508908	Definition, AR inheritance, prevalence, QTc>500 ms	Human case + review
12097719	KCNQ1/KCNE1 K⁺ transport into endolymph by marginal/dark cells	Review/mechanism
20012478	KCNQ1/KCNE1 contributes to endocochlear potential	Mechanism
12031509	Full cochlear/vestibular K⁺ cycle; KCNQ1/KCNE1 apical secretory step	Review
15891643	Kcnq1 KO mouse recapitulates inner-ear pathology	Mouse model
22805636	GI phenotype: hypochlorhydria, hypergastrinemia, iron-deficiency anemia	Human cohort (14 pts)
24552659	R518X founder allele; severe recessive vs benign dominant phenotype	Human genealogy/genetics
38825991	Gene-dosage QTc stratification	Human cohort
31846911	Peri-operative arrhythmia risk in cochlear implantation	Human case series
18805595	Cochlear implant outcomes equal to non-syndromic deafness	Human review
27451284	Cardiac treatment options; atrial pacing + beta-blockade	Human
32581825	I_Ks complex composition (KCNQ1/KCNE1/PIP2/CaM/yotiao)	Review
20660394	Patient iPSC-CM recapitulate APD prolongation	In vitro
31245483	M437V KCNQ1 iPSC-CM: reduced I_Ks, prolonged APD	In vitro
29925535	hiPSC-CM engineered heart tissue as QT/arrhythmia test system	In vitro
40794559	I_Ks-activator fails in LQT1	Rabbit/in vitro
33504163	KCNQ1-SupRep gene therapy proof-of-concept	In vitro/iPSC-CM
32061134	NOS1AP modifier of arrhythmia penetrance	GP-CM/iPSC-CM
42466893	JLNS as high-risk genotype in paediatric LQTS registry	Human registry (371)
34308870	JLNS prevalence (~0.9%) in deaf-school ECG screening	Human screening
41563185	Genetic testing distinguishes true JLNS from coincidental deafness+LQT	Human case
24268954	Thoracoscopic LCSD reduces ventricular arrhythmia burden	Human series
33040543	Ablation of triggering PVC in JLNS arrhythmia storm	Human case
23668803	Inbred family; hearing/QT severity correlation; consanguinity	Human family study

Limitations and Knowledge Gaps

Rarity limits epidemiology. Prevalence estimates span a five-fold range (1/1,000,000–1/200,000); incidence and geographic/variant distribution data are sparse outside founder populations.
GI phenotype based on a single small cohort. The hypochlorhydria/anemia/hypergastrinemia arm rests largely on 14 Swedish patients (PMID: 22805636); the proposed long-term gastric-cancer risk is inferred, not demonstrated longitudinally.
Model species differences. Mice have different ventricular repolarization reserve, so the Kcnq1 KO reproduces deafness far better than the human QT/arrhythmia phenotype; iPSC-CMs model the cardiac arm but not the intact organ or the auditory/gastric arms.
Therapeutic gap for null I_Ks. Beta-blockers are only partially effective and I_Ks-activators cannot rescue biallelic-null channels; SupRep gene therapy remains pre-clinical (in vitro/iPSC-CM only), with no in vivo JLNS1 efficacy data.
Modifier landscape incomplete. Beyond NOS1AP, the genetic/environmental determinants of the wide cardiac-severity variability are not fully mapped.
Abstract availability. Several key papers (e.g., PMID 17646758, 38825991, 27451284, 33504163, 31846911) had limited/no abstract text available; claims rely on the verified snippets recorded during the investigation.

Proposed Follow-up Experiments / Actions

Advance KCNQ1-SupRep toward in vivo proof of concept in a humanized/biallelic-null JLNS1 model (AAV delivery to cardiomyocytes; evaluate QT correction and safety), given that activator drugs cannot rescue null I_Ks.
Longitudinal GI surveillance cohort to quantify hypochlorhydria, hypergastrinemia, iron-deficiency anemia frequency, and gastric-neoplasia risk across JLNS1 patients internationally; test iron/gastrin as biomarkers.
Multi-organ JLNS1 modeling — inner-ear-specific vs cardiac-specific conditional Kcnq1 knockouts, plus iPSC-derived otic and gastric organoids — to dissect tissue-specific consequences and test correction per arm.
Genotype–phenotype and modifier studies in an expanded JLNS registry to identify modifiers (beyond NOS1AP) explaining cardiac-severity variability and refine risk stratification.
Prospective ECG screening programs in congenitally deaf children (building on PMID: 34308870) to reduce first-event sudden death through early diagnosis and beta-blockade.
Peri-operative protocol standardization for cochlear implantation in LQTS/JLNS (beta-blockade, magnesium, defibrillator standby, pacing readiness), validated across centers.

Report compiled from an autonomous 5-iteration literature-based investigation. Evidence types are labeled human clinical, model organism, or in vitro throughout. All quoted snippets were verified against source abstracts where available.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	25
Resolved	25
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	20
Quoted claims found in source	20
Quoted claims not found in source	0
References weighed for topical relevance	25
On topic	16
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	35
Resolved	32
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	28
Terms named correctly	16
Terms named as a different term	7
Terms whose name is worth a second look	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0024540 (3 mentions) - the report calls it "if available"; MONDO calls it Jervell and Lange-Nielsen syndrome 1
UBERON:0002215 (2 mentions) - the report calls it "stria vascularis", "Strial marginal cell"; UBERON calls it synchondrosis
UBERON:0007499 (1 mention) - the report calls it "endolymph"; UBERON calls it epithelial sac
CL:0000710 (1 mention) - the report calls it "marginal cell of stria vascularis"; CL calls it neurecto-epithelial cell
UBERON:0002228 (1 mention) - the report calls it "spiral ganglion"; UBERON calls it rib
HP:0011473 (1 mention) - the report calls it "Achlorhydria"; HP calls it Villous atrophy
HP:0003637 (1 mention) - the report calls it "Hypergastrinemia"; HP calls it Reduced circulating 4-Hydroxyphenylpyruvate dioxygenase activity

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CHEBI:29103 (2 mentions) - the report calls it "potassium ion, K⁺", "potassium ion"; CHEBI calls it potassium(1+), and lists "POTASSIUM ION" among its other names
HP:0004308 (2 mentions) - the report calls it "Ventricular arrhythmia / torsade de pointes"; HP calls it Ventricular arrhythmia, and lists "Ventricular arrhythmias" among its other names
UBERON:0002227 (2 mentions) - the report calls it "cochlea"; UBERON calls it spiral organ of cochlea, and lists "cochlear spiral organ" among its other names
UBERON:0002365 (1 mention) - the report calls it "organ of Corti"; UBERON calls it exocrine gland, and lists "glandula exocrina" among its other names
GO:0086089 (1 mention) - the report calls it "voltage-gated potassium channel activity involved in cardiac repolarization"; GO calls it voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization, and lists "voltage-gated potassium channel activity involved in atrial cardiomyocyte action potential repolarization" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CHEBI:29103 - called "potassium ion, K⁺", "potassium ion"
UBERON:0002215 - called "stria vascularis", "Strial marginal cell"
CL:0000162 - called "parietal cell", "Gastric parietal cell"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

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Prevalence

Clinical Burden

Clinical Trials

Experimental Models

Animal Models

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References & Deep Research

References

Deep Research

Jervell and Lange-Nielsen Syndrome 1: Disease Characteristics Report

Scope and evidence conventions

1. Disease information

Definition

Identifiers and synonyms

2. Etiology

Causal factors and genetic risk

Modifiers and protective factors

Gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Gene and protein

Functional consequences

5. Environmental information

6. Mechanism and pathophysiology

Cardiac causal chain

Auditory/vestibular causal chain

Other molecular profiling

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Epidemiology

Recurrence and penetrance

10. Diagnostics

Clinical and functional evaluation

Genetic testing

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment

Standard strategy

Experimental therapy and trials

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Mouse

Heterologous cellular models

Human iPSC models

Recent developments and expert assessment

Overall expert interpretation

Evidence gaps

Artifacts

Reference Validation

Jervell and Lange-Nielsen Syndrome Type 1 (JLNS1): A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — JLNS1 is an autosomal recessive channelopathy caused by biallelic KCNQ1 mutations (~90% of cases)

Finding 2 — JLNS is a severe, early-onset LQTS variant with a high cardiac-event rate and only partial beta-blocker efficacy

Finding 3 — Mechanism: loss of KCNQ1/KCNE1 IKs abolishes marginal-cell K⁺ secretion into endolymph, causing deafness

Finding 4 — The Kcnq1 knockout mouse recapitulates JLNS inner-ear pathology

Finding 5 — Management combines cardiac risk reduction with cochlear implantation

Finding 6 — Heterozygous carriers have milder LQT1; a common founder allele (R518X) exists

Finding 7 — JLNS has an extra-cardiac gastrointestinal phenotype: hypochlorhydria, hypergastrinemia, and iron-deficiency anemia

Finding 8 — IKs is a multi-subunit regulated complex; patient iPSC-cardiomyocytes recapitulate LQT1 and reveal therapeutic limits for null-IKs JLNS

Finding 9 — KCNQ1 suppression-and-replacement (SupRep) gene therapy is a mutation-independent proof-of-concept for LQT1/JLNS1

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Comparison of phenotypic arms

Finding 3 — Mechanism: loss of KCNQ1/KCNE1 I_Ks abolishes marginal-cell K⁺ secretion into endolymph, causing deafness

Finding 8 — I_Ks is a multi-subunit regulated complex; patient iPSC-cardiomyocytes recapitulate LQT1 and reveal therapeutic limits for null-I_Ks JLNS