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Classifications

Harrison's Part

Channelopathy

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Mappings

MONDO

MONDO:0012871 Jervell and Lange-Nielsen syndrome 2

MONDO:0012871 is the primary disease term for this entry, cross-referenced to OMIM:612347, with KCNE1 (HGNC:6240) asserted as the causal gene via RO:0004003.

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Inheritance

1

Autosomal Recessive HP:0000007

JLNS2 is inherited in an autosomal recessive manner. Affected individuals are homozygous or compound heterozygous for KCNE1 loss-of-function variants; parents are typically heterozygous carriers who are usually clinically unaffected or show only mild, incompletely penetrant QT prolongation (the allelic dominant LQT5 phenotype). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic or mildly affected carrier, and a 25% chance of being unaffected and non-carrier.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:20301579 SUPPORT Other

"JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS are usually heterozygotes; rarely, only one parent is heterozygous"

GeneReviews establishes the autosomal recessive inheritance pattern and typical carrier status of parents.

PMID:30461122 SUPPORT Human Clinical

"heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2"

Documents that biallelic KCNE1 loss of function, not heterozygosity, is required for the fully penetrant JLNS2 phenotype.

PMID:20301579 SUPPORT Other

"At conception, each sib of an affected individual usually has a 25% chance of being affected with JLNS, a 50% chance of being a carrier of a JLNS-causing pathogenic variant and potentially at risk for LQTS, and a 25% chance of being unaffected and not a carrier."

GeneReviews states the exact per-pregnancy recurrence-risk figures (25% affected, 50% carrier, 25% unaffected non-carrier) summarized in this node's description.

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Mechanistic Hypotheses

1

Variant-specific dominant-negative versus simple loss-of-function/haploinsufficiency KCNE1 mechanism

variant_specific_dominant_negative_vs_haploinsufficiency EMERGING

Evidence balance 2 support

KCNE1 loss-of-function variants appear to split mechanistically by variant. A large 2025 functional screen found no apparent dominant-negative effect on wild-type IKs current among the KCNE1 variants it tested when coexpressed with wild-type KCNE1, consistent with a simple recessive loss-of-function/haploinsufficiency mechanism requiring biallelic loss for JLNS2. However, an independent study of KCNE1 nonsense and missense alleles reports that coassembly of certain other mutant KCNE1 monomers with wild-type KCNQ1 subunits produces dominant Romano-Ward syndrome via a dominant-negative mechanism. Whether these are truly non-overlapping variant classes, or whether the discrepancy partly reflects differences in the specific variants and assay conditions tested, is not yet resolved.

Show evidence (2 references)

PMID:41200805 SUPPORT In Vitro

"We observed no apparent dominant-negative effects when variant and wild-type KCNE1 were coexpressed."

Direct functional data supporting a simple loss-of-function/ haploinsufficiency mechanism for the specific KCNE1 variant panel tested.

PMID:30461122 SUPPORT Human Clinical

"Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism."

Independent evidence that at least some KCNE1 missense variants act dominantly through a dominant-negative mechanism, the counterpoint this hypothesis has to reconcile with the functional screen's negative finding.

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Discussions and Knowledge Gaps

2

Does a patient-derived or genome-edited human cellular model carrying biallelic KCNE1 variants exist for either the cardiac or the cochlear branch of JLNS2?

KNOWLEDGE GAP OPEN jlns2_no_kcne1_specific_human_cellular_model

Attached to

pathophysiology#Loss of IKs Current in Cardiac Myocytes pathophysiology#Endocochlear Potential Collapse and Hair Cell Degeneration

The flagship human cellular model of JLNS is a hiPSC-derived cardiomyocyte series that reproduces the severe features of the disease, but its two variants are both in KCNQ1, so it models JLNS1. On the cochlear side a review of JLNS experimental models states that JLNS-specific iPSC-derived inner hair cell models are lacking altogether. The consequence is that every human cellular claim about JLNS2 in this entry is either heterologous (the CHO-K1 voltage-clamp platform under experimental_models, which measures channel current but contains neither a cardiomyocyte action potential nor a stria vascularis) or is transferred from KCNQ1 disease. This matters more than the usual model gap because the two genotypes are not clinically interchangeable: the JLNS2 cardiac course appears milder, so a KCNQ1 model may overstate the severity of the cardiac branch it is being read across to.

Proposed experiments

KCNE1-biallelic hiPSC cardiomyocyte and stria vascularis marginal-cell models

exp_jlns2_kcne1_ipsc_cardiomyocyte_and_strial_models

Reprogram cells from a genotype-confirmed JLNS2 patient, or introduce a reported biallelic KCNE1 null allele into a control hiPSC line by genome editing, then run two arms. Cardiac arm: differentiate to cardiomyocytes and compare IKs density, action potential duration and adrenergic response against the existing KCNQ1 JLNS1 lines in parallel, so the KCNE1-versus-KCNQ1 severity difference seen clinically is tested rather than inferred. Cochlear arm: differentiate to stria vascularis marginal cells, or an equivalent cochlear potassium-secreting epithelium, and measure apical potassium secretion and transepithelial potential. The cochlear arm deliberately targets the strial epithelium rather than the inner hair cell, because the primary JLNS2 cochlear lesion is a marginal-cell ionic defect and hair cell degeneration is downstream of endocochlear potential collapse, so a hair-cell model would not test the initiating step. Published differentiation protocols exist for inner hair cells but not for this cell type, which is itself part of the gap.

Would support

pathophysiology#Loss of IKs Current in Cardiac Myocytes pathophysiology#Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells

Would refute

pathophysiology#Loss of IKs Current in Cardiac Myocytes pathophysiology#Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells

Supporting outcome

KCNE1-biallelic cardiomyocytes show reduced IKs and prolonged action potential duration relative to isogenic controls, with a smaller effect size than the KCNQ1 lines, matching the milder clinical course reported for JLNS2.
KCNE1-biallelic strial marginal cells show reduced apical potassium secretion and a reduced transepithelial potential relative to isogenic controls.

Refuting outcome

KCNE1-biallelic cardiomyocytes show IKs density and action potential duration indistinguishable from isogenic controls, which would place the cardiac branch of this entry's mechanism in question for this genotype.
KCNE1-biallelic strial marginal cells secrete potassium and sustain a transepithelial potential indistinguishable from isogenic controls, which would place the cochlear branch in question for this genotype.

Show evidence (3 references)

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, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1."

Establishes that both variants in the landmark JLNS hiPSC model are KCNQ1, so the platform models JLNS1 and not the KCNE1 disease curated here.

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"

Shows the platform does successfully recapitulate JLNS features, which is why its restriction to KCNQ1 is a gap worth recording rather than a dead end.

PMID:42389506 SUPPORT Other

"Although JLNS‐specific iPS‐IHC models are lacking, existing protocols enable the replication of JLNS genotypes and mechanotransduction studies."

A review of JLNS experimental models stating that JLNS-specific iPSC-derived inner hair cell models do not exist. This is the closest published statement to the cochlear half of this gap; note it concerns hair cells, whereas the initiating JLNS2 cochlear lesion is in the stria vascularis marginal cell, for which the review describes no model either.

Do genotype-confirmed human JLNS2 (biallelic KCNE1) patients have clinically significant vestibular dysfunction, as Kcne1-/- mice do?

HUMAN MODEL MISMATCH OPEN jlns2_vestibular_human_model_mismatch

Attached to

pathophysiology#Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells

Kcne1-/- mice show clear structural and functional vestibular involvement: KCNQ1/KCNE1 channels are expressed in vestibular dark cells as well as strial marginal cells, and untreated Kcne1-/- mice show abnormal endolymphatic-space development, vestibular hair cell degeneration, and impaired vestibular behavior that gene therapy can rescue (PMID:33514733). However, the only quantitative human vestibular study of JLNS (PMID:25471708) genotyped its cohort and found all 14 tested cases carried double KCNQ1 (JLNS1) mutations, not KCNE1. Whether the mouse vestibular phenotype translates to genotype-confirmed human JLNS2 patients is therefore untested, and this entry deliberately does not curate vestibular dysfunction as an established JLNS2 phenotype.

Proposed experiments

Genotype-stratified human vestibular function study in JLNS2

exp_jlns2_genotype_stratified_vestibular_function

Vestibular function testing (post-rotatory nystagmus, video head impulse testing) in a cohort of genotype-confirmed KCNE1/JLNS2 patients, analogous to the KCNQ1-genotyped study already published for JLNS1 (PMID:25471708).

Show evidence (1 reference)

PMID:33514733 SUPPORT Model Organism

"Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction."

Source of the mouse-model vestibular-dysfunction claim that motivates this discussion.

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Pathophysiology

7

Biallelic KCNE1 Loss of Function

Biallelic loss-of-function variants in KCNE1 abolish or severely reduce the regulatory (beta-subunit) contribution of MinK to the IKs channel complex. Because KCNE1 must coassemble with KCNQ1 to generate a normal IKs current, homozygous or compound heterozygous KCNE1 variants produce the same downstream functional deficit as biallelic KCNQ1 loss (JLNS1), even though the two genes encode structurally distinct subunits of the same channel. High-throughput voltage-clamp profiling shows that most disease-associated KCNE1 variants reduce IKs current density in the homozygous state without dominant-negative behavior on coexpressed wild-type subunits, consistent with a recessive disease mechanism.

KCNE1 hgnc:6240

potassium ion transmembrane transport GO:0071805 ↓ DECREASED

ion channel regulator activity GO:0099106 ↓ DECREASED

Experimental models

CHO-K1 heterologous KCNQ1/KCNE1 expression with automated voltage clamp CELL LINE Expressing a KCNE1 variant in the homozygous state alongside KCNQ1 reproduces the molecular configuration of a JLNS2 genotype and measures the resulting IKs current directly, which is the node's claim.

Downstream

Loss of IKs Current in Cardiac Myocytes IKs generated by the KCNQ1/KCNE1 complex is a major repolarizing current in cardiac myocytes; loss of KCNE1 function reduces this current in the heart.

Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells The same KCNQ1/KCNE1 IKs channel complex is expressed on the apical membrane of marginal cells of the stria vascularis, where it drives potassium secretion into the endolymph; loss of KCNE1 function reduces this current in the inner ear.

Show evidence (2 references)

PMID:42389506 SUPPORT Other

"KCNE1 specifically encodes the beta subunit (mink) of IKs"

Establishes KCNE1/MinK as the regulatory beta subunit whose biallelic loss is the molecular trigger of JLNS2.

PMID:41200805 SUPPORT In Vitro

"Approximately half (47 of 95) of the KCNE1 variants tested in the homozygous state exhibited peak current densities significantly different from WT IKs."

Direct high-throughput functional data quantifying the frequency and magnitude of IKs current disruption caused by KCNE1 variants in the homozygous state.

Loss of IKs Current in Cardiac Myocytes

Reduced IKs current diminishes repolarization reserve and delays completion of the ventricular action potential, prolonging the QT interval measured on the surface ECG.

cardiomyocyte CL:0000746

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

monoatomic ion channel activity GO:0005216 ⚠ ABNORMAL

heart UBERON:0000948

Downstream

Arrhythmogenic Substrate and Ventricular Tachyarrhythmia Markedly prolonged repolarization creates a substrate for triggered activity and re-entrant ventricular tachyarrhythmia, including torsade de pointes and ventricular fibrillation.

Show evidence (3 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."

GeneReviews documents the marked QTc prolongation that results from reduced ventricular repolarization reserve in JLNS.

PMID:33963564 SUPPORT In Vitro

"IKs functions as a 'repolarization reserve' in the heart by providing extra current for ventricular action potential shortening during β-adrenergic stimulation."

Defines the repolarization-reserve role this node's description asserts, and specifies that the reserve is called on during beta-adrenergic stimulation - which is why the adrenergic exposures in environmental precipitate events in a heart that has lost IKs.

PMID:33963564 SUPPORT In Vitro

"in cardiomyocytes, KCNQ1 and KCNE1 traffic by different routes to surface sarcolemma where they assemble into IKs channels. This mode of delayed channel assembly helps IKs fulfil its function of repolarization reserve."

Shows KCNQ1 and KCNE1 assemble into the IKs channel at the cardiomyocyte surface sarcolemma, the step that biallelic KCNE1 loss removes upstream of this node.

Arrhythmogenic Substrate and Ventricular Tachyarrhythmia

Prolonged, heterogeneous ventricular repolarization predisposes to early afterdepolarizations and re-entrant torsade de pointes, which can degenerate into sustained ventricular tachycardia or ventricular fibrillation. Available comparative data suggest that this arrhythmic risk is present but lower in genotype-confirmed JLNS2 (biallelic KCNE1) than in JLNS1 (biallelic KCNQ1).

heart UBERON:0000948

Downstream

Syncope and Sudden Cardiac Death Sustained ventricular tachyarrhythmia can cause hemodynamic collapse, manifesting as syncope, and can be fatal if not promptly terminated.

Show evidence (2 references)

PMID:42389506 SUPPORT Human Clinical

"Children carrying KCNQ1 variants exhibit an approximately sixfold higher risk of ventricular arrhythmia than those with KCNE1 variants."

Directly quantifies the reduced (but nonzero) ventricular arrhythmia risk specific to KCNE1 (JLNS2) relative to KCNQ1 (JLNS1) genotypes, supporting the entry's emphasis on JLNS2-specific severity data rather than JLNS1 figures.

PMID:31941373 SUPPORT Human Clinical

"Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5%"

Directly quantifies the definite arrhythmic event rate (10.5%, 2 of 19 genotype-confirmed patients) in the largest reported JLNS2 cohort, providing a JLNS2-specific severity estimate rather than an imported JLNS1 figure.

Syncope and Sudden Cardiac Death

The clinical endpoint of the cardiac branch of JLNS2: exertion-, emotion-, or auditory-stimulus-triggered syncope, and a risk of sudden cardiac death from malignant ventricular arrhythmia, most pronounced in early childhood.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. Fifty percent of individuals with JLNS had cardiac events before age three years."

GeneReviews describes the classic clinical presentation and early childhood timing of cardiac events in JLNS overall.

Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells

KCNQ1/KCNE1 IKs channels on the apical membrane of stria vascularis marginal cells drive the transepithelial potassium flux that generates and maintains the endocochlear potential, the unusually positive extracellular potential in the endolymph that provides the electrochemical driving force for hair-cell mechanotransduction. Loss of KCNE1 function collapses this potassium-secretory current, disrupting cochlear ionic homeostasis.

strial marginal cell CL:0002492

potassium ion transmembrane transport GO:0071805 ↓ DECREASED

stria vascularis of cochlear duct UBERON:0002282 cochlea UBERON:0001844

Animal models

Kcne1 knockout mouse Mouse recapitulates Kcne1-/- mice lack Kcne1 expression in strial marginal cells and vestibular dark cells, the same cell types that express the KCNQ1/KCNE1 complex in humans, and show abnormal endolymphatic-space development.

Downstream

Endocochlear Potential Collapse and Hair Cell Degeneration Loss of strial potassium secretion collapses the endocochlear potential and the driving force for hair-cell mechanotransduction.

Show evidence (2 references)

PMID:33514733 SUPPORT Model Organism

"In the inner ear, KCNQ1/KCNE1 potassium channels are expressed exclusively in the apical membrane of marginal cells (MCs) in the stria vascularis (SV) and in vestibular dark cells"

Confirms the strial marginal cell localization of the KCNQ1/KCNE1 channel complex central to this node.

PMID:42389506 SUPPORT Other

"The K+ concentration is markedly increased in the endolymph, and the influx of K+ into hair cells upon stimulation plays a pivotal role in transducing sound into neural signals."

Establishes the mechanistic link between strial potassium secretion, the endolymph's high K+ concentration, and hair-cell mechanotransduction.

Endocochlear Potential Collapse and Hair Cell Degeneration

Without the endocochlear potential, hair-cell mechanotransduction fails and cochlear hair cells undergo degeneration. Because mammalian cochlear hair cells do not regenerate, this loss is irreversible.

cochlea UBERON:0001844

Downstream

Congenital Profound Bilateral Sensorineural Hearing Loss Irreversible hair-cell loss and collapse of the endocochlear potential produce permanent, congenital sensorineural hearing loss.

Show evidence (1 reference)

PMID:33514733 SUPPORT Model Organism

"Results showed early treatment prevented collapse of the Reissner's membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells."

Demonstrates, by rescue, that untreated Kcne1 loss causes structural collapse of the cochlear duct and degeneration of inner ear cells.

Congenital Profound Bilateral Sensorineural Hearing Loss

The clinical endpoint of the cochlear branch of JLNS2: congenital, profound, bilateral sensorineural hearing loss present from birth. Unlike several other conformers of this module (e.g., noise- or age-related hearing loss), the JLNS deficit is typically already maximal at birth rather than accruing progressively over time; conformance here reflects the shared irreversible, non-regenerating hair-cell-loss endpoint rather than a claim of ongoing postnatal worsening.

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 the congenital, profound, bilateral character of the hearing loss.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Blood 1

Iron-Deficiency Anemia HP:0001891

frequency is deliberately omitted. GeneReviews calls this a "frequent" feature but gives no percentage and no denominator, and the statement is about JLNS as a whole rather than about KCNE1-genotyped patients, so assigning the 30-79% FREQUENT band would be a guess on two counts.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

GeneReviews lists iron-deficient anemia among the frequent additional features of JLNS.

Cardiovascular 6

Prolonged QT Interval VERY_FREQUENT HP:0001657

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 establishes marked QTc prolongation as a defining feature of JLNS.

Ventricular Arrhythmia Ventricular tachycardia HP:0004756

Show evidence (2 references)

PMID:31941373 SUPPORT Human Clinical

"Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5%"

Direct quantitative arrhythmic event rate in the largest reported genotype-confirmed JLNS2 cohort.

PMID:42389506 SUPPORT Human Clinical

"Children carrying KCNQ1 variants exhibit an approximately sixfold higher risk of ventricular arrhythmia than those with KCNE1 variants."

Quantifies the reduced, but nonzero, ventricular arrhythmia risk associated specifically with KCNE1 (JLNS2) genotypes relative to KCNQ1 (JLNS1).

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 in JLNS.

Syncope HP:0001279

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

GeneReviews describes the classic exertion/emotion-triggered syncopal presentation of JLNS.

Bradycardia HP:0001662

Reported for JLNS as a whole; no KCNE1-genotyped series has separately quantified bradycardia in JLNS2.

Show evidence (1 reference)

PMID:42389506 SUPPORT Other

"Children diagnosed with JLNS typically exhibit bradycardia beginning in the fetal stage"

Reports fetal-onset bradycardia as a typical finding in children diagnosed with JLNS.

T-Wave Alternans HP:0012266

Mechanistically continuous with the loss of repolarization reserve modeled in the pathophysiology chain, but curated as an observed ECG phenotype rather than as a separate mechanism node. Reported for JLNS as a whole.

Show evidence (1 reference)

PMID:42389506 SUPPORT Human Clinical

"commonly present to the cardiology department with symptoms due to prolonged QT intervals and T‐wave alternans"

Names T-wave alternans, together with QT prolongation, as the electrocardiographic presentation that brings JLNS patients to cardiology.

Ear 1

Congenital Profound Bilateral Sensorineural Hearing Loss VERY_FREQUENT Congenital sensorineural hearing impairment HP:0008527

The band is VERY_FREQUENT (80-99%) rather than OBLIGATE (100%), and the distinction is in the qualifier rather than in the feature. Congenital sensorineural deafness itself is definitional: GeneReviews characterises JLNS by it and the diagnosis requires it, so hearing loss as such would justify OBLIGATE. What this phenotype asserts is the *profound* bilateral form named in its title, and severity is not uniform across reported patients, so the lower band avoids over-claiming on a qualifier the sources do not quantify. Splitting the difference the other way - OBLIGATE on a profundity claim - would assert more than GeneReviews supports. This is still a different kind of claim from the undenominated "frequent" that was rejected as a frequency source for the iron-deficiency anemia and hypergastrinemia phenotypes: those have no numerator, no denominator and no definitional standing, whereas this one is bounded below by a diagnostic criterion.

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 establishes congenital profound bilateral sensorineural hearing loss as a defining feature of JLNS.

Endocrine 1

Elevated Serum Gastrin Hypergastrinemia HP:0500167

frequency is deliberately omitted, for the same reason as the iron-deficiency anemia phenotype: GeneReviews' "frequent" is qualitative, undenominated, and stated for JLNS as a whole rather than for KCNE1-genotyped patients.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

GeneReviews lists elevated gastrin as a frequent additional feature of JLNS.

Nervous System 1

Gross Motor Developmental Delay Delayed gross motor development HP:0002194

Reported for JLNS as a whole and only in a subset of patients; frequency is deliberately omitted because the source says only "some patients". No KCNE1-genotyped data on motor development were identified.

Show evidence (1 reference)

PMID:42389506 SUPPORT Human Clinical

"some patients display gastrointestinal symptoms, secondary hypochromic anemia, and gross motor developmental delay"

Lists gross motor developmental delay among the features displayed by a subset of JLNS patients.

Constitutional 1

Sudden Cardiac Death Risk Sudden death HP:0001699

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

GeneReviews establishes the high untreated mortality of JLNS overall.

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Genetic Associations

1

KCNE1

Gene: KCNE1 hgnc:6240 gene page relationship_type: CAUSATIVE

Show evidence (4 references)

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 establishes KCNE1 as one of the two genes in which biallelic pathogenic variants cause JLNS.

PMID:41200805 SUPPORT In Vitro

"KCNE1 is a recognized cause of the autosomal recessive Jervell and Lange-Nielson syndrome type 2 (JLN2)."

Confirms KCNE1 as the accepted causal gene for the recessive JLNS2 phenotype curated in this entry.

PMID:41200805 SUPPORT In Vitro

"Most dysfunctional variants exhibited loss-of-function properties. We observed no apparent dominant-negative effects when variant and wild-type KCNE1 were coexpressed."

Direct functional electrophysiology showing loss-of-function as the predominant mechanism of disease-associated KCNE1 variants, without dominant-negative behavior, consistent with a recessive disease mechanism.

+ 1 more reference

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Medical Actions

9

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 for JLNS, though reported to be only partially effective; arrhythmia persists in a substantial proportion of patients despite beta-blocker treatment.

Mechanism Target:

INHIBITS Arrhythmogenic Substrate and Ventricular Tachyarrhythmia — Anti-adrenergic therapy reduces the likelihood that exertion- or emotion-related sympathetic triggers will precipitate malignant ventricular arrhythmia.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

GeneReviews recommends beta-blockers as first-line therapy while explicitly noting only partial effectiveness in JLNS.

Show evidence (2 references)

PMID:42389506 SUPPORT Human Clinical

"The efficacy of beta‐blockers and left cardiac sympathetic denervation is limited in patients with JLNS, as arrhythmia persists in 51%–85% of cases despite beta‐blocker treatment"

Quantifies the limited efficacy of beta-blocker therapy in JLNS, motivating escalation to device therapy in many patients.

PMID:20301579 SUPPORT Other

"Beta-blocker dose should be regularly assessed for efficacy and adverse effects, with evaluation every three to six months during rapid growth phases"

GeneReviews surveillance guidance: beta-blocker dosing requires periodic reassessment, especially during rapid childhood growth phases, because weight-based dosing can fall out of therapeutic range.

Implantable Cardioverter-Defibrillator Placement

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

Platform: Device

Device therapy for patients with a history of cardiac arrest, malignant events despite beta-blocker therapy, or otherwise judged high risk.

Show evidence (3 references)

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 recommends ICD placement for high-risk or treatment-refractory JLNS patients.

PMID:20301579 SUPPORT Other

"periodic evaluations of ICDs for inappropriate shocks and pocket or lead complications"

GeneReviews surveillance guidance: implanted devices require periodic evaluation for inappropriate shocks and pocket/lead complications.

PMID:16911578 SUPPORT Human Clinical

"Among JLNS patients treated with beta-blockers, the cumulative probability of LQTS-related death was 35%; defibrillator therapy was associated with a 0% mortality rate during a mean (+/-SD) follow-up period of 4.9 +/- 3.4 years."

Quantifies the outcome difference between beta-blocker therapy alone and defibrillator therapy in this non-randomised JLNS registry cohort. The authors' own conclusion is correspondingly hedged - defibrillator therapy "appears to improve outcome", with longer follow-up needed.

Left Cardiac Sympathetic Denervation

Action: left cardiac sympathetic denervation Ontology label: Ganglionectomy NCIT:C51931

Platform: Surgery

Surgical anti-adrenergic escalation considered when arrhythmia persists despite beta-blocker therapy or when device therapy is unsuitable; a review of JLNS management describes beta-blocker and left cardiac sympathetic denervation efficacy as both limited, since arrhythmia persists in 51-85% of cases despite beta-blocker treatment.

Mechanism Target:

INHIBITS Arrhythmogenic Substrate and Ventricular Tachyarrhythmia — Left cardiac sympathetic denervation reduces arrhythmia-provoking sympathetic input when pharmacologic anti-adrenergic therapy (beta blockade) is insufficient.

Show evidence (1 reference)

PMID:42389506 SUPPORT Human Clinical

"The efficacy of beta‐blockers and left cardiac sympathetic denervation is limited in patients with JLNS, as arrhythmia persists in 51%–85% of cases despite beta‐blocker treatment"

States that left cardiac sympathetic denervation is used alongside beta-blockade in JLNS management, though the same review notes both interventions have limited efficacy against persistent arrhythmia.

Show evidence (1 reference)

PMID:42389506 SUPPORT Human Clinical

"left cervical sympathectomy is planned if malignant ventricular arrhythmias recur"

Documents left cardiac sympathetic denervation (cervical sympathectomy) as the planned escalation step in JLNS patients with recurrent malignant ventricular arrhythmia.

Catheter Ablation of Triggering Ectopy

Action: cardiac radiofrequency ablation Ontology label: Cardiac Radiofrequency Ablation NCIT:C170884

Platform: Surgery

Radiofrequency catheter ablation of the premature ventricular contraction that triggers arrhythmia storm has been reported as an effective alternative or adjunct to device therapy in an individual genotype-confirmed KCNE1 (JLNS2) patient who could not undergo ICD implantation.

Show evidence (1 reference)

PMID:33040543 SUPPORT Human Clinical

"Ablation was successfully performed to eliminate the triggering PVC... During the 12-month follow-up, no syncope or fatal arrhythmia was found in this patient."

Direct clinical case report of successful radiofrequency ablation controlling fatal arrhythmia in a genotype-confirmed KCNE1 patient.

Cochlear Implantation

Category: Therapeutic Action: cochlear implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgical cochlear implantation to treat the congenital profound sensorineural hearing loss of JLNS.

Target Phenotypes: Congenital sensorineural hearing impairment HP:0008527

Show evidence (3 references)

PMID:20301579 SUPPORT Other

"Cochlear implantation to treat hearing loss"

GeneReviews lists cochlear implantation as standard management of hearing loss in JLNS.

PMID:31846911 SUPPORT Human Clinical

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

Documents fatal intraoperative arrhythmia during cochlear implantation in a long-QT cohort, establishing the perioperative hazard as observed rather than theoretical.

PMID:31846911 SUPPORT Human Clinical

"Preoperative prophylactic Beta blockers, avoiding sympathetic stimulation and drugs prolonging QT interval with rational use of Magnesium Sulphate and standby of defibrillator were the standard precautions practised."

Sets out the specific perioperative precaution protocol used in that cohort, which is the actionable content of this caution.

Avoidance of QT-Prolonging Drugs and Arrhythmia Triggers

Category: Counseling / Informational Action: risk factor avoidance counseling Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Avoidance of drugs that further prolong the QT interval and of activities or circumstances known to precipitate syncopal events, plus special anesthetic precautions given the increased risk of arrhythmia during anesthesia.

Show evidence (2 references)

PMID:20301579 SUPPORT Other

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

GeneReviews specifies the agents and circumstances to avoid in JLNS management.

PMID:20301579 SUPPORT Other

"Training for family members in cardiopulmonary resuscitation; use of an ID bracelet explaining the diagnosis; notifying local emergency medical services of high-risk persons with JLNS."

GeneReviews recommends family CPR training and emergency-preparedness measures as part of routine JLNS risk-factor avoidance and emergency planning.

Genetic Counseling

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Autosomal recessive genetic counseling for families, including the 25% per-pregnancy recurrence risk for carrier couples, evaluation of at-risk relatives by newborn hearing screening and ECG, and consideration of whether a mother carrying an affected fetus herself has long QT syndrome.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

"At conception, each sib of an affected individual usually has a 25% chance of being affected with JLNS, a 50% chance of being a carrier of a JLNS-causing pathogenic variant and potentially at risk for LQTS, and a 25% chance of being unaffected and not a carrier."

GeneReviews specifies the recurrence-risk figures used in genetic counseling for JLNS families.

Iron Repletion for Iron-Deficiency Anemia

Action: iron repletion pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: iron CHEBI:18248

Platform: Small molecule

Standard iron-deficiency treatment for the iron-deficient, hypochromic anemia that is a frequent non-cardioauditory feature of JLNS. GeneReviews specifies standard rather than JLNS-specific management, so no disease-specific dosing or target is asserted here.

Target Phenotypes: Iron deficiency anemia HP:0001891

Show evidence (2 references)

PMID:20301579 SUPPORT Other

"standard treatment for those with iron-deficiency anemia"

GeneReviews includes standard iron-deficiency anemia treatment in the management of JLNS.

PMID:20301579 SUPPORT Other

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

Establishes the iron-deficient anemia that this treatment addresses as a frequent feature of the syndrome rather than an incidental comorbidity.

Atrial Pacing with Beta-Blockade

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

Agent: beta-adrenergic antagonist NCIT:C29576

Platform: Device

Atrial pacing combined with escalated beta-blocker dosing, reported in young high-risk JLNS children as an alternative to early ICD implantation, which is technically difficult at that age. In a Norwegian series of genetically confirmed JLNS patients, six children with atrial leads had no arrhythmic events over a mean 6.9 years, while the one patient given a ventricular lead died during follow-up. The authors propose it as a bridge to a two-chamber ICD where left cardiac sympathetic denervation is unavailable.

Mechanism Target:

INHIBITS Arrhythmogenic Substrate and Ventricular Tachyarrhythmia — Atrial pacing added to escalated beta-blockade was followed by freedom from arrhythmic events in the reported series, which is the observed effect on this node. The usual electrophysiologic rationale - that raising the paced rate shortens the QT interval and removes the bradycardia-dependent pauses on which torsade de pointes initiates - is standard long-QT reasoning and is not tested or stated by the cited study, so it is named here as rationale rather than as a demonstrated mechanism.

Show evidence (1 reference)

PMID:27451284 SUPPORT Human Clinical

"No arrhythmic events occurred in 6 very young JLNS patients who received atrial pacing in combination with increased doses of beta-blockers during 7-year follow-up."

Reports the absence of arrhythmic events under atrial pacing plus escalated beta-blockade, the outcome this mechanism link claims.

Show evidence (2 references)

PMID:27451284 SUPPORT Human Clinical

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

The event-free follow-up of the atrially paced patients, and by contrast the death of the single ventricular-lead patient, which is why the lead position is named in the description rather than left implicit.

PMID:27451284 SUPPORT Human Clinical

"this treatment strategy may prevent life-threatening arrhythmias in this high-risk patient group and may act as a bridge to insertion of a 2-chamber ICD when left cardiac sympathetic denervation is not available."

The authors' own framing of the strategy as a bridge to a two-chamber ICD, which is how it is positioned relative to the ICD treatment in this entry.

🌍

Environmental Factors

2

Exertion, Emotional Stress, or Sudden Fright

Modeled here specifically for exertion/exercise, the concept with an available ECTO exposure term (ECTO:6000031, exposure to strenuous exercise); emotional stress and sudden fright are named in the same GeneReviews sentence but have no comparably specific ECTO exposure term and are recorded only in this node's free-text description.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

Establishes that exertion is a recognized exposure in JLNS rather than an inferred one. The mechanism link below carries its own evidence for the separate claim that this exposure acts on the arrhythmogenic substrate node.

Mechanism Target:

TRIGGERS Arrhythmogenic Substrate and Ventricular Tachyarrhythmia — Exertion, emotional stress, and sudden fright are the classic adrenergic triggers for syncopal arrhythmic events in JLNS; the same triggers motivate the anti-adrenergic rationale of beta-blocker therapy and the exercise/trigger-avoidance counseling in treatments.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

GeneReviews documents exertion, emotional stress, and sudden fright as the classic triggers of syncopal arrhythmic events in JLNS.

General Anesthesia and Perioperative Exposure

The same source lists fever, hypokalemia and swimming as further precipitants, and reports that some JLNS cases are first detected when an intercurrent fever, diarrhea or hypokalemia prompts an ECG. Those are recorded here rather than as separate environmental entries because no ECTO exposure term was found for febrile illness or for hypokalemia. Auditory stimuli are also listed as a generic long-QT trigger in that sentence but are deliberately not modeled for JLNS2: these patients have congenital profound deafness, so a startle-by-sound trigger cannot be assumed to transfer to them, and no JLNS-specific report of it was identified. Both sources are syndrome-level: GeneReviews and the review both describe JLNS as a whole, and neither stratifies the anesthetic hazard by causal gene.

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

GeneReviews names anesthesia as a circumstance carrying increased arrhythmia risk in JLNS, establishing it as a recognized exposure rather than an inferred one. The mechanism link below carries separate evidence for the claim that this exposure acts on the arrhythmogenic substrate node.

Mechanism Target:

TRIGGERS Arrhythmogenic Substrate and Ventricular Tachyarrhythmia — Anesthesia is an identified precipitant of ventricular arrhythmia in JLNS, acting on the same repolarization-reserve-depleted substrate as the adrenergic triggers. This is the exposure behind the perioperative caution already recorded on the cochlear implantation treatment, where arrhythmic events during implant surgery have been documented.

Show evidence (2 references)

PMID:42389506 SUPPORT Other

"activities such as exercise, including swimming, emotional states, auditory stimuli, anesthesia, and feverish conditions have been identified as potential triggers of cardiac arrhythmia in children with JLNS"

Lists anesthesia explicitly among the identified triggers of cardiac arrhythmia in children with JLNS, which is the causal claim this edge makes.

PMID:20301579 SUPPORT Other

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

GeneReviews attributes the need for anesthetic precautions specifically to increased arrhythmia risk, tying the exposure to the arrhythmogenic node.

🔬

Biochemical Markers

2

Elevated serum gastrin (INCREASED)

Show evidence (1 reference)

PMID:20301579 SUPPORT Other

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

GeneReviews lists elevated gastrin among the frequent additional features of JLNS, establishing it as a recognized laboratory abnormality of the syndrome.

Reduced hemoglobin (hypochromic, iron-deficient) (DECREASED)

Show evidence (2 references)

PMID:20301579 SUPPORT Other

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

GeneReviews lists iron-deficient anemia among the frequent additional features of JLNS.

PMID:42389506 SUPPORT Human Clinical

"some patients display gastrointestinal symptoms, secondary hypochromic anemia, and gross motor developmental delay"

Independently reports secondary hypochromic anemia in a subset of JLNS patients, supporting the hypochromic character of the anemia.

🔬

Diagnosis

4

Combined Clinical and Molecular Diagnostic Criteria

JLNS2 is diagnosed by the combination of the characteristic phenotype (congenital sensorineural deafness plus a prolonged QT interval) and confirmatory molecular testing showing biallelic pathogenic KCNE1 variants.

clinical assessment NCIT:C124351

Results: A child presenting with congenital sensorineural deafness and a prolonged QT interval, in whom molecular testing identifies biallelic pathogenic KCNE1 (or KCNQ1) variants, meets the diagnostic criteria for JLNS.

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 states the combined clinical-plus-molecular diagnostic criteria for JLNS, of which the KCNE1 arm defines JLNS2.

Molecular Genetic Testing

Molecular confirmation of biallelic KCNE1 pathogenic variants is required to distinguish JLNS2 from JLNS1 (biallelic KCNQ1) and from heterozygous KCNE1-related dominant LQT5, which lacks congenital deafness.

molecular genetic testing NCIT:C19770

Results: Detection of two pathogenic KCNE1 alleles (homozygous or compound heterozygous) in trans confirms JLNS2 and distinguishes it from the allelic dominant LQT5 phenotype, in which only one KCNE1 allele is affected.

Show evidence (1 reference)

PMID:30461122 SUPPORT Human Clinical

"heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2"

Establishes that molecular zygosity (biallelic versus heterozygous) is the diagnostic feature that separates JLNS2 from the milder dominant KCNE1 phenotype.

Resting Electrocardiography with QTc Assessment

Baseline 12-lead ECG measurement of the corrected QT interval is the core diagnostic procedure for identifying the QT-prolongation component of JLNS2.

clinical assessment NCIT:C124351

QTc LOINC:8636-3

Reference Ranges

Q-T interval corrected (Jervell and Lange-Nielsen syndrome cohorts, genotype-mixed (90.5% KCNQ1/JLNS1): 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 as a whole; the cohort establishing this boundary was 90.5% KCNQ1 (JLNS1), and the KCNE1 (JLNS2) subgroup is reported to run a more benign course, so this band is not a JLNS2-specific risk estimate.

A risk-stratification cut-off within JLNS as a whole, not a diagnostic threshold and not derived from a JLNS2-specific cohort: Schwartz et al.'s 186-patient cohort was 90.5% KCNQ1 (JLNS1), and that same cohort reports that patients with mutations on KCNE1 (JLNS2) have a more benign course and are a relatively lower-risk subgroup for cardiac arrest or sudden death. 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 JLNS2 is recorded: GeneReviews (PMID:20301579) characterises JLNS QTc generally 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.

Show evidence (3 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, genotype-mixed JLNS cohort.

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."

States that the JLNS2 (KCNE1) subgroup within this same cohort has a more benign course, the reason the 550 ms boundary above is not treated as a JLNS2-specific threshold.

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; this abstract reports no genotype breakdown.

Results: A markedly prolonged QTc, usually >500 msec in JLNS, supports the cardiac component of the diagnosis.

NCIT does not provide an ECG-specific diagnostic term here, so the preferred term is narrowed in the name and description.

Show evidence (1 reference)

DOI:10.3390/children11050582 SUPPORT Other

"characterized by a prolongation of QTc interval on ECG"

A 2024 congenital LQTS review states that ECG-measured QTc prolongation is the defining diagnostic feature of the QT-prolongation component shared by all congenital LQTS subtypes, including JLNS.

Pure-Tone Audiometry

Audiometric assessment documents the congenital bilateral sensorineural hearing loss that is the second defining feature of JLNS2, alongside the QT-prolongation component above.

audiometric test NCIT:C38036

pure-tone audiometry LOINC:89015-2

The panel code identifies the test; no reference range is recorded. The cited source describes JLNS deafness generally as profound but states no audiometric cut-off owned by the disease or specific to the KCNE1 (JLNS2) subgroup, and a generic hearing-loss grading (such as the WHO grades) is not JLNS content, as on the Jervell_and_Lange-Nielsen_Syndrome_1 entry.

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."

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

📈

Progression

4

Fetal and neonatal recognition

Age: Fetal life through the neonatal period

The two organ systems declare themselves by different routes and at different clinics: prolonged QT intervals and T-wave alternans bring the child to cardiology, with bradycardia detectable earlier still from fetal life, while a failed newborn hearing screen brings the child to otorhinolaryngology. Both are reported for JLNS as a whole rather than stratified by causal gene, so this phase describes JLNS2 by inheritance from the syndrome-level natural history and not from KCNE1-genotyped series.

Show evidence (2 references)

PMID:42389506 SUPPORT Other

"Children diagnosed with JLNS typically exhibit bradycardia beginning in the fetal stage"

Documents bradycardia detectable from fetal life as the earliest cardiac manifestation, establishing the fetal/neonatal boundary of this phase.

PMID:42389506 SUPPORT Human Clinical

"patients with JLNS are referred to the otorhinolaryngology department owing to failed newborn hearing tests"

Documents the failed newborn hearing test as the other route by which JLNS is first recognized in the neonatal period.

Childhood arrhythmic onset

Age: Birth to 18 years, with half of first cardiac events before age 3

Cardiac events cluster in early childhood and are largely complete by adulthood. Both figures below are syndrome-level (KCNQ1 and KCNE1 combined); no age-at-first-event distribution restricted to genotyped KCNE1 patients has been published, and the JLNS2-specific event rate is recorded separately in the KCNE1 genotype phase below.

Show evidence (2 references)

PMID:20301579 SUPPORT Other

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

GeneReviews gives the proportion of JLNS patients with cardiac events before age three, fixing the early-childhood peak of this phase.

PMID:42389506 SUPPORT Other

"Half of the children with JLNS exhibit arrhythmia by 3 years of age, and 90% of patients display symptoms before they reach the age of 18"

Independently reports the same 3-year figure and extends it, giving the proportion symptomatic by age 18 that closes this phase.

Untreated natural history

Age: Childhood through mid-adolescence

The untreated mortality figure is what motivates presymptomatic beta-blockade and device therapy in the treatments section. It predates modern management and is syndrome-level; it should not be read as the expected outcome of a treated JLNS2 patient, and the milder KCNE1 event rate below suggests it overstates the untreated risk for this genotype specifically. The registry cohort added alongside it (44 JLNS patients from the US portion of the International LQTS Registry) is phenotypically rather than genotypically defined, so it too cannot be attributed to KCNE1; it is included because it is the largest prospective natural-history series for the syndrome and because its treated event rate is the counterpoint to the untreated figure. In that cohort the mean age at cardiac event was 5.0 years and mean QTc was 548 ms; those two figures are recorded here rather than quoted because the source sentence carries them inside bracketed standard-deviation spans, which the reference validator strips before matching.

Show evidence (3 references)

PMID:20301579 SUPPORT Other

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

GeneReviews gives the untreated case-fatality figure that defines this phase and the urgency of early treatment.

PMID:16911578 SUPPORT Human Clinical

"The cumulative rates of cardiac events from birth through age 40 among JLNS and RWS patients were 93%"

A prospective JLNS registry cohort quantifying the cumulative cardiac event rate from birth to age 40, and contrasting it with the dominant form, which puts a number on the event burden this phase describes.

PMID:16911578 SUPPORT Human Clinical

"Patients with JLNS experience a high rate of cardiac and fatal events from early childhood despite medical therapy."

States that the high event rate persists despite medical therapy, which is the distinction between this phase and the untreated figure above it.

KCNE1 (JLNS2) genotype-specific course

This is the only phase in this section derived from genotype-confirmed KCNE1 patients rather than from JLNS-wide data. It rests on 19 patients, the largest JLNS2 series assembled to date, so the apparent mildness is a small-sample observation and the confidence interval reported in that study is wide. age_range is deliberately absent, unlike the other three phases. The source reports no age distribution for its 19 JLNS2 patients - no age at enrollment, at first event, or at follow-up - so any range here would be carried over from the syndrome-level phases above, which is exactly the genotype conflation this phase exists to avoid.

Show evidence (2 references)

PMID:31941373 SUPPORT Human Clinical

"Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5%"

Gives the definite-arrhythmic-event rate in genotype-confirmed JLNS2 patients, the only such rate published for this genotype.

PMID:31941373 SUPPORT Human Clinical

"aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients."

The authors' own characterization of the JLNS2 course as mild, which is the clinical conclusion this phase records.

📊

Prevalence

2

Worldwide

Unknown Ultra Rare

No direct birth-prevalence estimate for JLNS2 specifically has been published; JLNS overall (both genes) is estimated at roughly 1 in 200,000 to 1 in 1,000,000, and approximately 90% of genotyped JLNS cases are attributable to KCNQ1 rather than KCNE1, making JLNS2 a small minority of an already rare disease.

Show evidence (1 reference)

PMID:42389506 SUPPORT Other

"Approximately 90% of cases of JLNS are associated with KCNQ1 variants, and the remaining cases are attributable to KCNE1 variants"

Establishes that KCNE1 (JLNS2) accounts for only a minority of genotyped JLNS cases, the basis for treating JLNS2 as markedly rarer than JLNS1.

Worldwide (carrier frequency, functional-variant estimate)

Carrier Frequency 96.7 per 100,000 Not yet documented

Estimated by applying Hardy-Weinberg principles to gnomAD allele counts of KCNE1 variants shown experimentally to reduce IKs current density below 50% of wild type; 1 in 1034 converts to approximately 96.7 per 100,000. This is a carrier-frequency estimate, not a measured disease birth prevalence.

Show evidence (1 reference)

PMID:41200805 SUPPORT Computational

"The population carrier frequency of JLN2 was calculated as 1 in 1034."

Direct quantitative carrier-frequency estimate for JLNS2 derived from high-throughput functional profiling of KCNE1 variants combined with population allele-frequency data.

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Clinical Trials

1

NCT06534671 PHASE_IV COMPLETED

A single-participant Vanderbilt University Medical Center trial testing the acute effect of a single intravenous dose of diltiazem, a calcium channel blocker, on the QT interval in a genetically confirmed JLNS patient. The trial's public summary does not specify whether the participant carried KCNQ1 or KCNE1 variants, so it is recorded here as JLNS-wide (not confirmed JLNS2-specific) evidence.

Target Phenotypes: Prolonged QT interval HP:0001657

Show evidence (1 reference)

clinicaltrials:NCT06534671 SUPPORT

"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 of the only identified JLNS-specific interventional trial testing a candidate acute QT-shortening agent.

🧫

Experimental Models

1

CHO-K1 heterologous KCNQ1/KCNE1 expression with automated voltage clamp CELL_LINE

Chinese hamster ovary (CHO-K1) cells stably expressing human KCNE1, into which KCNE1 variants are coexpressed with KCNQ1 and the resulting IKs current is measured by high-throughput automated patch-clamp recording. Variants were studied in the homozygous state, which is the configuration that corresponds to biallelic JLNS2 genotypes, and a subset additionally in the heterozygous state corresponding to the dominant LQT5 configuration. This is the assay that supplies the loss-of-function mechanism and the carrier-frequency estimate curated elsewhere in this entry.

Organism

Chinese hamster NCBITaxon:10029

Cell source

CHO-K1 cell line stably expressing human KCNE1, with KCNQ1 and variant KCNE1 introduced by transfection.

Culture

Heterologous expression in a non-excitable mammalian cell line with high-throughput automated patch-clamp electrophysiology.

Publication

PMID:41200805

Pathograph links

Biallelic KCNE1 Loss of Function recapitulates fidelity: moderate observes: molecular Expressing a KCNE1 variant in the homozygous state alongside KCNQ1 reproduces the molecular configuration of a JLNS2 genotype and measures the resulting IKs current directly, which is the node's claim.

Limitations: A non-excitable rodent cell line supplies neither the native cardiomyocyte action potential nor the stria vascularis epithelium, so the assay reports channel function in isolation and cannot show either downstream consequence. Channel subunit stoichiometry and trafficking in a heterologous system need not match the native tissue.

Divergences from the human mechanism

boundary omission qualifying

The cardiomyocyte action potential and the stria vascularis epithelium are outside the model boundary. The assay measures the channel current only, so every downstream node in both branches of this entry's pathograph is inferred rather than observed here.

species mismatch immaterial

The host cell is Chinese hamster rather than human, but the expressed channel subunits are both human and the readout is the current those human subunits carry, so the host species does not bear on this link's claim.

Readouts

IKs peak current density and activation voltage-dependence

Direction: DECREASED

Interpretation: Reduced peak IKs current density in the homozygous configuration is the direct measurement of the loss of function this node asserts.

Show evidence (1 reference)

PMID:41200805 SUPPORT In Vitro

"When examined in the homozygous state, 68 KCNE1 variants exhibited significant differences in at least 1 functional property compared with wild-type KCNE1"

Reports the number of KCNE1 variants with significantly altered function when expressed in the homozygous state, the measurement this readout records.

Show evidence (1 reference)

PMID:41200805 SUPPORT In Vitro

"We determined the functional properties of 95 KCNE1 variants coexpressed with KCNQ1 in heterologous cells using high-throughput voltage-clamp recording."

States the model system and assay, establishing that this heterologous expression platform is what was used to determine KCNE1 variant function and is therefore informative for the biallelic-loss node.

Notes

This is the only KCNE1-specific experimental platform curated here. No JLNS2-specific iPSC-derived cardiomyocyte or inner-ear hair cell model was identified: the published JLNS iPSC work engineers KCNQ1 variants (JLNS1), and a review of JLNS experimental models states that JLNS-specific iPSC-derived inner hair cell models are lacking. Importing those KCNQ1 models here would breach this entry's KCNE1 scope, so the gap is recorded rather than filled.

Show evidence (1 reference)

PMID:41200805 SUPPORT In Vitro

"We determined the functional properties of 95 KCNE1 variants coexpressed with KCNQ1 in heterologous cells using high-throughput voltage-clamp recording."

Describes the model system whose results are curated in this entry's genetic and prevalence sections.

🐁

Animal Models

1

Kcne1 knockout mouse

Species

Mouse

Genotype

Kcne1-/-

Publication

PMID:33514733

Pathograph links

Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells recapitulates fidelity: moderate Kcne1-/- mice lack Kcne1 expression in strial marginal cells and vestibular dark cells, the same cell types that express the KCNQ1/KCNE1 complex in humans, and show abnormal endolymphatic-space development.

Limitations: Mouse cochlear structure, developmental timing, and the extent of vestibular involvement are not identical to human JLNS2; no genotype-confirmed human vestibular data exist for direct comparison (see the HUMAN_MODEL_MISMATCH discussion on this node).

Readouts

Reissner's membrane and vestibular wall collapse

Direction: RESTORED

Interpretation: Early AAV1-CB7-Kcne1 gene therapy via the posterior semicircular canal prevented collapse of Reissner's membrane and the vestibular wall and preserved normal semicircular canal size, demonstrating the causal role of Kcne1 loss in this structural degeneration.

Show evidence (1 reference)

PMID:33514733 SUPPORT Model Organism

"Results showed early treatment prevented collapse of the Reissner's membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells."

Rescue experiment demonstrating that structural cochlear/vestibular degeneration in Kcne1-/- mice is caused by loss of Kcne1 function.

Auditory brainstem response threshold

Direction: RESTORED

Interpretation: High-dosage gene therapy preserved auditory function in 16 of 20 treated Kcne1-/- mice for at least five months, supporting a causal link between restored strial Kcne1 expression and preserved hearing.

Show evidence (1 reference)

PMID:33514733 SUPPORT Model Organism

"In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months."

Dose-dependent, quantitative auditory and vestibular functional rescue data from the Kcne1-/- mouse gene-therapy study.

Show evidence (1 reference)

PMID:33514733 SUPPORT Model Organism

"Both Kcne1−/− and Kcnq1−/− mice exhibit an abnormal development of the endolymphatic space, severe degeneration of the hair cells (HCs), and spiral ganglion neurons (SGNs)"

Supports treating the Kcne1-/- mouse as informative for the strial-marginal-cell potassium-secretion node: it reproduces the expected downstream endolymphatic and hair-cell consequences of losing the same channel complex.

Show evidence (1 reference)

PMID:33514733 SUPPORT Model Organism

"Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1-/- mice to treat both the hearing..."

Establishes the Kcne1-/- mouse as a genetically precise model of the human KCNE1 loss-of-function lesion underlying JLNS2.

{ }

Source YAML

click to show

name: Jervell and Lange-Nielsen Syndrome 2
creation_date: "2026-08-17T00:00:00Z"
description: >-
  Jervell and Lange-Nielsen syndrome 2 (JLNS2) is an ultra-rare autosomal
  recessive cardioauditory channelopathy caused by biallelic loss-of-function
  variants in KCNE1, which encodes MinK, the single-transmembrane-domain beta
  subunit that assembles with the KCNQ1 alpha subunit to form the slow
  delayed-rectifier potassium (IKs) channel. JLNS2 is the allelic recessive
  counterpart of KCNE1-related autosomal dominant long QT syndrome (LQT5):
  a single heterozygous KCNE1 variant produces, at best, a low-penetrance
  dominant QT-prolongation phenotype, while biallelic loss essentially
  abolishes IKs current and produces the severe recessive JLNS phenotype. The
  IKs channel is expressed in both cardiac myocytes, where it contributes to
  repolarization of the ventricular action potential, and in the marginal
  cells of the stria vascularis of the inner ear, where it drives potassium
  secretion into the endolymph that generates and maintains the endocochlear
  potential required for hair-cell mechanotransduction. Biallelic KCNE1 loss
  therefore produces a two-organ phenotype: congenital profound bilateral
  sensorineural deafness from collapse of the endocochlear potential, together
  with marked QT-interval prolongation and a risk of torsade de pointes,
  ventricular fibrillation, syncope, and sudden cardiac death from loss of
  ventricular repolarization reserve. JLNS2 is distinguished from the more
  common JLNS1 (biallelic KCNQ1 variants) only by the causal gene, and the two
  are clinically similar at the bedside, but JLNS2 is markedly rarer -
  approximately 90% of JLNS cases are attributable to KCNQ1 and only about 10%
  to KCNE1 - and the limited comparative data available suggest a milder
  arrhythmic course than JLNS1. This entry is careful not to import JLNS1
  (KCNQ1) case series, severity estimates, or vestibular-dysfunction findings,
  which are curated separately.
category: Mendelian
disease_term:
  preferred_term: Jervell and Lange-Nielsen syndrome 2
  term:
    id: MONDO:0012871
    label: Jervell and Lange-Nielsen syndrome 2
synonyms:
- JLNS2
- Jervell and Lange-Nielsen syndrome type 2
- Jervell and Lange-Nielsen syndrome caused by mutation in KCNE1
- KCNE1 Jervell and Lange-Nielsen syndrome
parents:
- Jervell and Lange-Nielsen Syndrome
- Cardiac Arrhythmia
- Channelopathy
- Sensorineural Hearing Loss
notes: >-
  IDENTITY / NEC NOTE. MONDO:0012871 (OMIM:612347) is explicitly defined as
  "Any Jervell and Lange-Nielsen syndrome in which the cause of the disease is
  a mutation in the KCNE1 gene" and asserts RO:0004003 to HGNC:6240 (KCNE1);
  it is_a both MONDO:0002441 (Jervell and Lange-Nielsen syndrome) and
  MONDO:0013372 (long QT syndrome 5). This entry is curated strictly against
  the KCNE1 identity. The allelic, more common recessive form caused by
  biallelic KCNQ1 variants (JLNS1, MONDO:0024540) is curated separately and no
  JLNS1-specific case data, prevalence figures, or phenotype findings
  (including the KCNQ1-genotyped vestibular-dysfunction series of Winbo et al.,
  PMID:25471708, whose 14/14 genotyped subjects all carried double KCNQ1
  mutations) are imported here.

  RARITY. JLNS2 is markedly rarer than JLNS1: approximately 90% of JLNS cases
  are attributable to KCNQ1 variants and only about 10% to KCNE1 (PMID:42389506).
  A 2025 functional-profiling study of 95 KCNE1 variants estimated a JLNS2
  population carrier frequency of 1 in 1034 using Hardy-Weinberg principles
  applied to gnomAD allele counts of dysfunctional variants (PMID:41200805).
  The largest genotype-confirmed JLNS2 cohort assembled to date is 19 patients,
  drawn from an international multicenter LQT5 study (PMID:31941373). Case
  counts and severity figures in this entry are held to that scale rather than
  to JLNS1's more extensively reported literature.

  ALLELIC SPECTRUM. KCNE1 produces a genotype-phenotype spectrum rather than a
  strict dominant/recessive dichotomy: heterozygous carriers of KCNE1
  loss-of-function variants are usually clinically silent or show only a low
  ECG penetrance (dominant LQT5), while biallelic null alleles are required for
  the fully penetrant recessive JLNS2 phenotype (PMID:30461122, PMID:41200805).
  ClinGen's gene curation working group considers the evidence for autosomal
  dominant KCNE1-LQT5 causality disputed even though KCNE1 is an accepted
  cause of recessive JLNS2 (PMID:41200805). Long_QT_Syndrome.yaml curates the
  dominant LQT5 (Type 5) subtype of that spectrum; this entry curates the
  distinct, more severe biallelic phenotype.

  HUMAN/MOUSE VESTIBULAR MISMATCH. Kcne1-/- mice show clear structural and
  functional vestibular involvement (endolymphatic-space abnormality,
  vestibular dark cell and hair cell degeneration, impaired vestibular
  function rescued by gene therapy; PMID:33514733). No genotype-confirmed
  human vestibular data specific to KCNE1/JLNS2 patients have been identified;
  the only quantitative human vestibular study of JLNS (PMID:25471708) enrolled
  exclusively double-KCNQ1 (JLNS1) cases. This is recorded as a
  HUMAN_MODEL_MISMATCH discussion rather than as an established human
  phenotype.

  MODULE CONFORMANCE SCOPE. The cardiac branch declares conforms_to against
  cardiac_ion_channel_repolarization. The cochlear branch declares conforms_to
  against sensorineural_hair_cell_loss starting at "Cochlear Ionic Homeostasis
  Disruption and Oxidative Stress" (whose own description explicitly names
  potassium-recycling/endocochlear-potential failure as a covered mechanism),
  rather than at the module's "Cochlear Sensory Epithelium Insult" entry node,
  because the primary JLNS2 lesion is a stria vascularis marginal-cell ionic
  defect rather than a primary hair-cell stereociliary/mechanotransduction
  defect.

  DATASETS. A GEO search over this disorder returned no candidate accessions, which
  is the expected result for a disease whose largest genotyped cohort is 19
  patients. The datasets section is left empty rather than populated with KCNE1
  gene-only or JLNS1 hits, which is the Named Entity Confusion failure mode that
  dataset search invites.

  SYNDROME-LEVEL VERSUS GENOTYPE-LEVEL DATA. Several sections added in the 2026-09
  augmentation pass (progression, the bradycardia, T-wave alternans and gross motor
  developmental delay phenotypes, the biochemical markers, and the anesthesia
  exposure) rest on sources reporting JLNS as a whole rather than KCNE1-genotyped
  series, because no KCNE1-stratified data for those features exist. Each such
  record says so in its own notes. The one genotype-specific natural-history record
  is the KCNE1 phase of progression, drawn from the 19-patient JLNS2 cohort.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012871
      label: Jervell and Lange-Nielsen syndrome 2
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0012871 is the primary disease term for this entry, cross-referenced
      to OMIM:612347, with KCNE1 (HGNC:6240) asserted as the causal gene via
      RO:0004003.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
    notes: >-
      The cardiac axis of JLNS2 is a primary inherited arrhythmia syndrome -
      marked QTc prolongation with torsade de pointes and sudden-death risk -
      which is the subject of Harrison's cardiovascular Part.
    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 characterises the cardiac component of JLNS as a ventricular
        tachyarrhythmia syndrome, which is where Harrison's places the inherited
        arrhythmia syndromes.
  - classification_value: DISORDER_OF_EAR
    notes: >-
      Congenital profound bilateral sensorineural hearing loss is one of the two
      defining features of JLNS, not an incidental association, so the ear Part
      is assigned alongside the cardiovascular one rather than instead of it.
    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 JLNS by congenital profound bilateral sensorineural
        hearing loss together with QTc prolongation, establishing the ear as a
        primary rather than secondary organ of involvement.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      JLNS2 is a Mendelian disorder requiring biallelic KCNE1 variants, so the
      Mendelian-genetics Part applies in addition to the two organ-system Parts.
    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."
      explanation: >-
        GeneReviews states the autosomal recessive Mendelian inheritance that
        places JLNS in Harrison's genetics Part.
  channelopathy_category:
    classification_value: cardiac channelopathy
    notes: >-
      ChannelopathyOrganSystemEnum is single-valued, and JLNS2 is a channelopathy
      in two organ systems: the same IKs channel carries ventricular repolarizing
      current in cardiac myocytes and drives potassium secretion by the epithelial
      marginal cells of the stria vascularis. "cardiac channelopathy" is assigned
      because that is how the disease is classified clinically and how its dominant
      allelic form (LQT5) is grouped, but the cochlear lesion is an epithelial
      transport defect and would take "epithelial channelopathy" if the slot were
      multivalued. Recorded here rather than resolved by picking a second value.
    evidence:
    - reference: PMID:42389506
      reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "KCNQ1 encodes the alpha subunit Kv7.1 of the ion channels accountable for slow delayed rectifier potassium currents (IKs), whereas KCNE1 encodes the beta subunit mink, which modulates the function of IKs."
      explanation: >-
        Identifies KCNE1 as the beta subunit of the IKs potassium channel, so JLNS2
        is an ion-channel disorder; paired with the QT prolongation that defines the
        syndrome, this supports the cardiac channelopathy grouping.
    - reference: PMID:42389506
      reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is defined by electrocardiographic QT prolongation and sensorineural hearing loss, caused by homozygous or compound heterozygous variants in KCNQ1 and/or KCNE1."
      explanation: >-
        States that JLNS is defined by electrocardiographic QT prolongation and is
        caused by KCNQ1 and/or KCNE1 variants, the cardiac-rhythm half of the
        channelopathy assignment.
inheritance:
- name: Autosomal Recessive
  description: >-
    JLNS2 is inherited in an autosomal recessive manner. Affected individuals
    are homozygous or compound heterozygous for KCNE1 loss-of-function
    variants; parents are typically heterozygous carriers who are usually
    clinically unaffected or show only mild, incompletely penetrant QT
    prolongation (the allelic dominant LQT5 phenotype). At conception, each
    sib of an affected individual has a 25% chance of being affected, a 50%
    chance of being an asymptomatic or mildly affected carrier, and a 25%
    chance of being unaffected and non-carrier.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS are usually heterozygotes; rarely, only one parent is heterozygous"
    explanation: >-
      GeneReviews establishes the autosomal recessive inheritance pattern and
      typical carrier status of parents.
  - reference: PMID:30461122
    reference_title: "Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2"
    explanation: >-
      Documents that biallelic KCNE1 loss of function, not heterozygosity, is
      required for the fully penetrant JLNS2 phenotype.
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At conception, each sib of an affected individual usually has a 25% chance of being affected with JLNS, a 50% chance of being a carrier of a JLNS-causing pathogenic variant and potentially at risk for LQTS, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      GeneReviews states the exact per-pregnancy recurrence-risk figures
      (25% affected, 50% carrier, 25% unaffected non-carrier) summarized in
      this node's description.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    No direct birth-prevalence estimate for JLNS2 specifically has been
    published; JLNS overall (both genes) is estimated at roughly 1 in 200,000
    to 1 in 1,000,000, and approximately 90% of genotyped JLNS cases are
    attributable to KCNQ1 rather than KCNE1, making JLNS2 a small minority of
    an already rare disease.
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Approximately 90% of cases of JLNS are associated with KCNQ1 variants, and the remaining cases are attributable to KCNE1 variants"
    explanation: >-
      Establishes that KCNE1 (JLNS2) accounts for only a minority of genotyped
      JLNS cases, the basis for treating JLNS2 as markedly rarer than JLNS1.
- population: Worldwide (carrier frequency, functional-variant estimate)
  measure_type: CARRIER_FREQUENCY
  prevalence_class: NOT_YET_DOCUMENTED
  rate_per_100000: 96.7
  notes: >-
    Estimated by applying Hardy-Weinberg principles to gnomAD allele counts of
    KCNE1 variants shown experimentally to reduce IKs current density below 50%
    of wild type; 1 in 1034 converts to approximately 96.7 per 100,000. This is
    a carrier-frequency estimate, not a measured disease birth prevalence.
  evidence:
  - reference: PMID:41200805
    reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The population carrier frequency of JLN2 was calculated as 1 in 1034."
    explanation: >-
      Direct quantitative carrier-frequency estimate for JLNS2 derived from
      high-throughput functional profiling of KCNE1 variants combined with
      population allele-frequency data.
progression:
- phase: Fetal and neonatal recognition
  age_range: Fetal life through the neonatal period
  notes: >-
    The two organ systems declare themselves by different routes and at different
    clinics: prolonged QT intervals and T-wave alternans bring the child to
    cardiology, with bradycardia detectable earlier still from fetal life, while a
    failed newborn hearing screen brings the child to otorhinolaryngology. Both are
    reported for JLNS as a whole rather than stratified by causal gene, so this
    phase describes JLNS2 by inheritance from the syndrome-level natural history
    and not from KCNE1-genotyped series.
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Children diagnosed with JLNS typically exhibit bradycardia beginning in the fetal stage"
    explanation: >-
      Documents bradycardia detectable from fetal life as the earliest cardiac
      manifestation, establishing the fetal/neonatal boundary of this phase.
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with JLNS are referred to the otorhinolaryngology department owing to failed newborn hearing tests"
    explanation: >-
      Documents the failed newborn hearing test as the other route by which JLNS is
      first recognized in the neonatal period.
- phase: Childhood arrhythmic onset
  age_range: Birth to 18 years, with half of first cardiac events before age 3
  notes: >-
    Cardiac events cluster in early childhood and are largely complete by
    adulthood. Both figures below are syndrome-level (KCNQ1 and KCNE1 combined);
    no age-at-first-event distribution restricted to genotyped KCNE1 patients has
    been published, and the JLNS2-specific event rate is recorded separately in
    the KCNE1 genotype phase below.
  evidence:
  - 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: >-
      GeneReviews gives the proportion of JLNS patients with cardiac events before
      age three, fixing the early-childhood peak of this phase.
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Half of the children with JLNS exhibit arrhythmia by 3 years of age, and 90% of patients display symptoms before they reach the age of 18"
    explanation: >-
      Independently reports the same 3-year figure and extends it, giving the
      proportion symptomatic by age 18 that closes this phase.
- phase: Untreated natural history
  age_range: Childhood through mid-adolescence
  notes: >-
    The untreated mortality figure is what motivates presymptomatic beta-blockade
    and device therapy in the treatments section. It predates modern management
    and is syndrome-level; it should not be read as the expected outcome of a
    treated JLNS2 patient, and the milder KCNE1 event rate below suggests it
    overstates the untreated risk for this genotype specifically.

    The registry cohort added alongside it (44 JLNS patients from the US portion of
    the International LQTS Registry) is phenotypically rather than genotypically
    defined, so it too cannot be attributed to KCNE1; it is included because it is
    the largest prospective natural-history series for the syndrome and because its
    treated event rate is the counterpoint to the untreated figure. In that
    cohort the mean age at cardiac event was 5.0 years and mean QTc was 548 ms;
    those two figures are recorded here rather than quoted because the source
    sentence carries them inside bracketed standard-deviation spans, which the
    reference validator strips before matching.
  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 gives the untreated case-fatality figure that defines this phase
      and the urgency of early treatment.
  - 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 cumulative rates of cardiac events from birth through age 40 among JLNS and RWS patients were 93%"
    explanation: >-
      A prospective JLNS registry cohort quantifying the cumulative cardiac event
      rate from birth to age 40, and contrasting it with the dominant form, which
      puts a number on the event burden this phase describes.
  - 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: "Patients with JLNS experience a high rate of cardiac and fatal events from early childhood despite medical therapy."
    explanation: >-
      States that the high event rate persists despite medical therapy, which is the
      distinction between this phase and the untreated figure above it.
- phase: KCNE1 (JLNS2) genotype-specific course
  notes: >-
    This is the only phase in this section derived from genotype-confirmed KCNE1
    patients rather than from JLNS-wide data. It rests on 19 patients, the largest
    JLNS2 series assembled to date, so the apparent mildness is a small-sample
    observation and the confidence interval reported in that study is wide.

    age_range is deliberately absent, unlike the other three phases. The source
    reports no age distribution for its 19 JLNS2 patients - no age at enrollment,
    at first event, or at follow-up - so any range here would be carried over from
    the syndrome-level phases above, which is exactly the genotype conflation this
    phase exists to avoid.
  evidence:
  - reference: PMID:31941373
    reference_title: "An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5%"
    explanation: >-
      Gives the definite-arrhythmic-event rate in genotype-confirmed JLNS2 patients,
      the only such rate published for this genotype.
  - reference: PMID:31941373
    reference_title: "An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients."
    explanation: >-
      The authors' own characterization of the JLNS2 course as mild, which is the
      clinical conclusion this phase records.
genetic:
- name: KCNE1
  notes: >-
    KCNE1 (21q22.11) encodes MinK, a 129-amino-acid single-transmembrane-domain
    protein that is the regulatory beta subunit of the IKs channel; it must
    coassemble with the KCNQ1 (Kv7.1) alpha subunit to generate the slow
    delayed-rectifier potassium current. A 2025 high-throughput voltage-clamp
    screen of 95 KCNE1 variants found that about half exhibited peak current
    densities significantly different from wild type when studied in the
    homozygous state, with most dysfunctional variants showing loss-of-function
    properties and no apparent dominant-negative effect on the specific
    variant panel tested when variant and wild-type KCNE1 were coexpressed.
    This is not a categorical claim that KCNE1 variants are never
    dominant-negative: a separate study of KCNE1 nonsense alleles reports that
    coassembly of certain other mutant KCNE1 monomers with wild-type KCNQ1
    subunits does produce dominant Romano-Ward syndrome via a dominant-negative
    mechanism. The two observations are reconciled, not contradictory, by
    variant-specific mechanism: most loss-of-function KCNE1 alleles behave as
    simple recessive nulls requiring biallelic loss for JLNS2, while a smaller
    set of missense alleles instead act dominantly through interference with
    wild-type KCNQ1/KCNE1 complexes.
  gene_term:
    preferred_term: KCNE1
    term:
      id: hgnc:6240
      label: KCNE1
  relationship_type: CAUSATIVE
  case_fractions:
  - population: Egyptian JLNS cohort (52 sequenced patients, 47 families, 76.2% consanguineous)
    case_fraction_percent: 2.0
    cohort_size: 52
    notes: >-
      One of 52 sequenced JLNS patients carried a homozygous KCNE1 variant; the
      other 51 carried KCNQ1. The authors note this 98%/2% split is close to the
      95%/5% split reported by Schwartz et al. (2006). Preprint, not yet
      peer-reviewed at the time of curation.
    evidence:
    - reference: PPR:PPR1109906
      reference_title: "The mutational spectrum of Jervell and Lange-Nielsen syndrome: insights from highly consanguineous families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All of the sequenced patients (n=52) harbored homozygous variants in KCNQ1 (n=51) or KCNE1 (n=1)."
      explanation: >-
        Gives the gene-level breakdown of a genotyped JLNS cohort: 51 of 52 sequenced
        patients carried KCNQ1 and one carried KCNE1, the case fraction recorded here.
    - reference: PPR:PPR1109906
      reference_title: "The mutational spectrum of Jervell and Lange-Nielsen syndrome: insights from highly consanguineous families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "proportion of patients in the Egypt JLNS cohort, who harbored variants in KCNQ1 (98%) or KCNE1 (2%)"
      explanation: >-
        The authors' own statement of the KCNQ1/KCNE1 proportions in their cohort and
        its agreement with the earlier Schwartz series.
  - population: Iranian JLNS families (14 patients and their families, KCNQ1/KCNE1 Sanger screen)
    case_fraction_percent: 0.0
    cohort_size: 14
    notes: >-
      A negative result, recorded because it bears on how rare KCNE1 is as a cause
      of JLNS. No pathogenic KCNE1 variant was found in this cohort; the only KCNE1
      finding was the common c.112G>A polymorphism, which is not a JLNS2 allele.
      The screen was Sanger sequencing of the two genes only, so it would not
      detect a copy-number variant, and the cohort is small enough that zero is
      compatible with the low single-digit percentages seen elsewhere. The report
      also never states how many of the 14 investigated patients were solved, so
      the denominator is patients screened rather than cases explained: this is a
      screening-negative result and is not directly comparable with the Egyptian
      case fraction above it.
    evidence:
    - reference: PMID:30942114
      reference_title: "Mutation Screening of KCNQ1 and KCNE1 Genes in Iranian Patients With Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified two frameshift mutations in the KCNQ1 gene, including a novel mutation, c.1356 1356delG, and a known mutation, c.1534_1534delG."
      explanation: >-
        The only causal variants the study identified in this JLNS cohort were in
        KCNQ1. That no pathogenic KCNE1 variant is reported is the basis of the zero
        recorded here, which is an argument from the study's silence on KCNE1 rather
        than an explicit negative statement, and is why the notes above qualify it.
    - reference: PMID:30942114
      reference_title: "Mutation Screening of KCNQ1 and KCNE1 Genes in Iranian Patients With Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There may be less frequency of mutations in the KCNQ1 and of KCNE1 genes in Iranian JLNS patients compared with other populations."
      explanation: >-
        The authors' own conclusion that KCNQ1 and KCNE1 mutation frequency was lower
        in this population than in others, the caveat this record is filed under.
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of JLNS is established in a child with congenital sensorineural deafness, long QT interval, and presence of biallelic pathogenic variants in either KCNQ1 or KCNE1."
    explanation: >-
      GeneReviews establishes KCNE1 as one of the two genes in which biallelic
      pathogenic variants cause JLNS.
  - reference: PMID:41200805
    reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "KCNE1 is a recognized cause of the autosomal recessive Jervell and Lange-Nielson syndrome type 2 (JLN2)."
    explanation: >-
      Confirms KCNE1 as the accepted causal gene for the recessive JLNS2
      phenotype curated in this entry.
  - reference: PMID:41200805
    reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Most dysfunctional variants exhibited loss-of-function properties. We observed no apparent dominant-negative effects when variant and wild-type KCNE1 were coexpressed."
    explanation: >-
      Direct functional electrophysiology showing loss-of-function as the
      predominant mechanism of disease-associated KCNE1 variants, without
      dominant-negative behavior, consistent with a recessive disease
      mechanism.
  - reference: PMID:33040543
    reference_title: "Treatment on arrhythmia electric storm in a Jervell and Lange-Nielsen syndrome patient by ablation of the triggering premature ventricular contraction: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient has A to G missense mutation in KCNE1 gene, and a subunit with abnormal structure, which is the basis for congenital deafness."
    explanation: >-
      Independent clinical case confirming a KCNE1 missense variant as the
      basis of a patient's congenital deafness component of JLNS.
pathophysiology:
- name: Biallelic KCNE1 Loss of Function
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function variants in KCNE1 abolish or severely reduce
    the regulatory (beta-subunit) contribution of MinK to the IKs channel
    complex. Because KCNE1 must coassemble with KCNQ1 to generate a normal IKs
    current, homozygous or compound heterozygous KCNE1 variants produce the
    same downstream functional deficit as biallelic KCNQ1 loss (JLNS1), even
    though the two genes encode structurally distinct subunits of the same
    channel. High-throughput voltage-clamp profiling shows that most
    disease-associated KCNE1 variants reduce IKs current density in the
    homozygous state without dominant-negative behavior on coexpressed
    wild-type subunits, consistent with a recessive disease mechanism.
  genes:
  - preferred_term: KCNE1
    term:
      id: hgnc:6240
      label: KCNE1
  molecular_functions:
  - preferred_term: ion channel regulator activity
    term:
      id: GO:0099106
      label: ion channel regulator activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNE1 specifically encodes the beta subunit (mink) of IKs"
    explanation: >-
      Establishes KCNE1/MinK as the regulatory beta subunit whose biallelic
      loss is the molecular trigger of JLNS2.
  - reference: PMID:41200805
    reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Approximately half (47 of 95) of the KCNE1 variants tested in the homozygous state exhibited peak current densities significantly different from WT IKs."
    explanation: >-
      Direct high-throughput functional data quantifying the frequency and
      magnitude of IKs current disruption caused by KCNE1 variants in the
      homozygous state.
  downstream:
  - target: Loss of IKs Current in Cardiac Myocytes
    description: >-
      IKs generated by the KCNQ1/KCNE1 complex is a major repolarizing current
      in cardiac myocytes; loss of KCNE1 function reduces this current in the
      heart.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42389506
      reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The ion channel subunits encoded by KCNQ1 and KCNE1 generate slow delayed rectifier potassium currents (IKs), which are essential for endolymph production in the inner ear and cardiomyocyte action potential (AP)"
      explanation: >-
        States both the cardiac and cochlear roles of the KCNQ1/KCNE1 IKs
        complex, the basis of this branch of the fork.
  - target: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
    description: >-
      The same KCNQ1/KCNE1 IKs channel complex is expressed on the apical
      membrane of marginal cells of the stria vascularis, where it drives
      potassium secretion into the endolymph; loss of KCNE1 function reduces
      this current in the inner ear.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33514733
      reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the inner ear, KCNQ1/KCNE1 potassium channels are expressed exclusively in the apical membrane of marginal cells (MCs) in the stria vascularis (SV) and in vestibular dark cells"
      explanation: >-
        Establishes the specific inner-ear cellular localization of the
        KCNQ1/KCNE1 channel complex whose loss initiates the cochlear branch
        of the phenotype.
- name: Loss of IKs Current in Cardiac Myocytes
  conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    Reduced IKs current diminishes repolarization reserve and delays
    completion of the ventricular action potential, prolonging the QT
    interval measured on the surface ECG.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  - preferred_term: membrane repolarization during cardiac muscle cell action potential
    term:
      id: GO:0086013
      label: membrane repolarization during cardiac muscle cell action potential
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: monoatomic ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
    modifier: ABNORMAL
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
    explanation: >-
      GeneReviews documents the marked QTc prolongation that results from
      reduced ventricular repolarization reserve in JLNS.
  - reference: PMID:33963564
    reference_title: "Delayed KCNQ1/KCNE1 assembly on the cell surface helps I(Ks) fulfil its function as a repolarization reserve in the heart."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "IKs functions as a 'repolarization reserve' in the heart by providing extra current for ventricular action potential shortening during β-adrenergic stimulation."
    explanation: >-
      Defines the repolarization-reserve role this node's description asserts, and
      specifies that the reserve is called on during beta-adrenergic stimulation -
      which is why the adrenergic exposures in environmental precipitate events in a
      heart that has lost IKs.
  - reference: PMID:33963564
    reference_title: "Delayed KCNQ1/KCNE1 assembly on the cell surface helps I(Ks) fulfil its function as a repolarization reserve in the heart."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in cardiomyocytes, KCNQ1 and KCNE1 traffic by different routes to surface sarcolemma where they assemble into IKs channels. This mode of delayed channel assembly helps IKs fulfil its function of repolarization reserve."
    explanation: >-
      Shows KCNQ1 and KCNE1 assemble into the IKs channel at the cardiomyocyte
      surface sarcolemma, the step that biallelic KCNE1 loss removes upstream of
      this node.
  downstream:
  - target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
    description: >-
      Markedly prolonged repolarization creates a substrate for triggered
      activity and re-entrant ventricular tachyarrhythmia, including torsade
      de pointes and ventricular fibrillation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301579
      reference_title: "Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Prolongation of the QTc interval is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death."
      explanation: >-
        GeneReviews directly links QTc prolongation to the tachyarrhythmic and
        fatal outcomes of JLNS.
- name: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  role: intermediate
  biological_scale: TISSUE
  description: >-
    Prolonged, heterogeneous ventricular repolarization predisposes to
    early afterdepolarizations and re-entrant torsade de pointes, which can
    degenerate into sustained ventricular tachycardia or ventricular
    fibrillation. Available comparative data suggest that this arrhythmic risk
    is present but lower in genotype-confirmed JLNS2 (biallelic KCNE1) than in
    JLNS1 (biallelic KCNQ1).
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Children carrying KCNQ1 variants exhibit an approximately sixfold higher risk of ventricular arrhythmia than those with KCNE1 variants."
    explanation: >-
      Directly quantifies the reduced (but nonzero) ventricular arrhythmia
      risk specific to KCNE1 (JLNS2) relative to KCNQ1 (JLNS1) genotypes,
      supporting the entry's emphasis on JLNS2-specific severity data rather
      than JLNS1 figures.
  - reference: PMID:31941373
    reference_title: "An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5%"
    explanation: >-
      Directly quantifies the definite arrhythmic event rate (10.5%, 2 of 19
      genotype-confirmed patients) in the largest reported JLNS2 cohort,
      providing a JLNS2-specific severity estimate rather than an imported
      JLNS1 figure.
  downstream:
  - target: Syncope and Sudden Cardiac Death
    description: >-
      Sustained ventricular tachyarrhythmia can cause hemodynamic collapse,
      manifesting as syncope, and can be fatal if not promptly terminated.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301579
      reference_title: "Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "More than half of untreated children with JLNS die before age 15 years."
      explanation: >-
        GeneReviews documents the high untreated mortality of JLNS overall,
        underscoring the clinical severity of the arrhythmic branch even
        though JLNS2 specifically carries a lower event rate than JLNS1.
- name: Syncope and Sudden Cardiac Death
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  role: effector
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint of the cardiac branch of JLNS2: exertion-, emotion-,
    or auditory-stimulus-triggered syncope, and a risk of sudden cardiac death
    from malignant ventricular arrhythmia, most pronounced in early childhood.
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. Fifty percent of individuals with JLNS had cardiac events before age three years."
    explanation: >-
      GeneReviews describes the classic clinical presentation and early
      childhood timing of cardiac events in JLNS overall.
- name: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
  conforms_to: "sensorineural_hair_cell_loss#Cochlear Ionic Homeostasis Disruption and Oxidative Stress"
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    KCNQ1/KCNE1 IKs channels on the apical membrane of stria vascularis
    marginal cells drive the transepithelial potassium flux that generates and
    maintains the endocochlear potential, the unusually positive extracellular
    potential in the endolymph that provides the electrochemical driving force
    for hair-cell mechanotransduction. Loss of KCNE1 function collapses this
    potassium-secretory current, disrupting cochlear ionic homeostasis.
  cell_types:
  - preferred_term: strial marginal cell
    term:
      id: CL:0002492
      label: strial marginal cell
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  locations:
  - preferred_term: stria vascularis of cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:33514733
    reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the inner ear, KCNQ1/KCNE1 potassium channels are expressed exclusively in the apical membrane of marginal cells (MCs) in the stria vascularis (SV) and in vestibular dark cells"
    explanation: >-
      Confirms the strial marginal cell localization of the KCNQ1/KCNE1
      channel complex central to this node.
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The K+ concentration is markedly increased in the endolymph, and the influx of K+ into hair cells upon stimulation plays a pivotal role in transducing sound into neural signals."
    explanation: >-
      Establishes the mechanistic link between strial potassium secretion,
      the endolymph's high K+ concentration, and hair-cell mechanotransduction.
  downstream:
  - target: Endocochlear Potential Collapse and Hair Cell Degeneration
    description: >-
      Loss of strial potassium secretion collapses the endocochlear potential
      and the driving force for hair-cell mechanotransduction.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33514733
      reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Both Kcne1−/− and Kcnq1−/− mice exhibit an abnormal development of the endolymphatic space, severe degeneration of the hair cells (HCs), and spiral ganglion neurons (SGNs)"
      explanation: >-
        Direct mouse-model evidence that Kcne1 loss produces endolymphatic
        abnormality and hair cell/spiral ganglion degeneration, mirroring the
        Kcnq1 (JLNS1) model.
- name: Endocochlear Potential Collapse and Hair Cell Degeneration
  conforms_to: "sensorineural_hair_cell_loss#Hair Cell Mechanotransduction Failure and Death"
  role: intermediate
  biological_scale: CELLULAR
  description: >-
    Without the endocochlear potential, hair-cell mechanotransduction fails
    and cochlear hair cells undergo degeneration. Because mammalian cochlear
    hair cells do not regenerate, this loss is irreversible.
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:33514733
    reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Results showed early treatment prevented collapse of the Reissner's membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells."
    explanation: >-
      Demonstrates, by rescue, that untreated Kcne1 loss causes structural
      collapse of the cochlear duct and degeneration of inner ear cells.
  downstream:
  - target: Congenital Profound Bilateral Sensorineural Hearing Loss
    description: >-
      Irreversible hair-cell loss and collapse of the endocochlear potential
      produce permanent, congenital sensorineural hearing loss.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301579
      reference_title: "Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
      explanation: >-
        GeneReviews establishes congenital profound bilateral sensorineural
        hearing loss as a defining, present-from-birth feature of JLNS.
- name: Congenital Profound Bilateral Sensorineural Hearing Loss
  conforms_to: "sensorineural_hair_cell_loss#Progressive Sensorineural Hearing Loss"
  role: effector
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint of the cochlear branch of JLNS2: congenital,
    profound, bilateral sensorineural hearing loss present from birth. Unlike
    several other conformers of this module (e.g., noise- or age-related
    hearing loss), the JLNS deficit is typically already maximal at birth
    rather than accruing progressively over time; conformance here reflects
    the shared irreversible, non-regenerating hair-cell-loss endpoint rather
    than a claim of ongoing postnatal worsening.
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
    explanation: >-
      GeneReviews defines the congenital, profound, bilateral character of the
      hearing loss.
mechanistic_hypotheses:
- hypothesis_group_id: variant_specific_dominant_negative_vs_haploinsufficiency
  hypothesis_label: Variant-specific dominant-negative versus simple loss-of-function/haploinsufficiency KCNE1 mechanism
  status: EMERGING
  description: >-
    KCNE1 loss-of-function variants appear to split mechanistically by
    variant. A large 2025 functional screen found no apparent dominant-negative
    effect on wild-type IKs current among the KCNE1 variants it tested when
    coexpressed with wild-type KCNE1, consistent with a simple recessive
    loss-of-function/haploinsufficiency mechanism requiring biallelic loss for
    JLNS2. However, an independent study of KCNE1 nonsense and missense
    alleles reports that coassembly of certain other mutant KCNE1 monomers
    with wild-type KCNQ1 subunits produces dominant Romano-Ward syndrome via a
    dominant-negative mechanism. Whether these are truly non-overlapping
    variant classes, or whether the discrepancy partly reflects differences in
    the specific variants and assay conditions tested, is not yet resolved.
  evidence:
  - reference: PMID:41200805
    reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed no apparent dominant-negative effects when variant and wild-type KCNE1 were coexpressed."
    explanation: >-
      Direct functional data supporting a simple loss-of-function/
      haploinsufficiency mechanism for the specific KCNE1 variant panel tested.
  - reference: PMID:30461122
    reference_title: "Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism."
    explanation: >-
      Independent evidence that at least some KCNE1 missense variants act
      dominantly through a dominant-negative mechanism, the counterpoint this
      hypothesis has to reconcile with the functional screen's negative
      finding.
discussions:
- discussion_id: jlns2_no_kcne1_specific_human_cellular_model
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of IKs Current in Cardiac Myocytes
  - pathophysiology#Endocochlear Potential Collapse and Hair Cell Degeneration
  prompt: >-
    Does a patient-derived or genome-edited human cellular model carrying biallelic
    KCNE1 variants exist for either the cardiac or the cochlear branch of JLNS2?
  rationale: >-
    The flagship human cellular model of JLNS is a hiPSC-derived cardiomyocyte
    series that reproduces the severe features of the disease, but its two variants
    are both in KCNQ1, so it models JLNS1. On the cochlear side a review of JLNS
    experimental models states that JLNS-specific iPSC-derived inner hair cell
    models are lacking altogether. The consequence is that every human cellular
    claim about JLNS2 in this entry is either heterologous (the CHO-K1 voltage-clamp
    platform under experimental_models, which measures channel current but contains
    neither a cardiomyocyte action potential nor a stria vascularis) or is
    transferred from KCNQ1 disease. This matters more than the usual model gap
    because the two genotypes are not clinically interchangeable: the JLNS2 cardiac
    course appears milder, so a KCNQ1 model may overstate the severity of the
    cardiac branch it is being read across to.
  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, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1."
    explanation: >-
      Establishes that both variants in the landmark JLNS hiPSC model are KCNQ1,
      so the platform models JLNS1 and not the KCNE1 disease curated here.
  - 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: >-
      Shows the platform does successfully recapitulate JLNS features, which is why
      its restriction to KCNQ1 is a gap worth recording rather than a dead end.
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although JLNS‐specific iPS‐IHC models are lacking, existing protocols enable the replication of JLNS genotypes and mechanotransduction studies."
    explanation: >-
      A review of JLNS experimental models stating that JLNS-specific iPSC-derived
      inner hair cell models do not exist. This is the closest published statement
      to the cochlear half of this gap; note it concerns hair cells, whereas the
      initiating JLNS2 cochlear lesion is in the stria vascularis marginal cell, for
      which the review describes no model either.
  proposed_experiments:
  - experiment_id: exp_jlns2_kcne1_ipsc_cardiomyocyte_and_strial_models
    name: KCNE1-biallelic hiPSC cardiomyocyte and stria vascularis marginal-cell models
    description: >-
      Reprogram cells from a genotype-confirmed JLNS2 patient, or introduce a
      reported biallelic KCNE1 null allele into a control hiPSC line by genome
      editing, then run two arms. Cardiac arm: differentiate to cardiomyocytes and
      compare IKs density, action potential duration and adrenergic response against
      the existing KCNQ1 JLNS1 lines in parallel, so the KCNE1-versus-KCNQ1 severity
      difference seen clinically is tested rather than inferred. Cochlear arm:
      differentiate to stria vascularis marginal cells, or an equivalent cochlear
      potassium-secreting epithelium, and measure apical potassium secretion and
      transepithelial potential. The cochlear arm deliberately targets the strial
      epithelium rather than the inner hair cell, because the primary JLNS2 cochlear
      lesion is a marginal-cell ionic defect and hair cell degeneration is downstream
      of endocochlear potential collapse, so a hair-cell model would not test the
      initiating step. Published differentiation protocols exist for inner hair cells
      but not for this cell type, which is itself part of the gap.
    would_support:
    - pathophysiology#Loss of IKs Current in Cardiac Myocytes
    - pathophysiology#Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
    supporting_outcome:
    - >-
        KCNE1-biallelic cardiomyocytes show reduced IKs and prolonged action potential
        duration relative to isogenic controls, with a smaller effect size than the
        KCNQ1 lines, matching the milder clinical course reported for JLNS2.
    - >-
        KCNE1-biallelic strial marginal cells show reduced apical potassium secretion
        and a reduced transepithelial potential relative to isogenic controls.
    would_refute:
    - pathophysiology#Loss of IKs Current in Cardiac Myocytes
    - pathophysiology#Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
    refuting_outcome:
    - >-
        KCNE1-biallelic cardiomyocytes show IKs density and action potential duration
        indistinguishable from isogenic controls, which would place the cardiac branch
        of this entry's mechanism in question for this genotype.
    - >-
        KCNE1-biallelic strial marginal cells secrete potassium and sustain a
        transepithelial potential indistinguishable from isogenic controls, which
        would place the cochlear branch in question for this genotype.
- discussion_id: jlns2_vestibular_human_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - "pathophysiology#Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells"
  prompt: >-
    Do genotype-confirmed human JLNS2 (biallelic KCNE1) patients have
    clinically significant vestibular dysfunction, as Kcne1-/- mice do?
  rationale: >-
    Kcne1-/- mice show clear structural and functional vestibular involvement:
    KCNQ1/KCNE1 channels are expressed in vestibular dark cells as well as
    strial marginal cells, and untreated Kcne1-/- mice show abnormal
    endolymphatic-space development, vestibular hair cell degeneration, and
    impaired vestibular behavior that gene therapy can rescue (PMID:33514733).
    However, the only quantitative human vestibular study of JLNS
    (PMID:25471708) genotyped its cohort and found all 14 tested cases carried
    double KCNQ1 (JLNS1) mutations, not KCNE1. Whether the mouse vestibular
    phenotype translates to genotype-confirmed human JLNS2 patients is
    therefore untested, and this entry deliberately does not curate vestibular
    dysfunction as an established JLNS2 phenotype.
  evidence:
  - reference: PMID:33514733
    reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction."
    explanation: >-
      Source of the mouse-model vestibular-dysfunction claim that motivates
      this discussion.
  proposed_experiments:
  - experiment_id: exp_jlns2_genotype_stratified_vestibular_function
    name: Genotype-stratified human vestibular function study in JLNS2
    description: >-
      Vestibular function testing (post-rotatory nystagmus, video head impulse
      testing) in a cohort of genotype-confirmed KCNE1/JLNS2 patients,
      analogous to the KCNQ1-genotyped study already published for JLNS1
      (PMID:25471708).
phenotypes:
- category: Ear
  name: Congenital Profound Bilateral Sensorineural Hearing Loss
  description: >-
    Congenital, profound, bilateral sensorineural hearing loss is a defining
    feature of JLNS, present from birth or identified on newborn hearing
    screening.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
    explanation: >-
      GeneReviews establishes congenital profound bilateral sensorineural
      hearing loss as a defining feature of JLNS.
  notes: >-
    The band is VERY_FREQUENT (80-99%) rather than OBLIGATE (100%), and the
    distinction is in the qualifier rather than in the feature. Congenital
    sensorineural deafness itself is definitional: GeneReviews characterises
    JLNS by it and the diagnosis requires it, so hearing loss as such would
    justify OBLIGATE. What this phenotype asserts is the *profound* bilateral
    form named in its title, and severity is not uniform across reported
    patients, so the lower band avoids over-claiming on a qualifier the sources
    do not quantify. Splitting the difference the other way - OBLIGATE on a
    profundity claim - would assert more than GeneReviews supports.

    This is still a different kind of claim from the undenominated "frequent"
    that was rejected as a frequency source for the iron-deficiency anemia and
    hypergastrinemia phenotypes: those have no numerator, no denominator and no
    definitional standing, whereas this one is bounded below by a diagnostic
    criterion.
- category: Cardiovascular
  name: Prolonged QT Interval
  description: >-
    Marked prolongation of the corrected QT interval (QTc), usually greater
    than 500 msec, is a defining feature of JLNS.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec."
    explanation: >-
      GeneReviews establishes marked QTc prolongation as a defining feature of
      JLNS.
- category: Cardiovascular
  name: Ventricular Arrhythmia
  description: >-
    Genotype-confirmed KCNE1 (JLNS2) patients are at risk of definite
    arrhythmic events (appropriate ICD shock, aborted cardiac arrest, or
    sudden cardiac death), reported at a lower rate than in KCNQ1 (JLNS1)
    patients in the largest comparative cohort to date.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:31941373
    reference_title: "An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5%"
    explanation: >-
      Direct quantitative arrhythmic event rate in the largest reported
      genotype-confirmed JLNS2 cohort.
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Children carrying KCNQ1 variants exhibit an approximately sixfold higher risk of ventricular arrhythmia than those with KCNE1 variants."
    explanation: >-
      Quantifies the reduced, but nonzero, ventricular arrhythmia risk
      associated specifically with KCNE1 (JLNS2) genotypes relative to KCNQ1
      (JLNS1).
- category: Cardiovascular
  name: Torsade de Pointes
  description: >-
    QTc prolongation in JLNS is associated with episodes of torsade de pointes
    ventricular tachycardia, which may culminate in syncope or sudden death.
  phenotype_term:
    preferred_term: Torsade de pointes
    term:
      id: HP:0001664
      label: Torsade de pointes
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Prolongation of the QTc interval is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death."
    explanation: >-
      GeneReviews documents torsade de pointes as a characteristic
      tachyarrhythmia in JLNS.
- category: Cardiovascular
  name: Syncope
  description: >-
    The classic presentation of JLNS is a deaf child who experiences
    syncopal episodes during periods of stress, exercise, or fright.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright."
    explanation: >-
      GeneReviews describes the classic exertion/emotion-triggered syncopal
      presentation of JLNS.
- category: Cardiovascular
  name: Sudden Cardiac Death Risk
  description: >-
    Untreated JLNS carries a high risk of premature death from malignant
    ventricular arrhythmia; more than half of untreated children die before
    age 15 years.
  phenotype_term:
    preferred_term: Sudden death
    term:
      id: HP:0001699
      label: Sudden death
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More than half of untreated children with JLNS die before age 15 years."
    explanation: >-
      GeneReviews establishes the high untreated mortality of JLNS overall.
- category: Hematologic
  name: Iron-Deficiency Anemia
  description: >-
    Iron-deficient anemia is a frequent, non-cardioauditory feature of JLNS,
    of uncertain mechanistic relationship to the primary channelopathy.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."
    explanation: >-
      GeneReviews lists iron-deficient anemia among the frequent additional
      features of JLNS.
  notes: >-
    frequency is deliberately omitted. GeneReviews calls this a "frequent" feature
    but gives no percentage and no denominator, and the statement is about JLNS as
    a whole rather than about KCNE1-genotyped patients, so assigning the 30-79%
    FREQUENT band would be a guess on two counts.
- category: Gastrointestinal
  name: Elevated Serum Gastrin
  description: >-
    Elevated serum gastrin levels are a frequent, non-cardioauditory feature
    of JLNS.
  phenotype_term:
    preferred_term: Hypergastrinemia
    term:
      id: HP:0500167
      label: Hypergastrinemia
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."
    explanation: >-
      GeneReviews lists elevated gastrin as a frequent additional feature of
      JLNS.
  notes: >-
    frequency is deliberately omitted, for the same reason as the iron-deficiency
    anemia phenotype: GeneReviews' "frequent" is qualitative, undenominated, and
    stated for JLNS as a whole rather than for KCNE1-genotyped patients.
- category: Cardiovascular
  name: Bradycardia
  description: >-
    Bradycardia is reported as the earliest cardiac manifestation of JLNS,
    detectable from fetal life. It is not the documented reason for cardiologic
    referral: the same source attributes presentation to cardiology to prolonged
    QT intervals and T-wave alternans.
  phenotype_term:
    preferred_term: Bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Children diagnosed with JLNS typically exhibit bradycardia beginning in the fetal stage"
    explanation: >-
      Reports fetal-onset bradycardia as a typical finding in children diagnosed
      with JLNS.
  notes: >-
    Reported for JLNS as a whole; no KCNE1-genotyped series has separately
    quantified bradycardia in JLNS2.
- category: Cardiovascular
  name: T-Wave Alternans
  description: >-
    Beat-to-beat alternation of T-wave amplitude or polarity, a marker of
    repolarization instability, is a presenting electrocardiographic finding in
    JLNS alongside the prolonged QT interval.
  phenotype_term:
    preferred_term: T-wave alternans
    term:
      id: HP:0012266
      label: T-wave alternans
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "commonly present to the cardiology department with symptoms due to prolonged QT intervals and T‐wave alternans"
    explanation: >-
      Names T-wave alternans, together with QT prolongation, as the
      electrocardiographic presentation that brings JLNS patients to cardiology.
  notes: >-
    Mechanistically continuous with the loss of repolarization reserve modeled in
    the pathophysiology chain, but curated as an observed ECG phenotype rather
    than as a separate mechanism node. Reported for JLNS as a whole.
- category: Neurologic
  name: Gross Motor Developmental Delay
  description: >-
    Gross motor developmental delay is reported in a subset of JLNS patients. It
    is one of the non-cardioauditory features of the syndrome and its relationship
    to the primary channel defect is not established; vestibular involvement and
    the consequences of recurrent cerebral hypoperfusion during arrhythmic events
    are both plausible contributors and neither has been demonstrated in JLNS2.
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some patients display gastrointestinal symptoms, secondary hypochromic anemia, and gross motor developmental delay"
    explanation: >-
      Lists gross motor developmental delay among the features displayed by a
      subset of JLNS patients.
  notes: >-
    Reported for JLNS as a whole and only in a subset of patients; frequency is
    deliberately omitted because the source says only "some patients". No
    KCNE1-genotyped data on motor development were identified.
biochemical:
- name: Elevated serum gastrin
  presence: INCREASED
  biomarker_term:
    preferred_term: serum gastrin concentration
    term:
      id: NCIT:C74858
      label: Gastrin Measurement
  notes: >-
    The measurable counterpart of the Hypergastrinemia phenotype. KCNQ1/KCNE1
    channels are expressed in gastric parietal cells as well as in heart and inner
    ear, which is the usual explanation offered for this finding, but no study has
    demonstrated that mechanism in KCNE1-genotyped JLNS2 patients and it is not
    modeled as a pathophysiology node here. No readouts are declared for the same
    reason: there is no mechanism node in this entry that gastrin would report on,
    and pointing the readout at the phenotype it already restates would be
    circular.
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."
    explanation: >-
      GeneReviews lists elevated gastrin among the frequent additional features of
      JLNS, establishing it as a recognized laboratory abnormality of the syndrome.
- name: Reduced hemoglobin (hypochromic, iron-deficient)
  presence: DECREASED
  biomarker_term:
    preferred_term: hemoglobin concentration
    term:
      id: NCIT:C64848
      label: Hemoglobin Measurement
  notes: >-
    The measurable counterpart of the Iron-Deficiency Anemia phenotype, and the
    laboratory finding behind the GeneReviews recommendation to give standard
    iron-deficiency treatment (curated in treatments). Two independent sources
    describe the anemia as hypochromic and iron-deficient; neither stratifies by
    causal gene.
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS."
    explanation: >-
      GeneReviews lists iron-deficient anemia among the frequent additional features
      of JLNS.
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some patients display gastrointestinal symptoms, secondary hypochromic anemia, and gross motor developmental delay"
    explanation: >-
      Independently reports secondary hypochromic anemia in a subset of JLNS
      patients, supporting the hypochromic character of the anemia.
environmental:
- name: Exertion, Emotional Stress, or Sudden Fright
  exposure_term:
    preferred_term: exposure to strenuous exercise
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright."
    explanation: >-
      Establishes that exertion is a recognized exposure in JLNS rather
      than an inferred one. The mechanism link below carries its own
      evidence for the separate claim that this exposure acts on the
      arrhythmogenic substrate node.
  influences_mechanisms:
  - target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Exertion, emotional stress, and sudden fright are the classic
      adrenergic triggers for syncopal arrhythmic events in JLNS; the same
      triggers motivate the anti-adrenergic rationale of beta-blocker
      therapy and the exercise/trigger-avoidance counseling in
      treatments.
    evidence:
    - reference: PMID:20301579
      reference_title: "Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright."
      explanation: >-
        GeneReviews documents exertion, emotional stress, and sudden fright
        as the classic triggers of syncopal arrhythmic events in JLNS.
  notes: >-
    Modeled here specifically for exertion/exercise, the concept with an
    available ECTO exposure term (ECTO:6000031, exposure to strenuous
    exercise); emotional stress and sudden fright are named in the same
    GeneReviews sentence but have no comparably specific ECTO exposure term
    and are recorded only in this node's free-text description.
- name: General Anesthesia and Perioperative Exposure
  exposure_term:
    preferred_term: exposure to anesthetics
    term:
      id: ECTO:2000059
      label: exposure to anesthetics
  evidence:
  - 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 names anesthesia as a circumstance carrying increased arrhythmia
      risk in JLNS, establishing it as a recognized exposure rather than an
      inferred one. The mechanism link below carries separate evidence for the
      claim that this exposure acts on the arrhythmogenic substrate node.
  influences_mechanisms:
  - target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Anesthesia is an identified precipitant of ventricular arrhythmia in JLNS,
      acting on the same repolarization-reserve-depleted substrate as the adrenergic
      triggers. This is the exposure behind the perioperative caution already
      recorded on the cochlear implantation treatment, where arrhythmic events
      during implant surgery have been documented.
    evidence:
    - reference: PMID:42389506
      reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "activities such as exercise, including swimming, emotional states, auditory stimuli, anesthesia, and feverish conditions have been identified as potential triggers of cardiac arrhythmia in children with JLNS"
      explanation: >-
        Lists anesthesia explicitly among the identified triggers of cardiac
        arrhythmia in children with JLNS, which is the causal claim this edge makes.
    - 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 attributes the need for anesthetic precautions specifically to
        increased arrhythmia risk, tying the exposure to the arrhythmogenic node.
  notes: >-
    The same source lists fever, hypokalemia and swimming as further precipitants,
    and reports that some JLNS cases are first detected when an intercurrent fever,
    diarrhea or hypokalemia prompts an ECG. Those are recorded here rather than as
    separate environmental entries because no ECTO exposure term was found for
    febrile illness or for hypokalemia. Auditory stimuli are also listed as a
    generic long-QT trigger in that sentence but are deliberately not modeled for
    JLNS2: these patients have congenital profound deafness, so a startle-by-sound
    trigger cannot be assumed to transfer to them, and no JLNS-specific report of
    it was identified.

    Both sources are syndrome-level: GeneReviews and the review both describe JLNS
    as a whole, and neither stratifies the anesthetic hazard by causal gene.
treatments:
- name: Beta-Blocker Therapy
  description: >-
    First-line anti-adrenergic pharmacotherapy for JLNS, though reported to be
    only partially effective; arrhythmia persists in a substantial proportion
    of patients despite beta-blocker treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: beta-blocker therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  target_mechanisms:
  - target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
    treatment_effect: INHIBITS
    description: >-
      Anti-adrenergic therapy reduces the likelihood that exertion- or
      emotion-related sympathetic triggers will precipitate malignant
      ventricular arrhythmia.
    evidence:
    - reference: PMID:20301579
      reference_title: "Jervell and Lange-Nielsen Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "beta-adrenergic blockers for long QT interval (Note: Beta-blocker treatment is only partially effective.)"
      explanation: >-
        GeneReviews recommends beta-blockers as first-line therapy while
        explicitly noting only partial effectiveness in JLNS.
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The efficacy of beta‐blockers and left cardiac sympathetic denervation is limited in patients with JLNS, as arrhythmia persists in 51%–85% of cases despite beta‐blocker treatment"
    explanation: >-
      Quantifies the limited efficacy of beta-blocker therapy in JLNS,
      motivating escalation to device therapy in many patients.
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Beta-blocker dose should be regularly assessed for efficacy and adverse effects, with evaluation every three to six months during rapid growth phases"
    explanation: >-
      GeneReviews surveillance guidance: beta-blocker dosing requires
      periodic reassessment, especially during rapid childhood growth
      phases, because weight-based dosing can fall out of therapeutic range.
  notes: >-
    GeneReviews recommends reassessing beta-blocker dose for efficacy and
    adverse effects every three to six months during rapid growth phases.
- name: Implantable Cardioverter-Defibrillator Placement
  description: >-
    Device therapy for patients with a history of cardiac arrest, malignant
    events despite beta-blocker therapy, or otherwise judged high risk.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "implantable cardioverter defibrillators (ICDs) for those with a history of cardiac arrest and/or failure to respond to other treatments"
    explanation: >-
      GeneReviews recommends ICD placement for high-risk or treatment-refractory
      JLNS patients.
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "periodic evaluations of ICDs for inappropriate shocks and pocket or lead complications"
    explanation: >-
      GeneReviews surveillance guidance: implanted devices require periodic
      evaluation for inappropriate shocks and pocket/lead complications.
  - 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: "Among JLNS patients treated with beta-blockers, the cumulative probability of LQTS-related death was 35%; defibrillator therapy was associated with a 0% mortality rate during a mean (+/-SD) follow-up period of 4.9 +/- 3.4 years."
    explanation: >-
      Quantifies the outcome difference between beta-blocker therapy alone and
      defibrillator therapy in this non-randomised JLNS registry cohort. The
      authors' own conclusion is correspondingly hedged - defibrillator therapy
      "appears to improve outcome", with longer follow-up needed.
  notes: >-
    GeneReviews recommends periodic ICD evaluation for inappropriate shocks
    and pocket or lead complications.

    The device-versus-beta-blocker outcome figures come from a JLNS registry
    cohort that was defined phenotypically rather than genotypically, so they are
    syndrome-level and carry no KCNE1-specific efficacy claim.
- name: Left Cardiac Sympathetic Denervation
  description: >-
    Surgical anti-adrenergic escalation considered when arrhythmia persists
    despite beta-blocker therapy or when device therapy is unsuitable; a
    review of JLNS management describes beta-blocker and left cardiac
    sympathetic denervation efficacy as both limited, since arrhythmia
    persists in 51-85% of cases despite beta-blocker treatment.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: left cardiac sympathetic denervation
    term:
      id: NCIT:C51931
      label: Ganglionectomy
  target_mechanisms:
  - target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
    treatment_effect: INHIBITS
    description: >-
      Left cardiac sympathetic denervation reduces arrhythmia-provoking
      sympathetic input when pharmacologic anti-adrenergic therapy (beta
      blockade) is insufficient.
    evidence:
    - reference: PMID:42389506
      reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The efficacy of beta‐blockers and left cardiac sympathetic denervation is limited in patients with JLNS, as arrhythmia persists in 51%–85% of cases despite beta‐blocker treatment"
      explanation: >-
        States that left cardiac sympathetic denervation is used alongside
        beta-blockade in JLNS management, though the same review notes both
        interventions have limited efficacy against persistent arrhythmia.
  evidence:
  - reference: PMID:42389506
    reference_title: "Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "left cervical sympathectomy is planned if malignant ventricular arrhythmias recur"
    explanation: >-
      Documents left cardiac sympathetic denervation (cervical sympathectomy)
      as the planned escalation step in JLNS patients with recurrent
      malignant ventricular arrhythmia.
  notes: >-
    Efficacy data are JLNS-wide (both JLNS1 and JLNS2) rather than
    KCNE1-genotype-specific; no genotype-stratified LCSD outcome data for
    JLNS2 alone were identified.

    NCIT has no sympathectomy or denervation term: searches for sympathectomy,
    sympathetic denervation, cardiac sympathetic and denervation all return
    nothing. NCIT:C51931 (Ganglionectomy, "the surgical removal of a ganglion",
    reachable from NCIT:C25218 via NCIT:C15329) is bound instead of the generic
    Surgical Procedure because that is the procedure LCSD is - removal of the
    lower left stellate ganglion together with the upper thoracic ganglia. The
    laterality and the cardiac indication are carried by preferred_term, which
    the ontology term cannot express.
- name: Catheter Ablation of Triggering Ectopy
  description: >-
    Radiofrequency catheter ablation of the premature ventricular contraction
    that triggers arrhythmia storm has been reported as an effective
    alternative or adjunct to device therapy in an individual genotype-confirmed
    KCNE1 (JLNS2) patient who could not undergo ICD implantation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac radiofrequency ablation
    term:
      id: NCIT:C170884
      label: Cardiac Radiofrequency Ablation
  evidence:
  - reference: PMID:33040543
    reference_title: "Treatment on arrhythmia electric storm in a Jervell and Lange-Nielsen syndrome patient by ablation of the triggering premature ventricular contraction: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ablation was successfully performed to eliminate the triggering PVC... During the 12-month follow-up, no syncope or fatal arrhythmia was found in this patient."
    explanation: >-
      Direct clinical case report of successful radiofrequency ablation
      controlling fatal arrhythmia in a genotype-confirmed KCNE1 patient.
  notes: >-
    Reported in a single genotype-confirmed KCNE1 patient who could not
    undergo ICD implantation for economic reasons; not established as a
    JLNS2-specific standard of care.
- name: Cochlear Implantation
  description: >-
    Surgical cochlear implantation to treat the congenital profound
    sensorineural hearing loss of JLNS.
  therapeutic_modality: SURGERY
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cochlear implantation to treat hearing loss"
    explanation: >-
      GeneReviews lists cochlear implantation as standard management of
      hearing loss in JLNS.
  - reference: PMID:31846911
    reference_title: "Cochlear Implantation in Congenital Long-QT Syndrome: A Comprehensive Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fatal Arrhythmias were encountered intra-operatively in five patients which was treated with cardiac pacing."
    explanation: >-
      Documents fatal intraoperative arrhythmia during cochlear implantation in a
      long-QT cohort, establishing the perioperative hazard as observed rather than
      theoretical.
  - reference: PMID:31846911
    reference_title: "Cochlear Implantation in Congenital Long-QT Syndrome: A Comprehensive Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Preoperative prophylactic Beta blockers, avoiding sympathetic stimulation and drugs prolonging QT interval with rational use of Magnesium Sulphate and standby of defibrillator were the standard precautions practised."
    explanation: >-
      Sets out the specific perioperative precaution protocol used in that cohort,
      which is the actionable content of this caution.
  notes: >-
    Perioperative arrhythmia is the specific hazard of this operation in this
    population, which is why two of the three evidence items on this treatment are
    about the precautions rather than about the hearing outcome. The implantation series
    cited is a congenital long-QT-with-hearing-loss cohort that was not genotyped,
    so it is JLNS-spectrum rather than KCNE1-specific; it is used here for the
    procedural precaution, not for any JLNS2 outcome claim. A JLNS review makes the
    same point (PMID:42389506).
- name: Avoidance of QT-Prolonging Drugs and Arrhythmia Triggers
  description: >-
    Avoidance of drugs that further prolong the QT interval and of activities
    or circumstances known to precipitate syncopal events, plus special
    anesthetic precautions given the increased risk of arrhythmia during
    anesthesia.
  therapeutic_modality: BEHAVIORAL
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: risk factor avoidance counseling
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Agents/circumstances to avoid: Drugs that cause further prolongation of the QT interval; activities known to precipitate syncopal events in persons with long QT syndrome."
    explanation: >-
      GeneReviews specifies the agents and circumstances to avoid in JLNS
      management.
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Training for family members in cardiopulmonary resuscitation; use of an ID bracelet explaining the diagnosis; notifying local emergency medical services of high-risk persons with JLNS."
    explanation: >-
      GeneReviews recommends family CPR training and emergency-preparedness
      measures as part of routine JLNS risk-factor avoidance and emergency
      planning.
  notes: >-
    GeneReviews also recommends ensuring availability of automated external
    defibrillators where appropriate, family training in cardiopulmonary
    resuscitation, use of a medical-alert ID bracelet, and notifying local
    emergency medical services of high-risk individuals.
- name: Genetic Counseling
  description: >-
    Autosomal recessive genetic counseling for families, including the 25%
    per-pregnancy recurrence risk for carrier couples, evaluation of at-risk
    relatives by newborn hearing screening and ECG, and consideration of
    whether a mother carrying an affected fetus herself has long QT syndrome.
  therapeutic_modality: OTHER
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At conception, each sib of an affected individual usually has a 25% chance of being affected with JLNS, a 50% chance of being a carrier of a JLNS-causing pathogenic variant and potentially at risk for LQTS, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      GeneReviews specifies the recurrence-risk figures used in genetic
      counseling for JLNS families.
- name: Iron Repletion for Iron-Deficiency Anemia
  description: >-
    Standard iron-deficiency treatment for the iron-deficient, hypochromic anemia
    that is a frequent non-cardioauditory feature of JLNS. GeneReviews specifies
    standard rather than JLNS-specific management, so no disease-specific dosing or
    target is asserted here.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: iron repletion pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: iron
      term:
        id: CHEBI:18248
        label: iron atom
  target_phenotypes:
  - preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "standard treatment for those with iron-deficiency anemia"
    explanation: >-
      GeneReviews includes standard iron-deficiency anemia treatment in the
      management of JLNS.
  - 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: >-
      Establishes the iron-deficient anemia that this treatment addresses as a
      frequent feature of the syndrome rather than an incidental comorbidity.
  notes: >-
    The agent is bound to the element rather than to a salt: GeneReviews specifies
    only "standard treatment", so naming ferrous sulfate or any other preparation
    would assert more than the source does. NCIT has no generic iron pharmacologic
    substance under NCIT:C1909, and NCIT:C210688 (Iron Supplement) is outside the
    ChemicalEntityTerm hierarchy, so CHEBI:18248 is the most specific term that is
    both accurate and bindable here.

    No target_mechanisms link is declared: iron repletion treats a downstream
    hematologic consequence and does not act on any mechanism node in this entry's
    pathograph, whose two branches are cardiac and cochlear. Management guidance is
    syndrome-level and not stratified by causal gene.
- name: Atrial Pacing with Beta-Blockade
  description: >-
    Atrial pacing combined with escalated beta-blocker dosing, reported in young
    high-risk JLNS children as an alternative to early ICD implantation, which is
    technically difficult at that age. In a Norwegian series of genetically
    confirmed JLNS patients, six children with atrial leads had no arrhythmic
    events over a mean 6.9 years, while the one patient given a ventricular lead
    died during follow-up. The authors propose it as a bridge to a two-chamber ICD
    where left cardiac sympathetic denervation is unavailable.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cardiac 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: cardiac pacemaker
        term:
          id: NCIT:C94198
          label: Cardiac Pacemaker
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  target_mechanisms:
  - target: Arrhythmogenic Substrate and Ventricular Tachyarrhythmia
    treatment_effect: INHIBITS
    description: >-
      Atrial pacing added to escalated beta-blockade was followed by freedom from
      arrhythmic events in the reported series, which is the observed effect on this
      node. The usual electrophysiologic rationale - that raising the paced rate
      shortens the QT interval and removes the bradycardia-dependent pauses on which
      torsade de pointes initiates - is standard long-QT reasoning and is not tested
      or stated by the cited study, so it is named here as rationale rather than as
      a demonstrated mechanism.
    evidence:
    - reference: PMID:27451284
      reference_title: "The Jervell and Lange-Nielsen syndrome; atrial pacing combined with \u00df-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "No arrhythmic events occurred in 6 very young JLNS patients who received atrial pacing in combination with increased doses of beta-blockers during 7-year follow-up."
      explanation: >-
        Reports the absence of arrhythmic events under atrial pacing plus escalated
        beta-blockade, the outcome this mechanism link claims.
  evidence:
  - reference: PMID:27451284
    reference_title: "The Jervell and Lange-Nielsen syndrome; atrial pacing combined with \u00df-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?"
    supports: SUPPORT
    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: >-
      The event-free follow-up of the atrially paced patients, and by contrast the
      death of the single ventricular-lead patient, which is why the lead position
      is named in the description rather than left implicit.
  - reference: PMID:27451284
    reference_title: "The Jervell and Lange-Nielsen syndrome; atrial pacing combined with \u00df-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this treatment strategy may prevent life-threatening arrhythmias in this high-risk patient group and may act as a bridge to insertion of a 2-chamber ICD when left cardiac sympathetic denervation is not available."
    explanation: >-
      The authors' own framing of the strategy as a bridge to a two-chamber ICD,
      which is how it is positioned relative to the ICD treatment in this entry.
  notes: >-
    Nine patients, all Norwegian, and the authors present it as provisional
    ("if confirmed in additional patients"), so this is curated as a reported
    strategy rather than as standard care. The cohort is described as genetically
    confirmed JLNS but the causal gene is not broken out in the abstract, and
    Norwegian JLNS is predominantly KCNQ1, so no KCNE1-specific efficacy is claimed.
    The treatment term is the clinical action (NCIT:C80434, the sibling of the
    NCIT:C80435 used for ICD placement in this entry); the device itself is
    attached as a qualifier, per the device-versus-clinical-action convention.
    therapeutic_modality is DEVICE to match the ICD treatment, which is this
    treatment's nearest analogue in the file, even though the mechanical
    treatment_term-to-modality table would suggest SURGERY for a C15329-family
    procedure term.
animal_models:
- name: Kcne1 knockout mouse
  species: Mouse
  genotype: Kcne1-/-
  publication: PMID:33514733
  modeled_mechanisms:
  - target: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Kcne1-/- mice lack Kcne1 expression in strial marginal cells and
      vestibular dark cells, the same cell types that express the KCNQ1/KCNE1
      complex in humans, and show abnormal endolymphatic-space development.
    limitations: >-
      Mouse cochlear structure, developmental timing, and the extent of
      vestibular involvement are not identical to human JLNS2; no
      genotype-confirmed human vestibular data exist for direct comparison
      (see the HUMAN_MODEL_MISMATCH discussion on this node).
    evidence:
    - reference: PMID:33514733
      reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Both Kcne1−/− and Kcnq1−/− mice exhibit an abnormal development of the endolymphatic space, severe degeneration of the hair cells (HCs), and spiral ganglion neurons (SGNs)"
      explanation: >-
        Supports treating the Kcne1-/- mouse as informative for the
        strial-marginal-cell potassium-secretion node: it reproduces the
        expected downstream endolymphatic and hair-cell consequences of losing
        the same channel complex.
    readouts:
    - name: Reissner's membrane and vestibular wall collapse
      target: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
      direction: RESTORED
      interpretation: >-
        Early AAV1-CB7-Kcne1 gene therapy via the posterior semicircular canal
        prevented collapse of Reissner's membrane and the vestibular wall and
        preserved normal semicircular canal size, demonstrating the causal role
        of Kcne1 loss in this structural degeneration.
      evidence:
      - reference: PMID:33514733
        reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Results showed early treatment prevented collapse of the Reissner's membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells."
        explanation: >-
          Rescue experiment demonstrating that structural cochlear/vestibular
          degeneration in Kcne1-/- mice is caused by loss of Kcne1 function.
    - name: Auditory brainstem response threshold
      target: Loss of IKs-Mediated Potassium Secretion in Stria Vascularis Marginal Cells
      direction: RESTORED
      interpretation: >-
        High-dosage gene therapy preserved auditory function in 16 of 20
        treated Kcne1-/- mice for at least five months, supporting a causal
        link between restored strial Kcne1 expression and preserved hearing.
      evidence:
      - reference: PMID:33514733
        reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months."
        explanation: >-
          Dose-dependent, quantitative auditory and vestibular functional
          rescue data from the Kcne1-/- mouse gene-therapy study.
  evidence:
  - reference: PMID:33514733
    reference_title: "Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1-/- mice to treat both the hearing and vestibular symptoms."
    explanation: >-
      Establishes the Kcne1-/- mouse as a genetically precise model of the
      human KCNE1 loss-of-function lesion underlying JLNS2.
experimental_models:
- name: CHO-K1 heterologous KCNQ1/KCNE1 expression with automated voltage clamp
  description: >-
    Chinese hamster ovary (CHO-K1) cells stably expressing human KCNE1, into which
    KCNE1 variants are coexpressed with KCNQ1 and the resulting IKs current is
    measured by high-throughput automated patch-clamp recording. Variants were
    studied in the homozygous state, which is the configuration that corresponds to
    biallelic JLNS2 genotypes, and a subset additionally in the heterozygous state
    corresponding to the dominant LQT5 configuration. This is the assay that
    supplies the loss-of-function mechanism and the carrier-frequency estimate
    curated elsewhere in this entry.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Chinese hamster
    term:
      id: NCBITaxon:10029
      label: Cricetulus griseus
  cell_source: >-
    CHO-K1 cell line stably expressing human KCNE1, with KCNQ1 and variant KCNE1
    introduced by transfection.
  culture_system: >-
    Heterologous expression in a non-excitable mammalian cell line with
    high-throughput automated patch-clamp electrophysiology.
  conditions:
  - 95 KCNE1 variants expressed in the homozygous state
  - a subset of variants additionally coexpressed with wild-type KCNE1 (heterozygous state)
  publication: PMID:41200805
  modeled_mechanisms:
  - target: Biallelic KCNE1 Loss of Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Expressing a KCNE1 variant in the homozygous state alongside KCNQ1 reproduces
      the molecular configuration of a JLNS2 genotype and measures the resulting IKs
      current directly, which is the node's claim.
    limitations: >-
      A non-excitable rodent cell line supplies neither the native cardiomyocyte
      action potential nor the stria vascularis epithelium, so the assay reports
      channel function in isolation and cannot show either downstream consequence.
      Channel subunit stoichiometry and trafficking in a heterologous system need
      not match the native tissue.
    readouts:
    - name: IKs peak current density and activation voltage-dependence
      target: Biallelic KCNE1 Loss of Function
      direction: DECREASED
      interpretation: >-
        Reduced peak IKs current density in the homozygous configuration is the
        direct measurement of the loss of function this node asserts.
      evidence:
      - reference: PMID:41200805
        reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "When examined in the homozygous state, 68 KCNE1 variants exhibited significant differences in at least 1 functional property compared with wild-type KCNE1"
        explanation: >-
          Reports the number of KCNE1 variants with significantly altered function when
          expressed in the homozygous state, the measurement this readout records.
    evidence:
    - reference: PMID:41200805
      reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We determined the functional properties of 95 KCNE1 variants coexpressed with KCNQ1 in heterologous cells using high-throughput voltage-clamp recording."
      explanation: >-
        States the model system and assay, establishing that this heterologous
        expression platform is what was used to determine KCNE1 variant function and
        is therefore informative for the biallelic-loss node.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The cardiomyocyte action potential and the stria vascularis epithelium are
        outside the model boundary. The assay measures the channel current only, so
        every downstream node in both branches of this entry's pathograph is
        inferred rather than observed here.
      evidence:
      - reference: PMID:41200805
        reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The most widely used approach for determining the functional consequences of an ion channel variant involves heterologous expression of a recombinant channel coupled with voltage-clamp electrophysiological recording."
        explanation: >-
          Describes the assay as heterologous expression of a recombinant channel,
          which is what places the cardiomyocyte and the stria vascularis outside
          the model boundary.
    - divergence_type: SPECIES_MISMATCH
      materiality: IMMATERIAL
      description: >-
        The host cell is Chinese hamster rather than human, but the expressed
        channel subunits are both human and the readout is the current those human
        subunits carry, so the host species does not bear on this link's claim.
      evidence:
      - reference: PMID:41200805
        reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Chinese hamster ovary (CHO) subclone K1 (CHO-K1) cells (catalog #CCL-61, American Type Culture Collection, Manassas, VA), or CHO-K1 cells constitutively expressing human KCNE1 (designated CHO-KCNE1 cells)"
        explanation: >-
          Names the Chinese hamster host cell line, the species divergence recorded
          here, and shows the expressed KCNE1 subunit is the human one.
  evidence:
  - reference: PMID:41200805
    reference_title: "Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We determined the functional properties of 95 KCNE1 variants coexpressed with KCNQ1 in heterologous cells using high-throughput voltage-clamp recording."
    explanation: >-
      Describes the model system whose results are curated in this entry's genetic
      and prevalence sections.
  notes: >-
    This is the only KCNE1-specific experimental platform curated here. No
    JLNS2-specific iPSC-derived cardiomyocyte or inner-ear hair cell model was
    identified: the published JLNS iPSC work engineers KCNQ1 variants (JLNS1), and
    a review of JLNS experimental models states that JLNS-specific iPSC-derived
    inner hair cell models are lacking. Importing those KCNQ1 models here would
    breach this entry's KCNE1 scope, so the gap is recorded rather than filled.
diagnosis:
- name: Combined Clinical and Molecular Diagnostic Criteria
  description: >-
    JLNS2 is diagnosed by the combination of the characteristic phenotype
    (congenital sensorineural deafness plus a prolonged QT interval) and
    confirmatory molecular testing showing biallelic pathogenic KCNE1
    variants.
  results: >-
    A child presenting with congenital sensorineural deafness and a
    prolonged QT interval, in whom molecular testing identifies biallelic
    pathogenic KCNE1 (or KCNQ1) variants, meets the diagnostic criteria for
    JLNS.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:20301579
    reference_title: "Jervell and Lange-Nielsen Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of JLNS is established in a child with congenital sensorineural deafness, long QT interval, and presence of biallelic pathogenic variants in either KCNQ1 or KCNE1."
    explanation: >-
      GeneReviews states the combined clinical-plus-molecular diagnostic
      criteria for JLNS, of which the KCNE1 arm defines JLNS2.
- name: Molecular Genetic Testing
  description: >-
    Molecular confirmation of biallelic KCNE1 pathogenic variants is
    required to distinguish JLNS2 from JLNS1 (biallelic KCNQ1) and from
    heterozygous KCNE1-related dominant LQT5, which lacks congenital
    deafness.
  results: >-
    Detection of two pathogenic KCNE1 alleles (homozygous or compound
    heterozygous) in trans confirms JLNS2 and distinguishes it from the
    allelic dominant LQT5 phenotype, in which only one KCNE1 allele is
    affected.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:30461122
    reference_title: "Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2"
    explanation: >-
      Establishes that molecular zygosity (biallelic versus heterozygous) is
      the diagnostic feature that separates JLNS2 from the milder dominant
      KCNE1 phenotype.
- name: Resting Electrocardiography with QTc Assessment
  description: >-
    Baseline 12-lead ECG measurement of the corrected QT interval is the core
    diagnostic procedure for identifying the QT-prolongation component of
    JLNS2.
  results: >-
    A markedly prolonged QTc, usually >500 msec in JLNS, supports the
    cardiac component of the diagnosis.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  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, genotype-mixed (90.5%
      KCNQ1/JLNS1): 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 as a whole, not a diagnostic
      threshold and not derived from a JLNS2-specific cohort: Schwartz et
      al.'s 186-patient cohort was 90.5% KCNQ1 (JLNS1), and that same cohort
      reports that patients with mutations on KCNE1 (JLNS2) have a more
      benign course and are a relatively lower-risk subgroup for cardiac
      arrest or sudden death. 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 JLNS2 is
      recorded: GeneReviews (PMID:20301579) characterises JLNS QTc generally
      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.
    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, genotype-mixed JLNS cohort.
    - 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: >-
        States that the JLNS2 (KCNE1) subgroup within this same cohort has a
        more benign course, the reason the 550 ms boundary above is not
        treated as a JLNS2-specific threshold.
    - 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; this abstract reports no genotype breakdown.
    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 as a whole;
        the cohort establishing this boundary was 90.5% KCNQ1 (JLNS1), and
        the KCNE1 (JLNS2) subgroup is reported to run a more benign course,
        so this band is not a JLNS2-specific risk estimate.
  notes: >-
    NCIT does not provide an ECG-specific diagnostic term here, so the
    preferred term is narrowed in the name and description.
  evidence:
  - reference: DOI:10.3390/children11050582
    reference_title: "Congenital Long QT Syndrome in Children and Adolescents: A General Overview"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by a prolongation of QTc interval on ECG"
    explanation: >-
      A 2024 congenital LQTS review states that ECG-measured QTc
      prolongation is the defining diagnostic feature of the QT-prolongation
      component shared by all congenital LQTS subtypes, including JLNS.
- name: Pure-Tone Audiometry
  description: >-
    Audiometric assessment documents the congenital bilateral sensorineural
    hearing loss that is the second defining feature of JLNS2, alongside the
    QT-prolongation component above.
  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 source describes JLNS deafness generally as profound but states no
    audiometric cut-off owned by the disease or specific to the KCNE1
    (JLNS2) subgroup, and a generic hearing-loss grading (such as the WHO
    grades) is not JLNS content, as on the Jervell_and_Lange-Nielsen_Syndrome_1
    entry.
  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.
clinical_trials:
- name: NCT06534671
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    A single-participant Vanderbilt University Medical Center trial testing
    the acute effect of a single intravenous dose of diltiazem, a calcium
    channel blocker, on the QT interval in a genetically confirmed JLNS
    patient. The trial's public summary does not specify whether the
    participant carried KCNQ1 or KCNE1 variants, so it is recorded here as
    JLNS-wide (not confirmed JLNS2-specific) evidence.
  target_phenotypes:
  - preferred_term: Prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: clinicaltrials:NCT06534671
    reference_title: "Diltiazem in Jervell and Lange-Nielsen Syndrome"
    supports: SUPPORT
    snippet: "This study will test the effect of diltiazem, a calcium channel blocking drug, on the QT interval in patients with Jervell and Lange-Nielsen syndrome. This will be a single IV dose and acute effects (within minutes) will be observed."
    explanation: >-
      ClinicalTrials.gov summary of the only identified JLNS-specific
      interventional trial testing a candidate acute QT-shortening agent.
  notes: >-
    Completed October 2024 with a single enrolled participant; no
    peer-reviewed efficacy results have been identified. Experimental, not a
    standard-of-care treatment; not added to the treatments section pending
    published results.
datasets: []
references:
- reference: PMID:20301579
  title: Jervell and Lange-Nielsen Syndrome.
  tags:
  - GeneReviews
  findings: []

📚

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 (2)

Augment JLNS2: classifications, progression, biochemical, models, new phenotypes and treatments · 2026-09-06T17:48:40Z · View source

Augmentation pass over the existing JLNS2 (KCNE1) entry created in PR #8811. Deep research: two fresh runs this session, falcon (Edison, 23 citations, 7/7 references verified, confabulation_rate 0.0) and openscientist (19 citations, 19/19 verified). Both reports' Reference Validation and Term Validation sections were read before any content was taken. Neither reported an unresolved reference or an unresolved CURIE. Falcon's single "mislabelled term" is the template placeholder string "(if available)" being parsed as a label for MONDO:0012871, not a real term error. OpenScientist reported two genuine mislabels - it calls UBERON:0002282 "organ of Corti" (actually stria vascularis of cochlear duct) and UBERON:0002295 "stria vascularis" (actually scala media) - so neither CURIE was taken from that report; the entry's pre-existing UBERON:0002282 binding was checked and is correct. The prior falcon report (18 citations, 4 references) was overwritten by the fresh run; the previous version remains in git history. Sections added: classifications (harrisons_chapter CARDIOVASCULAR + DISORDER_OF_EAR + GENETICS_ENVIRONMENT_DISEASE, each separately cited; channelopathy_category "cardiac channelopathy", with a note recording that the enum is single-valued and that the cochlear lesion is an epithelial transport defect that would otherwise take a second value); progression (4 phases - fetal/neonatal recognition, childhood arrhythmic onset, untreated natural history, and a KCNE1-genotype-specific phase); biochemical (serum gastrin, hemoglobin); three phenotypes (Bradycardia HP:0001662, T-Wave Alternans HP:0012266, Gross Motor Developmental Delay HP:0001270); frequency: FREQUENT on Iron-Deficiency Anemia and Elevated Serum Gastrin per the GeneReviews "frequent features" sentence; an environmental entry for general anesthesia (ECTO:2000059) with a TRIGGERS mechanism link to the arrhythmogenic substrate node; two treatments (Iron Repletion for Iron-Deficiency Anemia; Atrial Pacing with Beta-Blockade); experimental_models (the CHO-K1 heterologous KCNQ1/KCNE1 automated-voltage-clamp platform, with a modeled_mechanisms link carrying model_scale MOLECULAR, a readout, and two typed divergences); a KNOWLEDGE_GAP discussion recording that no KCNE1-specific human cellular model exists; and case_fractions on the KCNE1 genetic entry. New evidence was also added to existing records: the IKs repolarization-reserve mechanism on the cardiac node (PMID:33963564), the Schwartz/Goldenberg JLNS registry natural history on progression and on the ICD treatment (PMID:16911578), and documented perioperative arrhythmia plus the precaution protocol on cochlear implantation (PMID:31846911). New references cached and cited: PMID:16911578, PMID:33963564, PMID:27451284, PMID:31846911, PMID:30942114, PMID:25453094, PPR:PPR1109906. PMID:25453094 (the landmark JLNS hiPSC-cardiomyocyte series) is cited only as evidence for the model gap, because both of its variants are in KCNQ1 and it therefore models JLNS1. PMID:30942114 is a negative result - no pathogenic KCNE1 variant in 14 Iranian JLNS families, only the common c.112G>A polymorphism - recorded as a 0% case fraction with the caveat that the Sanger-only screen would miss a CNV and that the cohort is too small for zero to exclude a low single-digit share. PPR:PPR1109906 is cited by its Europe PMC preprint identifier rather than its DOI so that its snippets are gate-validated; it gives 1/52 (2%) KCNE1 in an Egyptian JLNS cohort, which is a contemporary refinement of the historical ~10% figure the entry previously carried alone. Two candidate references were deliberately not used: PMID:34308870 (deaf-school ECG screening) genotyped its cases to KCNQ1, and PMID:32508908 is a KCNQ1 compound-heterozygote family; citing either here would be Named Entity Confusion. Scope discipline: most of the newly added clinical content is syndrome-level (KCNQ1 and KCNE1 pooled) because no KCNE1-stratified data for those features exist. Every such record says so in its own notes, and a paragraph was added to the top-level notes stating which sections rest on syndrome-level sources. The only genotype-specific natural-history record is the KCNE1 phase of progression, from the 19-patient JLNS2 cohort. The atrial-pacing treatment's mechanism description was rewritten during self-review to state the observed outcome and to name the rate-shortens-QT rationale explicitly as standard long-QT reasoning that the cited Norwegian series does not test; that series is also described as genetically confirmed JLNS without breaking out the gene, and Norwegian JLNS is predominantly KCNQ1, so no KCNE1-specific efficacy is claimed. datasets: was left empty: just discover-datasets returned no GEO candidates, and the falcon report independently reports that no validated JLNS2-specific organoid, iPSC series, CRISPR screen, or omics dataset was found; the reasoning is recorded in the top-level notes so the empty section is not mistaken for an unchecked one. Term work: an initial binding of NCIT:C210688 (Iron Supplement) failed dynamic-enum validation because it is outside ChemicalEntityTerm, and was replaced with CHEBI:18248 (iron atom), which also avoids over-specifying a salt that GeneReviews does not name. A first draft of the atrial-pacing device qualifier used NCIT:C62273, which is "Mixed Neoplastic Glandular and Squamous Cell Population"; this was caught before commit and corrected to NCIT:C94198 (Cardiac Pacemaker). All 14 newly added CURIEs were re-verified label-exact against OAK, and just check-qualifier-terms-online resolved the two device qualifier terms against the ontology since a qualifier-only CURIE is never cached by anything else. Validation: just validate (schema + terms + references) passes; just validate-disorders (the batched pre-PR gate CI runs) passes; snippet audit reports 103/104 verified with 1 skipped by prefix, and just count-verified-snippets --unskip-prefix DOI reports 104/104 with the pre-existing DOI-keyed item included. check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-qualifier-terms-online, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading and check-environmental-evidence all clean. One snippet from PMID:16911578 initially failed because the validator strips bracketed spans and the source sentence carries [+/-SD]; it was shortened to a bracket-free substring and the dropped mean-age and QTc figures were moved into the phase notes. Compliance 96.8% global / 97.2% weighted before the last two additions; the remaining reported gaps are the deliberately empty datasets section and evidence on proposed_experiments, which are proposals rather than performed work.

Create: Jervell and Lange-Nielsen Syndrome 2 (KCNE1/JLNS2) · 2026-08-18T04:42:47Z · View source

Created new dismech entry for Jervell and Lange-Nielsen syndrome 2 (MONDO:0012871, OMIM:612347, KCNE1), resolving issue #8744. Used the falcon (Edison Scientific) deep-research provider (research/Jervell_and_Lange-Nielsen_Syndrome_2-deep-research-falcon.md); ran just preflight-dr against MONDO:0012871 (verdict SKIP because the automated lookup found no MONDO RO:0004003 gene assertion, but manual OMIM cross-check confirmed an exact match on 612347 and KCNE1 dominated report gene mentions 33:17 over KCNQ1). GeneReviews baseline fetched (PMID:20301579, a shared article covering both JLNS1 and JLNS2). Curated pathophysiology as two branches from a shared KCNE1 loss-of-function trigger node: a cardiac branch conforming to cardiac_ion_channel_repolarization (Cardiac Ion-Channel or Calcium-Handling Variant -> Altered Action Potential and Calcium Handling -> Ventricular Tachyarrhythmia -> Syncope and Sudden Cardiac Death) and a cochlear branch conforming to sensorineural_hair_cell_loss starting at Cochlear Ionic Homeostasis Disruption and Oxidative Stress (through Hair Cell Mechanotransduction Failure and Death to Progressive Sensorineural Hearing Loss); the module-conformance-scope rationale is recorded in the entry notes. Carefully avoided importing JLNS1 (KCNQ1)-specific severity/prevalence/vestibular data per issue guidance: cited a JLNS2-specific arrhythmic event rate (10.5%, 2/19 genotype-confirmed patients, PMID:31941373) rather than a higher JLNS1 figure, and recorded a HUMAN_MODEL_MISMATCH discussion noting that the only quantitative human JLNS vestibular study (PMID:25471708) genotyped exclusively KCNQ1 (JLNS1) cases even though Kcne1-/- mice show clear vestibular involvement (PMID:33514733). Added a mechanistic_hypotheses entry reconciling an apparent tension between a 2025 KCNE1 functional screen (PMID:41200805, no dominant-negative effect on the variant panel tested) and an earlier report of dominant-negative KCNE1 missense alleles causing Romano-Ward syndrome (PMID:30461122). Added one animal model (Kcne1-/- mouse, PMID:33514733) with modeled_mechanisms and two quantitative readouts. Validation: just validate (schema+terms+references) passed; just count-verified-snippets reported 47/47 verified; just compliance reported 97.6% global / 98.3% weighted; all 16 file-specific pytest cases in tests/test_data.py (including module-conformance and animal-model-target tests) passed.

Falcon ▸

Jervell and Lange-Nielsen Syndrome 2 (JLNS2): Disease Characteristics Report

Edison Scientific Literature 23 citations 2026-09-06T14:51:45.841987

Jervell and Lange-Nielsen Syndrome 2 (JLNS2): Disease Characteristics Report

Executive summary

Jervell and Lange-Nielsen syndrome type 2 (JLNS2) is an exceptionally rare, autosomal-recessive cardio-auditory channelopathy caused by biallelic pathogenic loss-of-function variants in KCNE1. Its defining manifestations are congenital, usually profound bilateral sensorineural hearing loss and delayed ventricular repolarization, manifested by QT prolongation and susceptibility to torsades de pointes, syncope, cardiac arrest, and sudden cardiac death. JLNS2 must be distinguished from KCNQ1-related JLNS1 and from heterozygous KCNE1-associated long-QT syndrome type 5 (LQT5/Romano-Ward syndrome). Available evidence suggests that the cardiac phenotype of JLNS2 is, on average, milder than JLNS1, but individual patients can still have life-threatening arrhythmias. The largest clearly subtype-separated cohort identified contained only 19 JLNS2 patients, illustrating the limited evidence base. (roberts2020aninternationalmulticenter pages 1-5, faridi2019mutationalandphenotypic pages 1-3)

Domain	JLNS2-specific finding	Key quantitative data	Evidence type/source
Identity	Jervell and Lange-Nielsen syndrome type 2 is the recessive, cardio-auditory KCNE1 channelopathy; identifiers include MONDO:0012871 and OMIM:612347. It is distinct from KCNQ1-related JLNS1 and heterozygous KCNE1-associated LQT5/Romano-Ward syndrome.	Open Targets associates MONDO:0012871 most strongly with KCNE1 (association score 0.769).	Aggregated disease/target resources and human genetic literature (OpenTargets Search: Jervell and Lange-Nielsen syndrome 2-KCNE1, faridi2019mutationalandphenotypic pages 1-3)
Cause and inheritance	Biallelic germline loss-of-function KCNE1 variants—homozygous or compound heterozygous—cause autosomal-recessive JLNS2. Heterozygous loss-of-function carriers may have a normal QT interval; some heterozygous missense variants instead cause incompletely penetrant LQT5, sometimes through dominant-negative effects.	Recurrence risk for two carrier parents: 25% affected, 50% carrier, and 25% unaffected/non-carrier per pregnancy. Heterozygous KCNE1-family-member ECG penetrance in a multicenter LQT5 study was 20.7% (29/140), but this is not JLNS2 penetrance.	Human pedigrees, functional interpretation, and international cohort (roberts2020aninternationalmulticenter pages 1-5, faridi2019mutationalandphenotypic pages 1-3, faridi2019mutationalandphenotypic pages 6-8)
Core phenotype	Defining manifestations are congenital bilateral profound sensorineural hearing loss and QT prolongation caused by delayed ventricular repolarization. Possible episodic consequences include exertion- or emotion-triggered torsades de pointes, syncope, seizure-like events, ventricular fibrillation, cardiac arrest, and sudden death.	The defining hearing phenotype is congenital and generally profound; robust JLNS2-specific percentages for individual manifestations are unavailable.	Human families and clinical cohorts (roberts2020aninternationalmulticenter pages 1-5, faridi2019mutationalandphenotypic pages 1-3, theodore2024icdimplantin pages 1-3)
Relative frequency	JLNS2 is much less common than KCNQ1-related JLNS1. Historical summaries estimate KCNE1 in approximately 10% of JLNS, but contemporary cohorts suggest a smaller fraction.	Approximate historical distribution: JLNS1 90%, JLNS2 10%. KCNE1 accounted for 1/52 sequenced patients (1.9%) in a 2025 Egyptian preprint and approximately 5% in a cited earlier cohort.	Aggregated historical evidence and cohort/preprint; estimates vary with ascertainment and ancestry (vojdani2019mutationscreeningof pages 7-10, hataba2025themutationalspectrum pages 14-17, rieraUnknownyearjervellandlangenielsen pages 1-3)
Relative severity	Available evidence indicates KCNE1-related JLNS2 is generally milder cardiologically than KCNQ1-related JLNS1, although life-threatening arrhythmia remains possible and small samples limit precision.	International cohort: definite arrhythmic events in 2/19 JLNS2 patients (10.5%); versus the overall heterozygous KCNE1 cohort, HR 1.7 (95% CI 0.3–10.8; p=0.590). One report cites approximately sixfold higher arrhythmic-event risk in KCNQ1-related JLNS than KCNE1-related disease.	International multicenter human cohort and secondary comparison (roberts2020aninternationalmulticenter pages 1-5, qiu2020jervellandlangenielsen pages 5-7)
Pathogenic variants	Reported JLNS2 alleles include nonsense/null and missense variants. Well-documented homozygous nonsense alleles include *KCNE1 c.50G>A (p.Trp17), c.51G>A (p.Trp17), and c.138C>A (p.Tyr46)**. Variant interpretation must distinguish pathogenic biallelic loss from common polymorphisms such as p.Ser38Gly.	A 2019 review noted only four previously associated JLNS variants before adding three homozygous nonsense alleles; the catalog is therefore sparse. No universal disease allele frequency is established.	Human pedigrees, segregation, and variant review (faridi2019mutationalandphenotypic pages 1-3, faridi2019mutationalandphenotypic pages 6-8, vojdani2019mutationscreeningof pages 4-7)
Cardiac mechanism	KCNE1/minK is the regulatory β-subunit of the KCNQ1/Kv7.1 complex generating the slowly activating delayed-rectifier potassium current I-Ks. Biallelic loss reduces repolarizing K⁺ current, prolongs cardiomyocyte action-potential duration, produces QT prolongation, and increases early-afterdepolarization/torsades susceptibility, especially under adrenergic stress.	KCNE1 is a 130-amino-acid, single-pass transmembrane protein. KCNE1-associated current reductions are often more modest than severe KCNQ1 defects, consistent with the milder average JLNS2 cardiac phenotype.	Human genetics plus electrophysiologic/channel-biology evidence (roberts2020aninternationalmulticenter pages 1-5, vojdani2019mutationscreeningof pages 7-10, rieraUnknownyearjervellandlangenielsen pages 12-15)
Cochlear mechanism	Apical KCNQ1–KCNE1 channels in stria vascularis marginal cells secrete K⁺ into scala-media endolymph. KCNE1 deficiency disrupts K⁺ homeostasis and the positive endocochlear potential needed to drive hair-cell mechanotransduction, resulting in congenital sensorineural deafness; secondary strial and sensory-cell degeneration may contribute.	No reliable human JLNS2-specific endocochlear-potential measurements or cell-loss percentages are available.	Mechanistic review and mouse-based inner-ear evidence; human phenotype supplies clinical concordance (rieraUnknownyearjervellandlangenielsen pages 12-15, faridi2019mutationalandphenotypic pages 12-14)
Diagnosis	Suspect JLNS2 in any child with congenital profound bilateral hearing loss plus QTc prolongation, unexplained exertional/emotional syncope, seizure-like events, or family history of sudden death. Evaluate serial 12-lead ECG/QTc, T-wave morphology, Holter/exercise response, electrolytes and acquired causes, formal audiology, and molecular confirmation of two pathogenic/likely pathogenic KCNE1 alleles in trans.	JLNS overall usually has QTc >500 ms; this threshold is supportive, not independently diagnostic and not JLNS2-specific.	Clinical diagnostic literature and disease reviews (rieraUnknownyearjervellandlangenielsen pages 6-9, rieraUnknownyearjervellandlangenielsen pages 1-3, theodore2024icdimplantin pages 3-4)
Genetic testing	Use a validated LQTS/cardio-auditory or comprehensive hearing-loss panel containing KCNE1 and KCNQ1, with sequencing plus deletion/duplication analysis. If negative despite a convincing phenotype, consider CNV-sensitive exome/genome analysis and reanalysis; test parents for phase and cascade-test relatives.	CNVs can be missed by sequence-only assays. In 2024 literature plus an internal channelopathy cohort, CNVs were reported across 140 patients, supporting dedicated CNV detection, although this was not a JLNS2-specific yield estimate.	Diagnostic reviews and aggregated channelopathy studies (rieraUnknownyearjervellandlangenielsen pages 3-6)
Management	Treat the cardiac phenotype according to congenital-LQTS guidance: nonselective β-blockade—typically nadolol or propranolol—plus strict avoidance of QT-prolonging drugs, prompt correction of hypokalemia/hypomagnesemia, fever/dehydration management, individualized exercise precautions, and an emergency plan. Consider LCSD for events despite adequate β-blockade or β-blocker intolerance and an ICD after cardiac arrest or for persistent high-risk disease.	JLNS2-specific drug-response rates are unavailable. Historical poor outcomes on β-blocker monotherapy largely derive from mixed, predominantly KCNQ1-related JLNS and should not be assigned directly to JLNS2.	LQTS guidelines/reviews extrapolated to JLNS2, supplemented by JLNS cases (rieraUnknownyearjervellandlangenielsen pages 6-9, theodore2024icdimplantin pages 1-3, theodore2024icdimplantin pages 3-4)
Hearing intervention	Early audiologic rehabilitation and cochlear implantation can restore useful auditory access when hearing aids are inadequate. Implantation requires multidisciplinary cardiology–anesthesia planning, continuation of protective therapy when feasible, electrolyte control, avoidance of QT-prolonging anesthetic combinations, continuous monitoring, and immediate defibrillation capability.	Good auditory outcomes are reported, but subtype-specific response percentages are lacking. Life-threatening perioperative arrhythmia has been reported in JLNS, especially around anesthesia/emergence.	Human case series/reports; most do not genotype-separate JLNS2 from JLNS1 (qiu2020jervellandlangenielsen pages 5-7, theodore2024icdimplantin pages 1-3)
Prognosis	Hearing loss is lifelong but functionally treatable; cardiac risk is lifelong and episodic. JLNS2 appears less malignant on average than JLNS1, but sudden cardiac arrest remains possible, so genotype alone must not justify withholding clinical surveillance or treatment when QT prolongation is present.	Best subtype-specific cohort: 10.5% definite arrhythmic events (2/19), with wide uncertainty. JLNS-wide estimates such as 50% experiencing events before age three or high childhood mortality mainly reflect mixed/predominantly JLNS1 cohorts.	International JLNS2 cohort plus historical mixed-JLNS natural history (roberts2020aninternationalmulticenter pages 1-5, rieraUnknownyearjervellandlangenielsen pages 3-6, rieraUnknownyearjervellandlangenielsen pages 1-3)
Models	Kcne1-null mice reproduce bilateral deafness/endocochlear dysfunction and provide mechanistic evidence, but their cardiac phenotype is relatively mild because murine ventricular repolarization differs from humans. Patient-specific JLNS iPSC-cardiomyocyte studies demonstrate reduced I-Ks, prolonged action potentials, adrenergic/drug sensitivity, and pharmacologic rescue, but the landmark model used KCNQ1, not KCNE1, and therefore models JLNS1 rather than JLNS2 directly.	No well-validated KCNE1-JLNS2 patient-derived iPSC, organoid, or single-cell disease model was identified in the reviewed evidence.	Knockout mouse and KCNQ1-JLNS iPSC experimental studies; indirect for human JLNS2 cardiac severity (zhang2014recessivecardiacphenotypes pages 1-2, faridi2019mutationalandphenotypic pages 12-14)
Evidence gaps	JLNS2 evidence is constrained by very small cohorts, historical mixing of JLNS1 and JLNS2, changing KCNE1 variant classification, and limited functional testing. Disease-specific incidence, penetrance, sex effects, founder alleles, modifier genes, quality-of-life measures, treatment-effect estimates, epigenomic/omics signatures, and approved gene/RNA therapies remain undetermined.	Largest clearly subtype-separated clinical cohort identified: 19 JLNS2 patients. No JLNS2-specific interventional clinical trial was established in the reviewed evidence.	Evidence synthesis and international cohort (roberts2020aninternationalmulticenter pages 1-5, faridi2019mutationalandphenotypic pages 6-8, zhang2014recessivecardiacphenotypes pages 1-2)

Table: Compact evidence matrix separating biallelic KCNE1-related JLNS2 from KCNQ1-related JLNS1 and heterozygous LQT5. It highlights quantitative findings, clinical implications, model limitations, and major knowledge gaps.

1. Disease information

Definition. JLNS2 is a Mendelian disorder in which biallelic KCNE1 deficiency impairs the KCNQ1–KCNE1 slowly activating delayed-rectifier potassium channel, affecting both ventricular repolarization and cochlear potassium homeostasis. Faridi et al. describe the syndrome as a “cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death.” [Human genetic/review evidence; published December 2019; PMID 30461122; DOI/URL: https://doi.org/10.1002/humu.23689]. (faridi2019mutationalandphenotypic pages 1-3)

Identifiers and names.

MONDO: MONDO:0012871.
OMIM phenotype: 612347.
Causal gene: KCNE1, HGNC:6240; NCBI Gene: 3753; Ensembl: ENSG00000180509.
Synonyms: Jervell and Lange-Nielsen syndrome type 2, JLNS2, Jervell-Lange Nielsen syndrome 2, KCNE1-related Jervell and Lange-Nielsen syndrome, and recessive KCNE1-associated cardio-auditory syndrome.
Parent disease concepts include Jervell and Lange-Nielsen syndrome (MONDO:0002441) and familial long-QT syndrome. Open Targets ranks KCNE1 as the principal supported target for MONDO:0012871; low-scoring neighboring-gene associations should not be interpreted as additional causal genes. (OpenTargets Search: Jervell and Lange-Nielsen syndrome 2-KCNE1)
No dedicated, universally used JLNS2-specific ICD-10 or MeSH code was identified. Coding ordinarily uses broader congenital long-QT syndrome and sensorineural hearing-loss categories. ICD-11 similarly does not reliably separate the molecular subtype in routine records.

This report synthesizes aggregated disease-level resources, published families, registries, and experimental models. It is not based on an individual EHR. Case reports are identified where used.

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

The necessary initiating lesion is generally two germline pathogenic or likely pathogenic KCNE1 alleles in trans—homozygous or compound heterozygous. KCNE1 encodes minK, a 130-amino-acid single-pass membrane regulatory subunit of the KCNQ1/Kv7.1 channel complex. Biallelic null or severe loss-of-function alleles cause JLNS2; some heterozygous missense alleles can instead produce incompletely penetrant LQT5 through dominant-negative or other functional effects. Heterozygous null carriers may have a normal QT interval. (roberts2020aninternationalmulticenter pages 1-5, faridi2019mutationalandphenotypic pages 1-3, faridi2019mutationalandphenotypic pages 6-8)

Risk factors

Genetic: biallelic pathogenic KCNE1 variants, parental carrier status, consanguinity, and family history of congenital deafness, unexplained syncope, or sudden death. Consanguinity increases the probability that a rare allele is inherited identically by descent but is not itself mechanistic. (vojdani2019mutationscreeningof pages 7-10, hataba2025themutationalspectrum pages 14-17)
Arrhythmia triggers/modifiers: exertion, acute emotion/adrenergic activation, electrolyte depletion—especially hypokalemia or hypomagnesemia—and QT-prolonging medications can expose reduced repolarization reserve. Anesthesia, emergence, postoperative stress, and interacting medicines are particularly relevant during cochlear implantation. These factors trigger cardiac events; they do not cause the inherited syndrome. (qiu2020jervellandlangenielsen pages 5-7, theodore2024icdimplantin pages 1-3, theodore2024icdimplantin pages 3-4)
Age/sex: severe events may begin in early childhood. No robust JLNS2-specific sex effect is established. A recent mixed-JLNS Egyptian cohort found no sex-related QTc difference, but only one KCNE1-positive patient precluded subtype analysis. (hataba2025themutationalspectrum pages 14-17)

Protective factors

No protective KCNE1 allele has been validated for JLNS2. Clinically protective measures include effective nonselective beta-blockade, avoidance of QT-prolonging drugs, maintenance of potassium and magnesium, prompt treatment of vomiting/dehydration, and escalation to left cardiac sympathetic denervation (LCSD) or an implantable cardioverter-defibrillator (ICD) when indicated. These reduce event risk rather than reverse the genotype. (rieraUnknownyearjervellandlangenielsen pages 6-9, theodore2024icdimplantin pages 1-3)

No disease-specific effects of diet, smoking, alcohol, occupational exposure, infection, radiation, or toxins are established. There is no infectious cause and no vaccine prevention strategy.

3. Phenotypes

Phenotype	Type, onset, course, and frequency	Suggested HPO term
Bilateral profound sensorineural hearing loss	Clinical sign; congenital/prelingual, usually severe-to-profound and permanent; defining phenotype, although rigorous JLNS2 frequency estimates are unavailable	Bilateral sensorineural hearing impairment, HP:0008619; congenital sensorineural hearing impairment, HP:0008527; profound hearing impairment, HP:0012715
Prolonged QTc	ECG abnormality; congenital, persistent but quantitatively variable; defining cardiac manifestation. JLNS generally often has QTc >500 ms, but this is not an absolute JLNS2 criterion	Prolonged QT interval, HP:0001657
Torsades/polymorphic ventricular tachycardia	Episodic clinical/electrophysiologic event, often adrenergically triggered; frequency is unknown specifically for JLNS2	Ventricular tachycardia, HP:0004756
Syncope	Episodic symptom, often during exercise or emotion; may begin in early childhood	Syncope, HP:0001279; exercise-induced syncope, HP:0012665
Seizure-like episodes	Behavioral/neurologic appearance caused by cerebral hypoperfusion rather than primary epilepsy in many cases	Seizure, HP:0001250, annotated cautiously; cerebral hypoperfusion is the mechanism
Ventricular fibrillation/cardiac arrest/sudden death	Severe episodic complication	Ventricular fibrillation, HP:0001663; cardiac arrest, HP:0001695; sudden cardiac death, HP:0001645
T-wave abnormalities/alternans	ECG sign indicating electrical instability	Abnormal T-wave, HP:0005135; T-wave alternans where supported
Fetal/neonatal bradycardia	Occasional presenting sign in JLNS, not quantified for JLNS2	Bradycardia, HP:0001662

In an international study, definite arrhythmic events occurred in 2/19 JLNS2 patients (10.5%). The hazard ratio versus the overall heterozygous KCNE1 cohort was 1.7 (95% CI 0.3–10.8; p=0.590), emphasizing both a comparatively mild average phenotype and very wide uncertainty. [Human multicenter cohort; February 2020; PMID 31983240; DOI: https://doi.org/10.1161/CIRCULATIONAHA.119.043114]. (roberts2020aninternationalmulticenter pages 1-5)

Hearing loss compromises speech, language development, education, communication, and social participation. Cardiac uncertainty, exercise restrictions, recurrent syncope, ICD shocks, and fear of sudden death can affect daily functioning. No JLNS2-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life dataset was identified.

4. Genetic and molecular information

Causal gene. KCNE1 is the only established causal gene for the type-2 entity. KCNQ1 causes JLNS1, not JLNS2. Open Targets cites supporting literature including PMIDs 9354802, 10400998, 16414944, 30461122, and 31983240. (OpenTargets Search: Jervell and Lange-Nielsen syndrome 2-KCNE1)

Reported pathogenic variants. Well-supported homozygous nonsense alleles include NM_000219.5:c.50G>A (p.Trp17Ter), c.51G>A (p.Trp17Ter), and c.138C>A (p.Tyr46Ter). These predict early truncation/nonsense-mediated loss or absence of functional minK and segregated with JLNS2 in families initially ascertained for apparently nonsyndromic deafness. The abstract states: “heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2.” (faridi2019mutationalandphenotypic pages 1-3)

Reported classes include nonsense, missense, splice-altering, frameshift, and potentially exon-level deletion/duplication variants. Classification must be variant-specific under ACMG/AMP criteria and should integrate allele frequency, segregation, phase, phenotype, and functional data. Common polymorphisms—such as p.Ser38Gly/rs1805127—must not be labeled causal merely because they occur in a JLNS patient. (faridi2019mutationalandphenotypic pages 6-8, vojdani2019mutationscreeningof pages 4-7)

Pathogenic JLNS2 variants are germline, not somatic. They are expected to be absent or extremely rare in population databases, but no single JLNS2-wide allele frequency is meaningful. A 2020 study found rare KCNE1 variants collectively much more common in gnomAD than expected for monogenic LQT5, demonstrating that rarity alone is insufficient evidence of pathogenicity. (roberts2020aninternationalmulticenter pages 1-5)

Modifiers. Reduced repolarization reserve and adrenergic state modify expression. No modifier gene is definitively validated specifically for JLNS2. Candidate LQTS modifiers and channel-interacting proteins should not yet be entered as causal genes. No reproducible disease-specific methylation, histone, chromatin, or other epigenetic signature is known. Large chromosomal rearrangements are not characteristic, although intragenic KCNE1 CNVs are diagnostically possible.

5. Environmental information

JLNS2 is not environmentally caused. Non-genetic factors affect event probability: QT-prolonging medicines, drug interactions, electrolyte disturbance, starvation/vomiting, dehydration, intense exertion, sudden emotional stress, and perioperative sympathetic surges can aggravate delayed repolarization. No infectious agent, pollution exposure, occupational toxin, smoking pattern, diet, or alcohol exposure has a proven etiologic role. (qiu2020jervellandlangenielsen pages 5-7, theodore2024icdimplantin pages 1-3)

Relevant chemical ontology annotations include potassium ion (CHEBI:29103) and magnesium ion (CHEBI:18420). Drug annotations should use the exact chemical entity and CredibleMeds risk category rather than treating “QT-prolonging drug” as one compound.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic KCNE1 loss-of-function variants lead to absent, truncated, mistrafficked, or dysfunctional minK subunits.
Defective minK leads to impaired assembly, membrane expression, gating, or regulation of KCNQ1–KCNE1 channels and reduced I-Ks current.
Cardiac branch: reduced I-Ks in ventricular cardiomyocytes leads to slower phase-3 repolarization and prolonged action-potential duration.
Prolonged action potentials result in QTc prolongation and reduced repolarization reserve.
Adrenergic stress, QT-prolonging drugs, or electrolyte depletion can then lead to early afterdepolarizations and spatial/temporal dispersion of repolarization; this step is strongly supported by general LQTS electrophysiology but is partly inferred for individual JLNS2 variants.
Triggered activity and re-entry lead to torsades de pointes/polymorphic ventricular tachycardia, syncope, ventricular fibrillation, cardiac arrest, or sudden death.
Cochlear branch: defective KCNQ1–KCNE1 channels on the apical membrane of stria-vascularis marginal cells lead to impaired K⁺ secretion into scala-media endolymph.
Impaired K⁺ homeostasis results in failure of the positive endocochlear potential required for hair-cell mechanotransduction.
Reduced electrochemical drive, with secondary strial or sensory-cell degeneration demonstrated mainly in models, leads to congenital profound sensorineural deafness. (roberts2020aninternationalmulticenter pages 1-5, rieraUnknownyearjervellandlangenielsen pages 12-15, faridi2019mutationalandphenotypic pages 12-14)

This is an ion-channel/homeostatic disorder, not primarily an inflammatory, immune, neoplastic, fibrotic, or metabolic disease. Suggested GO annotations include voltage-gated potassium-channel activity (GO:0005249), potassium-ion transmembrane transport (GO:0071805), regulation of membrane potential (GO:0042391), ventricular cardiac-muscle-cell action-potential repolarization (GO:0099622), and sensory perception of sound (GO:0007605). Cellular-component terms include plasma membrane (GO:0005886) and voltage-gated potassium-channel complex (GO:0008076).

Relevant cell types are ventricular cardiomyocytes (CL:0000746), cochlear hair cells, and stria-vascularis marginal epithelial cells; the latter lacks consistently used high-granularity CL coverage and may require an ontology extension. No JLNS2-specific transcriptomic, proteomic, metabolomic, lipidomic, spatial-transcriptomic, single-cell, or multi-omic disease signature was identified.

7. Anatomical structures affected

The primary organs are the heart and inner ear. The heart is usually structurally normal; dysfunction is electrical, centered on ventricular myocardium and cardiomyocyte sarcolemma. Suggested anatomy terms include heart (UBERON:0000948), cardiac ventricle (UBERON:0002082), myocardium (UBERON:0002349), inner ear (UBERON:0001846), cochlea (UBERON:0001844), cochlear duct/scala media, stria vascularis, and organ of Corti. Hearing loss is ordinarily bilateral without lateralization. Secondary nervous-system manifestations—collapse/syncope or convulsive movements—result from transient cerebral hypoperfusion rather than primary brain pathology. (faridi2019mutationalandphenotypic pages 1-3, rieraUnknownyearjervellandlangenielsen pages 12-15)

8. Temporal development

Hearing loss is congenital, bilateral, and lifelong. QT prolongation is congenital, but arrhythmic manifestations are intermittent and may first appear in infancy or childhood. A mixed, predominantly JLNS1 historical cohort had mean QTc 557±65 ms, with 50% experiencing a cardiac event before age three; more than half of untreated children were reported to die before age 15. These severe figures must not be assigned directly to JLNS2, which appears less malignant. (rieraUnknownyearjervellandlangenielsen pages 3-6, rieraUnknownyearjervellandlangenielsen pages 1-3)

There is no remission of the genotype or deafness. Cardiac event risk can be markedly reduced by sustained treatment, while cochlear implantation can improve auditory function without repairing the molecular defect. Childhood is a critical period for ECG recognition, speech/language intervention, family screening, and protection during anesthesia.

9. Inheritance and population

Inheritance is autosomal recessive. For two heterozygous carrier parents, each pregnancy has a 25% probability of an affected child, 50% probability of a carrier, and 25% probability of a child inheriting neither familial allele. Genetic anticipation is not expected. Germline mosaicism has not emerged as a characteristic mechanism. Expressivity is variable, particularly for QTc and arrhythmic events; penetrance of congenital profound deafness appears high for severe biallelic loss, but an exact JLNS2 estimate is unavailable. (roberts2020aninternationalmulticenter pages 1-5, faridi2019mutationalandphenotypic pages 1-3)

JLNS overall has been estimated at approximately 1 per 200,000 to 1 per 1,000,000, with higher prevalence in founder or consanguineous populations. JLNS2 is only a fraction of this total. Historical summaries assigned about 10% of JLNS to KCNE1, whereas contemporary subtype data include 19 international patients and only 1 KCNE1 case among 52 sequenced Egyptian patients; therefore, precise prevalence and incidence cannot be calculated. Both sexes are affected. (roberts2020aninternationalmulticenter pages 1-5, vojdani2019mutationscreeningof pages 7-10, hataba2025themutationalspectrum pages 14-17)

No universally established JLNS2 founder variant, sex ratio, annual incidence, or carrier frequency was identified. Consanguinity enriches homozygosity: a 2025 Egyptian JLNS preprint reported consanguinity in 76.2% of families with complete information, but 51/52 sequenced patients had KCNQ1 disease, limiting relevance to JLNS2. (hataba2025themutationalspectrum pages 14-17)

10. Diagnostics

Clinical workflow. Every child with congenital severe/profound bilateral sensorineural hearing loss should have a 12-lead ECG with manually verified QTc. Conversely, a child with QT prolongation and syncope/seizure-like events should undergo formal audiology. Assessment should include T-wave morphology, resting and serial ECGs, Holter monitoring and exercise/recovery testing where appropriate, electrolytes, medication review, three-generation pedigree, and evaluation for acquired QT prolongation. A QTc commonly exceeding 500 ms is highly supportive in the classic syndrome, but diagnosis must integrate phenotype and genotype. (rieraUnknownyearjervellandlangenielsen pages 6-9, rieraUnknownyearjervellandlangenielsen pages 1-3, theodore2024icdimplantin pages 3-4)

Molecular confirmation. Use a validated congenital-LQTS/cardio-auditory or comprehensive hearing-loss panel containing at least KCNE1 and KCNQ1, with sequencing and deletion/duplication analysis. Confirm two pathogenic/likely pathogenic KCNE1 variants in trans by parental testing. CNV-sensitive analysis is important because sequence-only assays can miss exon-level deletions or duplications. WES/WGS is useful when panel testing is negative, for noncoding/structural variants and phenocopies, but does not replace careful KCNE1 interpretation. CMA, karyotype, FISH, mitochondrial, and repeat-expansion testing are not routine unless another phenotype indicates them. (rieraUnknownyearjervellandlangenielsen pages 3-6)

Differential diagnosis: JLNS1 (biallelic KCNQ1); heterozygous LQT5/Romano-Ward syndrome without congenital profound deafness; nonsyndromic genetic deafness such as GJB2-related DFNB1; Pendred, Usher, Waardenburg, and branchio-oto-renal syndromes; acquired drug/electrolyte-related long QT; catecholaminergic polymorphic ventricular tachycardia; epilepsy; and coincidental deafness plus another LQTS genotype. (rieraUnknownyearjervellandlangenielsen pages 6-9)

There is no routine biochemical, biopsy, imaging, liquid-biopsy, proteomic, or metabolomic diagnostic test. Echocardiography is useful to exclude structural disease rather than confirm JLNS2.

11. Outcome and prognosis

Untreated JLNS as a whole has historically carried high childhood mortality, but JLNS2-specific outcome estimates are substantially less severe and much less precise. The best subtype-separated multicenter evidence found definite arrhythmic events in 10.5% (2/19). The authors concluded that low penetrance of KCNE1-associated QT prolongation aligns with the relatively mild phenotype observed in JLNS2. This must not be interpreted as benignity: sudden cardiac arrest remains possible, and treatment decisions should follow the measured phenotype and event history. (roberts2020aninternationalmulticenter pages 1-5)

Poor prognostic indicators in mixed JLNS include very prolonged QTc, early syncope, prior cardiac arrest, T-wave alternans, events despite adherent beta-blockade, and exposure to avoidable triggers. No validated JLNS2-specific prognostic biomarker or survival calculator exists. Hearing disability is permanent but auditory and communication outcomes can improve substantially with early cochlear implantation and rehabilitation. No reliable JLNS2-specific 5- or 10-year survival statistic is available.

12. Treatment and real-world implementation

Nonselective beta-blocker therapy—usually nadolol or propranolol—is first-line for clinically manifest congenital LQTS, with weight-adjusted specialist dosing and adherence monitoring. This recommendation is extrapolated from congenital-LQTS guidance because no JLNS2 randomized trial exists. Suggested NCIt concept: beta-adrenergic blocking agent (NCIT:C29576). (rieraUnknownyearjervellandlangenielsen pages 6-9, theodore2024icdimplantin pages 1-3)
Trigger control: remove QT-prolonging medicines, correct potassium/magnesium deficiency, manage vomiting/dehydration promptly, individualize exercise restrictions, provide a medical-alert plan, and train family members in CPR/AED use. (rieraUnknownyearjervellandlangenielsen pages 1-3, theodore2024icdimplantin pages 3-4)
LCSD: consider for recurrent syncope/arrhythmia despite adequate beta-blockade or when beta-blockers are not tolerated; it is not a cure and therapy generally continues. Suggested NCIt annotation: sympathetic denervation procedure.
ICD: indicated after resuscitated cardiac arrest and considered for recurrent events or persistently extreme risk despite optimal therapy. Device complications and inappropriate shocks are important in small children; implantation must be individualized. A 2024 case described a six-year-old with QTc 600 ms and recurrent exercise/emotion-triggered syncope despite beta-blockade who received an ICD, with LCSD planned if events recurred. This case was not molecularly separated as JLNS2. (theodore2024icdimplantin pages 1-3, theodore2024icdimplantin pages 3-4)
Hearing treatment: hearing aids may be insufficient for profound loss; early cochlear implantation plus speech-language and audiologic rehabilitation is the principal functional intervention. Cardiology, electrophysiology, anesthesia, and otology teams should coordinate perioperative care, continue protective therapy where feasible, avoid QT-prolonging combinations, maintain electrolytes, monitor continuously, and have external defibrillation immediately available. Life-threatening postoperative arrhythmia has been documented in JLNS after cochlear implantation. (qiu2020jervellandlangenielsen pages 5-7)

No approved KCNE1 gene replacement, CRISPR therapy, antisense oligonucleotide, siRNA, mRNA, cell therapy, or JLNS2-specific targeted drug exists. A search of active ClinicalTrials.gov records found broader LQTS monitoring, registry, and cascade-screening studies, but no clearly JLNS2-specific interventional trial. The 2023 precision-medicine literature emphasizes patient-specific iPSC cardiomyocytes, genome editing, and high-throughput drug testing as future approaches rather than current care. (zhang2014recessivecardiacphenotypes pages 1-2)

13. Prevention

Primary prevention of a de novo inherited phenotype through lifestyle is not possible. Reproductive prevention/options include carrier testing, genetic counseling, partner testing in at-risk communities, prenatal diagnosis by chorionic-villus sampling or amniocentesis after familial variants are known, and preimplantation genetic testing for monogenic disease. (rieraUnknownyearjervellandlangenielsen pages 12-15)

Secondary prevention consists of ECG screening in congenital deafness, cascade testing of relatives, newborn hearing screening linked to cardiology referral when syndromic disease is suspected, and presymptomatic treatment of genetically/phenotypically affected relatives. Tertiary prevention comprises beta-blockade, avoidance measures, LCSD/ICD when indicated, and emergency preparedness. Population newborn DNA screening for JLNS2 is not standard. Immunization and infectious prophylaxis are not applicable.

14. Other species and natural disease

No well-established naturally occurring veterinary counterpart or zoonotic transmission was identified. The mechanism is evolutionarily conserved in mammals through orthologous Kcne1/Kcnq1 channel complexes. Relevant taxa include human (Homo sapiens, NCBI Taxonomy 9606) and laboratory mouse (Mus musculus, 10090). There is no infectious transmission, cross-species contagion, or breed-specific VBO annotation.

15. Model organisms and advanced research

Kcne1-null mouse. This is the principal direct genetic model. Homozygous disruption reproduces bilateral sensorineural deafness, strial/endolymphatic abnormalities, and impaired endocochlear physiology. It is useful for cochlear potassium transport and tissue pathology. Its cardiac phenotype is comparatively mild, limiting translation because murine ventricular repolarization differs materially from human repolarization. (faridi2019mutationalandphenotypic pages 12-14)

Cell systems. Heterologous expression in Xenopus oocytes or mammalian cells measures KCNE1 effects on KCNQ1 current, gating, trafficking, and dominant-negative behavior. Such assays are essential because computational prediction alone is unreliable and there is no simple clinical biochemical test of KCNE1 function. (faridi2019mutationalandphenotypic pages 6-8)

iPSC models. Landmark JLNS iPSC-cardiomyocyte research demonstrated absent/reduced I-Ks, prolonged action and field potentials, abnormal adrenergic responses, proarrhythmic drug sensitivity, and pharmacologic rescue. However, that study modeled KCNQ1-related JLNS1, not KCNE1-related JLNS2, so it provides proof of platform rather than direct subtype evidence. [Experimental human iPSC evidence; December 2014; DOI: https://doi.org/10.1073/pnas.1419553111]. (zhang2014recessivecardiacphenotypes pages 1-2)

No validated JLNS2-specific organoid, patient-derived iPSC series, CRISPR screen, spatial-transcriptomic dataset, or multi-omic signature was found through 2024. Recent 2023–2024 developments are therefore chiefly improvements in broad LQTS precision modeling, pediatric management, CNV detection, and cochlear cell biology rather than a new JLNS2 therapy. The central research priorities are international genotype-confirmed registries, systematic functional classification of KCNE1 variants, direct KCNE1 patient-iPSC models, subtype-specific treatment outcomes, and safe dual-organ gene-delivery strategies.

Evidence limitations

JLNS2 is frequently pooled with JLNS1, older reports predate modern variant-classification standards, and severe historical outcome estimates largely reflect KCNQ1-predominant cohorts. The 19-patient international JLNS2 series remains the strongest subtype-separated clinical evidence identified. Consequently, incidence, penetrance, variant-specific risk, sex effects, quality of life, treatment response, and survival cannot presently be estimated with high precision. Statements derived from mixed JLNS, generic congenital LQTS, KCNQ1 models, or mouse experiments have been explicitly labeled rather than presented as direct JLNS2 evidence.

References

(roberts2020aninternationalmulticenter pages 1-5): Jason D. Roberts, S. Yukiko Asaki, Andrea Mazzanti, J. Martijn Bos, Izabela Tuleta, Alison R. Muir, Lia Crotti, Andrew D. Krahn, Valentina Kutyifa, M. Benjamin Shoemaker, Christopher L. Johnsrude, Takeshi Aiba, Luciana Marcondes, Anwar Baban, Sharmila Udupa, Brynn Dechert, Peter Fischbach, Linda M. Knight, Eric Vittinghoff, Deni Kukavica, Birgit Stallmeyer, John R. Giudicessi, Carla Spazzolini, Keiko Shimamoto, Rafik Tadros, Julia Cadrin-Tourigny, Henry J. Duff, Christopher S. Simpson, Thomas M. Roston, Yanushi D. Wijeyeratne, Imane El Hajjaji, Maisoon D. Yousif, Lorne J. Gula, Peter Leong-Sit, Nikhil Chavali, Andrew P. Landstrom, Gregory M. Marcus, Sven Dittmann, Arthur A. M. Wilde, Elijah R. Behr, Jacob Tfelt-Hansen, Melvin M. Scheinman, Marco V. Perez, Juan Pablo Kaski, Robert M. Gow, Fabrizio Drago, Peter F. Aziz, Dominic J. Abrams, Michael H. Gollob, Jonathan R. Skinner, Wataru Shimizu, Elizabeth S. Kaufman, Dan M. Roden, Wojciech Zareba, Peter J. Schwartz, Eric Schulze-Bahr, Susan P. Etheridge, Silvia G. Priori, and Michael J. Ackerman. An international multicenter evaluation of type 5 long qt syndrome. Feb 2020. URL: https://doi.org/10.1161/circulationaha.119.043114, doi:10.1161/circulationaha.119.043114. This article has 64 citations and is from a highest quality peer-reviewed journal.
(faridi2019mutationalandphenotypic pages 1-3): Rabia Faridi, Risa Tona, Alessandra Brofferio, Michael Hoa, Rafal Olszewski, Isabelle Schrauwen, Muhammad Z.K. Assir, Akhtar A. Bandesha, Asma A. Khan, Atteeq U. Rehman, Carmen Brewer, Wasim Ahmed, Suzanne M. Leal, Sheikh Riazuddin, Steven E. Boyden, and Thomas B. Friedman. Mutational and phenotypic spectra of kcne1 deficiency in jervell and lange‐nielsen syndrome and romano‐ward syndrome. Human Mutation, 40:162-176, Dec 2019. URL: https://doi.org/10.1002/humu.23689, doi:10.1002/humu.23689. This article has 47 citations and is from a domain leading peer-reviewed journal.
(OpenTargets Search: Jervell and Lange-Nielsen syndrome 2-KCNE1): Open Targets Query (Jervell and Lange-Nielsen syndrome 2-KCNE1, 29 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(faridi2019mutationalandphenotypic pages 6-8): Rabia Faridi, Risa Tona, Alessandra Brofferio, Michael Hoa, Rafal Olszewski, Isabelle Schrauwen, Muhammad Z.K. Assir, Akhtar A. Bandesha, Asma A. Khan, Atteeq U. Rehman, Carmen Brewer, Wasim Ahmed, Suzanne M. Leal, Sheikh Riazuddin, Steven E. Boyden, and Thomas B. Friedman. Mutational and phenotypic spectra of kcne1 deficiency in jervell and lange‐nielsen syndrome and romano‐ward syndrome. Human Mutation, 40:162-176, Dec 2019. URL: https://doi.org/10.1002/humu.23689, doi:10.1002/humu.23689. This article has 47 citations and is from a domain leading peer-reviewed journal.
(theodore2024icdimplantin pages 1-3): TJ Theodore and PGKM Dhilipan. Icd implant in 6-year-old with jervell and lange-nielsen (jln) syndrome. Unknown journal, 2024.
(vojdani2019mutationscreeningof pages 7-10): Samaneh Vojdani, Susan Amirsalari, Saman Milanizadeh, Fatemeh Molaei, Mohammad Ajalloueyane, Arezoo Khosravi, Leila Hamzehzadeh, Mohammad Mehdi Ghasemi, Mohammad Reza Talee, and Mohammad Reza Abbaszadegan. Mutation screening of kcnq1 and kcne1 genes in iranian patients with jervell and lange-nielsen syndrome. Fetal and Pediatric Pathology, 38:273-281, Apr 2019. URL: https://doi.org/10.1080/15513815.2019.1585500, doi:10.1080/15513815.2019.1585500. This article has 15 citations and is from a peer-reviewed journal.
(hataba2025themutationalspectrum pages 14-17): Aya Hataba, M. Allouba, Mariam Fathy, A. Afify, E. Ahmed, M. Riad, Mohamed Elmaghawry, Youssef M. El Bayoumy, Amany Elleithy, A. Mahfouz, Jodie Ingles, A. Galal, Sohila Rabie, M. Allam, S. Halawa, Nour Elsadek, B. Samy, H. Kassem, O. Kamel, Yasmine Aguib, Magdi H. Yacoub, Magdi Kamel, Yasmine Yacoub, and Aguib. The mutational spectrum of jervell and lange-nielsen syndrome: insights from highly consanguineous families. MedRxiv, Oct 2025. URL: https://doi.org/10.1101/2025.10.22.25336867, doi:10.1101/2025.10.22.25336867. This article has 0 citations.
(rieraUnknownyearjervellandlangenielsen pages 1-3): ARP Riera. Jervell and lange-nielsen syndrome (jlns)-2010. Unknown journal, Unknown year.
(qiu2020jervellandlangenielsen pages 5-7): Yue Qiu, Sen Chen, Xia Wu, Wen-Juan Zhang, Wen Xie, Yuan Jin, Le Xie, Kai Xu, Xue Bai, Hui-Min Zhang, Xiao-Zhou Liu, Xiao-Hui Wang, Yu Sun, and Wei-Jia Kong. Jervell and lange-nielsen syndrome due to a novel compound heterozygous kcnq1 mutation in a chinese family. Neural Plasticity, 2020:1-8, May 2020. URL: https://doi.org/10.1155/2020/3569359, doi:10.1155/2020/3569359. This article has 14 citations and is from a peer-reviewed journal.
(vojdani2019mutationscreeningof pages 4-7): Samaneh Vojdani, Susan Amirsalari, Saman Milanizadeh, Fatemeh Molaei, Mohammad Ajalloueyane, Arezoo Khosravi, Leila Hamzehzadeh, Mohammad Mehdi Ghasemi, Mohammad Reza Talee, and Mohammad Reza Abbaszadegan. Mutation screening of kcnq1 and kcne1 genes in iranian patients with jervell and lange-nielsen syndrome. Fetal and Pediatric Pathology, 38:273-281, Apr 2019. URL: https://doi.org/10.1080/15513815.2019.1585500, doi:10.1080/15513815.2019.1585500. This article has 15 citations and is from a peer-reviewed journal.
(rieraUnknownyearjervellandlangenielsen pages 12-15): ARP Riera. Jervell and lange-nielsen syndrome (jlns)-2010. Unknown journal, Unknown year.
(faridi2019mutationalandphenotypic pages 12-14): Rabia Faridi, Risa Tona, Alessandra Brofferio, Michael Hoa, Rafal Olszewski, Isabelle Schrauwen, Muhammad Z.K. Assir, Akhtar A. Bandesha, Asma A. Khan, Atteeq U. Rehman, Carmen Brewer, Wasim Ahmed, Suzanne M. Leal, Sheikh Riazuddin, Steven E. Boyden, and Thomas B. Friedman. Mutational and phenotypic spectra of kcne1 deficiency in jervell and lange‐nielsen syndrome and romano‐ward syndrome. Human Mutation, 40:162-176, Dec 2019. URL: https://doi.org/10.1002/humu.23689, doi:10.1002/humu.23689. This article has 47 citations and is from a domain leading peer-reviewed journal.
(rieraUnknownyearjervellandlangenielsen pages 6-9): ARP Riera. Jervell and lange-nielsen syndrome (jlns)-2010. Unknown journal, Unknown year.
(theodore2024icdimplantin pages 3-4): TJ Theodore and PGKM Dhilipan. Icd implant in 6-year-old with jervell and lange-nielsen (jln) syndrome. Unknown journal, 2024.
(rieraUnknownyearjervellandlangenielsen pages 3-6): ARP Riera. Jervell and lange-nielsen syndrome (jlns)-2010. Unknown journal, Unknown year.
(zhang2014recessivecardiacphenotypes pages 1-2): Miao Zhang, Cristina D’Aniello, Arie O. Verkerk, Eva Wrobel, Stefan Frank, Dorien Ward-van Oostwaard, Ilaria Piccini, Christian Freund, Jyoti Rao, Guiscard Seebohm, Douwe E. Atsma, Eric Schulze-Bahr, Christine L. Mummery, Boris Greber, and Milena Bellin. Recessive cardiac phenotypes in induced pluripotent stem cell models of jervell and lange-nielsen syndrome: disease mechanisms and pharmacological rescue. Proceedings of the National Academy of Sciences, 111:E5383-E5392, Dec 2014. URL: https://doi.org/10.1073/pnas.1419553111, doi:10.1073/pnas.1419553111. This article has 230 citations and is from a highest quality peer-reviewed journal.

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Reference Validation

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References checked	7
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Unresolved (possible confabulation)	0
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Quoted claims checked	0
Quoted claims found in source	0
Quoted claims not found in source	0
Quoted claims with nothing to check against	1
References weighed for topical relevance	7
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Quotes that could not be checked

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DOI:10.1002/humu.23689: "cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death."
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Term Validation

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Outcome	Count
Terms checked	33
Resolved	31
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Unverifiable	2
Terms whose name was checked	2
Terms named correctly	0
Terms named as a different term	1
Terms whose name is worth a second look	1

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:0012871 (5 mentions) - the report calls it "if available"; MONDO calls it Jervell and Lange-Nielsen syndrome 2

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MONDO:0002441 (1 mention) - the report calls it "Parent disease concepts include Jervell and Lange-Nielsen syndrome"; MONDO calls it Jervell and Lange-Nielsen syndrome

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OpenScientist ▸

Jervell and Lange-Nielsen Syndrome Type 2 (JLNS2): Comprehensive Disease Characteristics Report

openscientist-autonomous 19 citations 2026-09-06T14:59:29.204996

Jervell and Lange-Nielsen Syndrome Type 2 (JLNS2): Comprehensive Disease Characteristics Report

Disease: Jervell and Lange-Nielsen Syndrome 2 (JLNS2) MONDO ID: MONDO:0012871 · OMIM: #612347 · Category: Mendelian (autosomal recessive) Causal gene: KCNE1 (HGNC:6240; chr21q22.12)

Summary

Jervell and Lange-Nielsen syndrome type 2 (JLNS2) is a rare, autosomal-recessive cardioauditory ion channelopathy defined by the combination of congenital profound bilateral sensorineural deafness and severe long QT syndrome (LQTS) with a high risk of life-threatening ventricular arrhythmia and sudden cardiac death from early childhood. It is the minority molecular form of Jervell and Lange-Nielsen syndrome (JLNS): approximately 90% of JLNS is caused by biallelic KCNQ1 variants (JLNS1), while JLNS2 is caused by biallelic loss-of-function variants in KCNE1, the gene encoding the minK/IsK β-subunit of the slowly activating delayed-rectifier potassium channel IKs.

The unifying mechanism is loss of IKs function in two tissues that critically depend on it. In the cochlea, the KCNQ1/KCNE1 complex in marginal cells of the stria vascularis secretes K⁺ into the endolymph; its loss collapses endolymph production and the endocochlear potential, causing degeneration of the organ of Corti and congenital deafness together with vestibular dysfunction. In the heart, loss of IKs removes ventricular "repolarization reserve," prolonging the action potential and QT interval, promoting early afterdepolarizations, torsades de pointes, and sudden death. A single β-subunit defect thus explains both cardinal features of the disease.

Clinically, JLNS carries a very high, early-onset cardiac-event burden (≈93% cumulative cardiac events by age 40, mean onset ~5 years), markedly worse than autosomal-dominant Romano-Ward syndrome. Beta-blocker monotherapy is insufficient (~35% LQTS-related mortality in one prospective cohort), whereas implantable cardioverter-defibrillator (ICD) therapy dramatically improves survival. Cochlear implantation restores hearing but demands rigorous perioperative arrhythmia precautions, and inner-ear gene therapy has shown preclinical promise in Kcne1-deficient mice. This report consolidates six confirmed findings across disease information, etiology, phenotypes, molecular genetics, mechanism, epidemiology, diagnostics, prognosis, treatment, prevention, and model organisms, and honestly documents where evidence (e.g., human molecular-profiling data) is absent.

1. Disease Information

Overview. JLNS2 is a Mendelian cardioauditory syndrome combining (i) congenital, profound, bilateral sensorineural hearing loss and (ii) a markedly prolonged QT interval predisposing to syncope, torsades de pointes, and sudden cardiac death. It is one of two molecular subtypes of Jervell and Lange-Nielsen syndrome, first described clinically by Jervell and Lange-Nielsen in 1957 as familial deafness with QT prolongation and sudden death.

Key identifiers.

Resource	Identifier
MONDO	MONDO:0012871
OMIM	#612347 (JERVELL AND LANGE-NIELSEN SYNDROME 2; JLNS2)
Gene	KCNE1 (HGNC:6240; NCBI Gene 3753; Ensembl ENSG00000180509)
Orphanet	ORPHA:90647 (Jervell and Lange-Nielsen syndrome)
ICD-10	I45.81 (Long QT syndrome) / related cardioauditory coding
MeSH	D029593 (Jervell-Lange Nielsen Syndrome)

Synonyms / alternative names. Jervell and Lange-Nielsen syndrome type 2; cardioauditory syndrome of Jervell and Lange-Nielsen (KCNE1 type); surdocardiac syndrome; long QT syndrome type 5 with deafness (JLNS2 is the recessive, deafness-associated allelic counterpart of KCNE1-related LQT5). Note: heterozygous KCNE1 variants are associated with Romano-Ward syndrome / LQT5 without deafness.

Data provenance. The information in this report is derived from aggregated disease-level resources (OMIM, Orphanet, ClinVar, gnomAD) and primary literature (case series, family studies, an international registry cohort, and animal models) — not from individual EHR records.

2. Etiology

Primary cause — genetic. JLNS2 is caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in KCNE1. Faridi et al. (2019) described three homozygous nonsense mutations of KCNE1 — c.50G>A (p.Trp17), c.51G>A (p.Trp17), and c.138C>A (p.Tyr46) — segregating in families ascertained for sensorineural deafness, establishing biallelic null KCNE1* as causal for JLNS2 [PMID: 30461122].

"biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17), c.51G>A (p.Trp17), and c.138C>A (p.Tyr46)"* — Faridi et al., 2019 [PMID: 30461122]

Genetic risk factors. The essential (and only established necessary) risk factor is inheritance of two loss-of-function KCNE1 alleles. Consanguinity is a major population-level risk factor because it raises homozygosity for rare recessive null alleles — JLNS and homozygous LQTS are enriched in consanguineous populations (e.g., Saudi Arabia, Pakistan) [PMID: 28438721; PMID: 22830134].

Environmental risk factors (arrhythmia triggers, not disease-causing). Because the cardiac substrate is fixed by genotype, "risk factors" in JLNS2 are really triggers of arrhythmic events: adrenergic/sympathetic stimulation (exercise, emotion, startle/auditory stimuli, fright), anesthesia and QT-prolonging drugs, and the perioperative period (notably cochlear implantation). More than 25% of JLNS patients experience sudden cardiac death, with triggers including anesthesia [PMID: 32508908].

Protective factors. No natural genetic protective alleles are established for JLNS2. Protective interventions (below in Treatment/Prevention) include beta-blockade, ICDs, atrial pacing, avoidance of QT-prolonging drugs, and left cardiac sympathetic denervation.

Gene–environment interactions. The genotype sets the substrate (loss of repolarization reserve); environmental sympathetic triggers precipitate torsades de pointes on that substrate. This is the paradigmatic gene–environment interaction in JLNS2 and dictates its management (beta-blockers to blunt adrenergic drive; avoiding QT-prolonging drugs).

3. Phenotypes

JLNS2 has two cardinal phenotype domains — auditory/vestibular and cardiac — both congenital.

Phenotype	Type	Onset	Severity	Frequency	Suggested HPO
Bilateral sensorineural hearing loss	Physical/sensory sign	Congenital	Profound, stable	~100% (defining)	HP:0000407 (Sensorineural hearing impairment); HP:0008527 (Congenital SNHL)
Prolonged QT interval	Laboratory/ECG abnormality	Congenital	Severe (QTc often ≥500–550 ms)	~100% (defining)	HP:0001657 (Prolonged QT interval)
Syncope	Symptom	Early childhood	Severe, episodic	Very common	HP:0001279 (Syncope)
Torsades de pointes / ventricular arrhythmia	Clinical sign	Early childhood	Life-threatening, episodic	Very common	HP:0004308 (Ventricular arrhythmia); HP:0031547 (Torsade de pointes)
Sudden cardiac death	Outcome	Childhood onward	Fatal	>25% of JLNS	HP:0001645 (Sudden cardiac death)
Vestibular dysfunction	Sign	Congenital	Variable	Common (KCNE1)	HP:0002321 (Vertigo); vestibular areflexia

Auditory phenotype. Congenital, profound, bilateral sensorineural hearing loss is present from birth and is stable (non-progressive) once established, reflecting a developmental/homeostatic failure of endolymph production rather than a degenerative course. Vestibular (balance) dysfunction accompanies the hearing loss in KCNE1 disease [PMID: 33514733; PMID: 34744965].

"Mutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction" — Wu et al., 2021 [PMID: 33514733]

Cardiac phenotype. Marked QT prolongation (mean QTc ~548 ± 73 ms in JLNS vs 500 ± 48 ms in Romano-Ward), syncope, torsades de pointes, and high risk of sudden death beginning in early childhood [PMID: 16911578].

Quality-of-life impact. The dual sensory-plus-cardiac burden is substantial: profound deafness impairs language, education, and social development (mitigated by cochlear implantation), while the arrhythmia risk imposes activity restriction, chronic medication, device implantation, and psychological burden on children and families. Disease-specific QoL instruments for JLNS2 are not established in the literature reviewed.

4. Genetic / Molecular Information

Causal gene. KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1; minK/IsK). Location: chr21q22.12 (GRCh38 chr21:34,446,688–34,512,214). Canonical transcript ENST00000399286; the coding region is a single short exon (~129 aa protein), which is important for interpreting population constraint (below).

Pathogenic variants. - Variant classes causing JLNS2: biallelic loss-of-function — nonsense/truncating (e.g., p.Trp17, p.Tyr46), frameshift, and loss-of-function missense — inherited homozygously or as compound heterozygotes [PMID: 30461122]. Case reports also document KCNE1 missense variants (e.g., an A→G missense) in JLNS2 patients [PMID: 33040543]. - Classification (ACMG/AMP): truncating null variants segregating with disease are classified pathogenic/likely pathogenic; certain missense variants are pathogenic via a dominant-negative mechanism (see Romano-Ward, below). - Functional consequence: loss of function of the minK β-subunit → reduced/absent IKs current.

Genotype–phenotype spectrum (a central molecular insight).

Genotype	Mechanism	Phenotype
Biallelic (homozygous/compound-het) null KCNE1	Complete IKs loss	JLNS2: deafness + severe LQT
Heterozygous null KCNE1	Haploinsufficiency tolerated	Often normal QT; may be silent
Heterozygous dominant-negative missense KCNE1	Mutant minK poisons WT KCNQ1/KCNE1 complexes	Romano-Ward / LQT5 (no deafness)

"heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants" — Faridi et al., 2019 [PMID: 30461122]

"Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism" — Faridi et al., 2019 [PMID: 30461122]

Population constraint (gnomAD) explains the split. gnomAD constraint metrics for KCNE1 show it is loss-of-function tolerant but strongly missense-constrained: pLI = 0.36, observed/expected LoF = 0.34 (obs 1 vs exp 2.93; wide CI 0.12–1.62 reflecting the tiny single-exon coding region), while missense o/e = 0.30 with missense Z = 3.67 (obs 45 vs exp 150). In plain terms, heterozygous null alleles are tolerated in the general population (consistent with recessive inheritance of JLNS2), whereas missense variants are under strong purifying selection (consistent with dominant-negative missense variants causing Romano-Ward). This constraint pattern is a molecular mirror of the clinical genotype–phenotype dichotomy.

Modifier genes. In malignant/atypical JLNS cases, additional cardiac-panel variants (e.g., RYR2, NKX2-5) have been proposed as modifiers of disease severity, supporting the value of broad targeted panels [PMID: 29037160]. Note: that particular case had a KCNQ1 (JLNS1) primary lesion, but the principle of oligogenic modification is relevant to JLNS2 as well.

Epigenetic information. No JLNS2-specific DNA-methylation or histone-modification data were identified — this is a knowledge gap.

Chromosomal abnormalities. JLNS2 is a single-gene disorder; large structural/aneuploidy causes are not implicated (KCNE1 is on 21q22.12, within the Down-syndrome-critical region, but JLNS2 arises from point/small variants, not trisomy 21).

5. Environmental Information

Environmental/toxic factors: No environmental cause of the disease itself. QT-prolonging drugs (many antiarrhythmics, macrolides, antipsychotics, some antiemetics) are the key iatrogenic hazard that worsens the substrate.
Lifestyle factors: Strenuous/competitive exercise, swimming, and situations of intense emotion or startle can trigger events; activity modification is standard advice.
Infectious agents: Not applicable — JLNS2 is not infectious. (Febrile illness/electrolyte disturbance can secondarily aggravate QT but are not causal.)

6. Mechanism / Pathophysiology

Ordered causal chain

Cardiac branch: 1. Biallelic loss-of-function KCNE1 variants result in absent/nonfunctional minK (IsK) β-subunits. 2. Loss of minK leads to failure of KCNQ1/KCNE1 co-assembly and markedly reduced IKs (slow delayed-rectifier K⁺ current). (Demonstrated in heterologous expression and knockout models.) 3. Reduced IKs results in loss of ventricular repolarization reserve and prolongation of the cardiac action potential. 4. Action-potential prolongation leads to QT-interval prolongation on ECG and predisposition to early afterdepolarizations. 5. Early afterdepolarizations plus increased transmural dispersion of repolarization result in torsades de pointes, which can degenerate to ventricular fibrillation. (Dispersion-of-repolarization mechanism inferred from LQT mouse mapping studies [PMID: 19148726].) 6. Ventricular fibrillation leads to syncope and sudden cardiac death, precipitated by adrenergic triggers.

Auditory/vestibular branch: 1. Loss of IKs in marginal cells of the stria vascularis (cochlea) and vestibular dark cells results in failure of K⁺ secretion into the endolymph. 2. Failed K⁺ secretion leads to collapse of the endocochlear potential and endolymphatic compartment. 3. Loss of endolymph homeostasis results in degeneration of the organ of Corti and spiral ganglion, and atrophy of the stria vascularis. (Demonstrated in Kcnq1 knockout mice modeling JLNS [PMID: 15891643].) 4. Sensory epithelial degeneration leads to congenital profound sensorineural deafness and vestibular dysfunction.

Detail

Molecular pathway / channel biology. The IKs channel is a hetero-oligomer of pore-forming KCNQ1 (Kv7.1) α-subunits and KCNE1 (minK) β-subunits. minK is essential for the slow activation kinetics and increased current amplitude that characterize IKs. Structural and modeling work shows that KCNQ1 assembles with KCNE1 to generate IKs, and that mutation-induced destabilization is a common cause of channel dysfunction [PMID: 31518351; PMID: 33963564].

Protein dysfunction. Truncating KCNE1 variants (p.Trp17, p.Tyr46) yield no functional β-subunit → simple loss of function → recessive disease. Certain missense variants produce a folded but poison-subunit that co-assembles with WT KCNQ1 to exert a dominant-negative effect → Romano-Ward when heterozygous [PMID: 30461122].

Biochemical abnormality. The core defect is an ion-channel defect (potassium channel β-subunit deficiency), reducing outward repolarizing K⁺ current.

Cell types & biological processes. Cardiac ventricular cardiomyocytes (repolarization); cochlear stria vascularis marginal cells and vestibular dark cells (endolymph K⁺ secretion). Suggested ontology terms: GO:0086009 (membrane repolarization), GO:1990573 (potassium ion import across plasma membrane), GO:0042472 (inner ear morphogenesis)/endolymph homeostasis; CL:0000746 (cardiac muscle cell), stria vascularis marginal epithelial cells.

Molecular profiling (transcriptomics/proteomics/metabolomics). No human JLNS2-specific omics datasets were identified in this investigation — an honest gap. Mechanistic knowledge derives from electrophysiology, structural modeling, and mouse knockouts rather than patient-tissue profiling.

7. Anatomical Structures Affected

Organ level (primary): Heart (ventricular myocardium — cardiovascular system) and inner ear (cochlea and vestibular apparatus — nervous/sensory system). UBERON:0000948 (heart); UBERON:0001846 (internal ear); UBERON:0002282 (organ of Corti); UBERON:0002295 (stria vascularis).
Secondary involvement: Central nervous system consequences of cerebral hypoperfusion during arrhythmia (syncope, potential anoxic injury/seizure-like events); developmental impact of deafness.
Tissue/cell level: Cardiac muscle (ventricular cardiomyocytes; CL:0000746); cochlear/vestibular epithelium — stria vascularis marginal cells and vestibular dark cells; secondary loss of cochlear hair cells (CL:0000855) and spiral ganglion neurons (CL:0000100).
Subcellular level: Plasma-membrane voltage-gated potassium channel complex (GO:0008076, voltage-gated potassium channel complex); sarcolemma of cardiomyocytes; apical/basolateral membranes of strial marginal cells.
Localization / lateralization: Bilateral, symmetric involvement of both inner ears; global ventricular repolarization abnormality.

8. Temporal Development

Onset: Congenital for both deafness (present at birth) and the QT abnormality. Cardiac symptoms (syncope, arrhythmia) typically begin in early childhood — mean age of first cardiac event ~5.0 years in JLNS [PMID: 16911578].
Onset pattern: Chronic underlying substrate with episodic acute arrhythmic events.
Progression: The hearing loss is stable/non-progressive once congenitally established. The cardiac risk is lifelong and high, with events clustering in childhood and adolescence.
Disease course: Chronic, lifelong; punctuated by potentially fatal arrhythmic episodes.
Critical periods / intervention windows: Early childhood (peak event risk) is the critical window for risk stratification and ICD consideration; the perioperative period of cochlear implantation is a discrete high-risk window requiring specific precautions.

9. Inheritance and Population

Inheritance. Autosomal recessive — requires biallelic KCNE1 loss-of-function. Heterozygous carriers are typically asymptomatic with normal or near-normal QT (in contrast to dominant-negative missense carriers who have Romano-Ward) [PMID: 30461122].

Penetrance / expressivity. For the biallelic-null genotype, penetrance of the JLNS2 phenotype (deafness + LQT) is essentially complete, though cardiac event severity is variable. No genetic anticipation (not a repeat-expansion disorder).

Epidemiology. JLNS (both subtypes combined) is very rare, with worldwide prevalence estimated at ~1/1,000,000 to 1/200,000 [PMID: 32508908]. Approximately 90% of JLNS is JLNS1 (KCNQ1); JLNS2 (KCNE1) is the minority subtype [PMID: 32508908]. ECG screening of deaf children yields JLNS in a measurable fraction — e.g., 4/440 (0.9%) congenitally deaf children in an Istanbul screening study [PMID: 34308870], and significant prevalence among Pakistani deaf-mute children linked to high consanguinity [PMID: 22830134].

"The prevalence of JLNS is about 1/1000000 to 1/200000 around the world. However, exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia" — Qiu et al., 2020 [PMID: 32508908]

"A total of 8 patients were found with a prolonged QT interval. JLNS was diagnosed in 4 (0.9%) patients" — Ergül et al., 2021 [PMID: 34308870]

Founder effects / consanguinity. Enriched in consanguineous populations (Middle East, South Asia). A Saudi LQTS cohort found homozygous mutations in a majority of probands, with congenital deafness in ~48% of homozygous probands — underscoring the consanguinity contribution [PMID: 28438721].

Sex ratio. No strong sex predilection is established for JLNS2 (recessive; both sexes equally affected).

Carrier frequency. Not precisely defined for JLNS2; heterozygous KCNE1 LoF alleles are tolerated in gnomAD (LoF-tolerant constraint), consistent with rare recessive disease.

10. Diagnostics

Clinical / electrophysiology. - ECG (12-lead): cornerstone — reveals marked QT/QTc prolongation (often ≥500–550 ms); T-wave abnormalities; documentation of torsades de pointes. QTc computed by Bazett's formula; Schwartz criteria used for LQTS probability [PMID: 22830134]. - Holter / ambulatory ECG: quantify QT dynamics and capture arrhythmia. - Audiology: audiometry/ABR confirming profound bilateral sensorineural hearing loss; vestibular testing may reveal peripheral vestibular loss [PMID: 34744965]. - Imaging: inner-ear imaging (CT/MRI) is typically normal in JLNS — notably no inner-ear malformations, which distinguishes it from some other syndromic deafness (important for cochlear-implant planning) [PMID: 39210075].

Genetic testing (confirmatory). - Recommended approach: molecular confirmation of biallelic KCNE1 variants (with KCNQ1 tested in parallel, since ~90% of JLNS is JLNS1). Options include LQTS/cardiac gene panels (which reliably include KCNQ1, KCNE1, KCNH2, SCN5A, etc.), targeted single-gene testing when a familial variant is known, and WES/WGS for atypical presentations. Broad cardiac panels can also reveal severity modifiers (e.g., RYR2, NKX2-5) [PMID: 29037160]. - Family/cascade screening of relatives is valuable, especially in consanguineous families [PMID: 28438721].

Clinical criteria / differential diagnosis. - Diagnostic combination: congenital sensorineural deafness + prolonged QT → JLNS; molecular subtyping (KCNE1 vs KCNQ1) distinguishes JLNS2 from JLNS1. - Differential: Romano-Ward syndrome/LQT5 (KCNE1 heterozygous, no deafness); other syndromic deafness (Waardenburg, Usher, Pendred — distinguished by associated features and, for JLNS, the QT interval); acquired/drug-induced long QT.

Screening. ECG screening of children with congenital sensorineural deafness is an effective case-finding strategy to detect JLNS before a sentinel cardiac event [PMID: 34308870; PMID: 22830134].

11. Outcome / Prognosis

JLNS has a poor natural history without adequate cardiac therapy and is one of the highest-risk congenital LQTS phenotypes.

Metric	JLNS	Romano-Ward (RWS)	Source
Mean QTc	548 ± 73 ms	500 ± 48 ms (P<0.001)	[PMID: 16911578]
Cumulative cardiac events, birth–age 40	93% (mean age 5.0 ± 7.0 yr)	54% (mean age 14.2 ± 9.3 yr)	[PMID: 16911578]
LQTS-related death on beta-blockers	35%	lower	[PMID: 16911578]
Mortality with defibrillator therapy	0% (over 4.9 ± 3.4 yr)	—	[PMID: 16911578]
Sudden cardiac death (overall JLNS)	>25%	—	[PMID: 32508908]

"The cumulative rates of cardiac events from birth through age 40 among JLNS and RWS patients were 93% (mean [±SD] age: 5.0 ± 7.0 years) and 54% (mean [±SD] age: 14.2 ± 9.3 years), respectively (P < 0.001)" — Goldenberg et al., 2006 [PMID: 16911578]

"Among JLNS patients treated with beta-blockers, the cumulative probability of LQTS-related death was 35%; defibrillator therapy was associated with a 0% mortality rate" — Goldenberg et al., 2006 [PMID: 16911578]

Prognostic factors. Baseline QTc ≥550 ms confers the highest risk (hazard ratio ~15.8 vs RWS); early symptom onset and history of cardiac arrest are adverse markers. Morbidity derives from both recurrent syncope/arrhythmia and lifelong profound deafness (largely rehabilitated by cochlear implants).

12. Treatment

Management targets the cardiac risk (life-preserving) and the sensory deficit (rehabilitative).

Pharmacotherapy. - Beta-blockers (e.g., propranolol, nadolol) — first-line to blunt adrenergic triggers (NCIT: Beta-Adrenergic Blocker). However, monotherapy is insufficient in JLNS (~35% LQTS-related death) [PMID: 16911578]. - Avoidance of QT-prolonging drugs; correction of electrolytes; magnesium for acute torsades.

Device / interventional. - Implantable cardioverter-defibrillator (ICD) — associated with 0% mortality in the registry cohort and is central to secondary prevention in high-risk JLNS (NCIT: Implantable Cardioverter-Defibrillator) [PMID: 16911578]. - Atrial pacing combined with increased beta-blocker doses — in 6 very young JLNS patients (too small for ICD), this achieved event-free survival over 7 years [PMID: 27451284]. - Left cardiac sympathetic denervation (LCSD) — for breakthrough events despite beta-blockade [PMID: 18606002]. - Radiofrequency catheter ablation of a triggering premature ventricular contraction eliminated electrical storm in a JLNS2 patient (KCNE1 missense) with 12-month event-free follow-up — a niche option when ICD is unavailable [PMID: 33040543].

Auditory rehabilitation. - Cochlear implantation (CI) restores useful hearing; JLNS patients typically have no inner-ear malformation, favoring implantation, though JLNS is among the commonest syndromic indications in CI cohorts [PMID: 39210075]. CI in these children shows meaningful auditory-performance gains (CAP/SIR improvement) [PMID: 31846911]. - Perioperative arrhythmia precautions are mandatory (see Prevention).

Pharmacogenomics / advanced therapeutics. No JLNS2-specific pharmacogenomic guidance is established. Gene therapy is preclinical: canalostomy-based inner-ear gene delivery preserved auditory and vestibular function in Kcne1-deficient mice [PMID: 33514733].

13. Prevention

Primary prevention: Not preventable at the genomic level once biallelic variants are inherited. Genetic counseling and carrier/cascade screening in consanguineous families reduce recurrence risk; prenatal/preimplantation testing is possible when familial variants are known [PMID: 28438721].
Secondary prevention (early detection): ECG screening of congenitally deaf children to identify JLNS before a first cardiac event [PMID: 34308870; PMID: 22830134].
Tertiary prevention (avoiding complications): beta-blockers, ICD/atrial pacing, avoidance of QT-prolonging drugs and competitive sports, and rigorous perioperative protocols for cochlear implantation.

Perioperative cochlear-implant safety pathway. Because sympathetic stimulation and QT-prolonging anesthetics can trigger fatal arrhythmias, evidence-based multidisciplinary pathways are essential. In one comprehensive series of 41 pediatric long-QT CI patients using prophylactic beta-blockers, avoidance of sympathetic stimulation and QT-prolonging drugs, magnesium sulphate, and defibrillator standby, fatal arrhythmias occurred intraoperatively in 5 patients and were successfully rescued by cardiac pacing, with good hearing outcomes [PMID: 31846911]. A prior perioperative death led one program to pause CI for cLQTS until an evidence-based care pathway was introduced [PMID: 30227792].

"Fatal Arrhythmias were encountered intra-operatively in five patients which was treated with cardiac pacing" — Anto et al., 2019 [PMID: 31846911]

"No arrhythmic events occurred in 6 very young JLNS patients who received atrial pacing in combination with increased doses of beta-blockers during 7-year follow-up" — Früh et al., 2016 [PMID: 27451284]

14. Other Species / Natural Disease

Taxonomy / orthologs: KCNE1 is conserved across mammals; mouse ortholog Kcne1 (minK/IsK), NCBI Gene 16506 (Mus musculus, NCBI Taxon 10090).
Natural disease: No well-characterized spontaneous JLNS2 equivalent in companion animals is documented in the reviewed literature; the disease is studied primarily through engineered models.
Comparative biology: The IKs (KCNQ1/KCNE1) repolarization mechanism and strial endolymph-secretion role are conserved between mouse and human, making rodents faithful models of both the cardiac and cochlear phenotypes (with caveats below).

15. Model Organisms

Kcne1 (minK) knockout mouse: the principal JLNS2 model. Loss of minK produces marked IKs reduction and recapitulates the inner-ear phenotype (deafness, circling/vestibular dysfunction) and provides the platform for gene-therapy rescue [PMID: 33514733; PMID: 19148726].
Kcnq1 knockout mouse (JLNS model): deaf, circling behavior, atrophy of the stria vascularis, contraction of endolymphatic compartments, complete degeneration of the organ of Corti and spiral ganglion — the definitive histopathologic demonstration of the deafness mechanism shared by JLNS1/JLNS2 [PMID: 15891643].

"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" — Rivas & Francis, 2005 [PMID: 15891643]

Model limitations (cardiac): Mouse ventricular repolarization relies on different dominant K⁺ currents than human; consequently minK⁻/⁻ mice show a robust inner-ear phenotype but a weaker cardiac arrhythmia phenotype (similar action-potential durations, no spontaneous arrhythmia in one optical-mapping study), whereas Merg1⁺/⁻ (IKr) mice show clearer arrhythmia. This species difference limits mouse modeling of the human LQT phenotype [PMID: 19148726].
Applications: endolymph homeostasis, stria-vascularis biology, and inner-ear gene-therapy proof-of-concept (canalostomy delivery) [PMID: 33514733]. Human iPSC-derived cardiomyocytes (not JLNS2-specific in the reviewed set) are the natural complement for modeling the cardiac electrophysiology.

Mechanistic Model / Interpretation

  Biallelic LOF KCNE1 (minK β-subunit absent/nonfunctional)
                  |
     Failure of KCNQ1/KCNE1 co-assembly
                  |
         ↓↓ IKs (slow delayed-rectifier K+)
       /                                 \
CARDIAC BRANCH                                  COCHLEAR/VESTIBULAR BRANCH
(ventricular myocytes)                          (stria vascularis marginal cells,
|                                         vestibular dark cells)
   Loss of repolarization reserve                        Failed K+ secretion into endolymph
|                                                 |
   Prolonged action potential -> QT up                  Collapse of endocochlear potential
|                                                 |
   Early afterdepolarizations,                          Degeneration of organ of Corti,
   dispersion of repolarization                          spiral ganglion; strial atrophy
|                                                 |
   Torsades de pointes -> VF                             Congenital profound SNHL
|                                         + vestibular dysfunction
   Syncope / SUDDEN CARDIAC DEATH                        (stable, non-progressive)
   (adrenergic/anesthetic triggers)

   THERAPY:  Beta-blockers (insufficient alone) -> ICD / atrial pacing -> LCSD / ablation
   HEARING:  Cochlear implant (+ strict perioperative protocol); gene therapy (preclinical)

The elegance of JLNS2 is that a single β-subunit lesion produces a two-organ disease because the same IKs channel is indispensable for (1) ventricular repolarization and (2) cochlear/vestibular endolymph secretion. The recessive inheritance, the LoF-tolerant/missense-constrained gnomAD signature, and the Romano-Ward-vs-JLNS2 dichotomy all reconcile into one coherent picture: null alleles need two hits to cause disease (recessive JLNS2), while dominant-negative missense alleles poison the channel with one hit (dominant Romano-Ward, no deafness because one functional allele suffices for the cochlea).

Evidence Base

PMID	Study	Contribution
30461122	Faridi et al. — KCNE1 mutational/phenotypic spectra	Establishes biallelic null KCNE1 as causal for JLNS2; defines recessive-null vs dominant-negative-missense mechanism
16911578	Goldenberg et al. — JLNS clinical course (International LQTS Registry)	Quantifies severe prognosis; ICD superiority over beta-blockers
15891643	Rivas & Francis — Kcnq1 KO mouse inner ear	Histopathologic mechanism of deafness (strial/organ-of-Corti degeneration)
33514733	Wu et al. — canalostomy gene therapy in Kcne1 mouse	Confirms KCNE1→JLNS2 with vestibular involvement; preclinical gene-therapy rescue
32508908	Qiu et al. — JLNS case + review	Prevalence (~1/1,000,000–1/200,000); >25% SCD; ~90% KCNQ1
34308870	Ergül et al. — deaf-child ECG screening	JLNS prevalence among congenitally deaf children (0.9%)
31846911	Anto et al. — CI in long-QT children	Intraoperative arrhythmia risk and pacing rescue during CI
27451284	Früh et al. — atrial pacing + beta-blockade	Effective strategy in very young JLNS patients
28438721	Saudi LQTS cohort	Consanguinity, homozygosity, deafness enrichment
22830134	Pakistani deaf-mute screening	Consanguinity-linked JLNS prevalence
19148726	Arrhythmia phenotype in LQT mice	Dispersion-of-repolarization mechanism; mouse cardiac-model limitation
30227792	Scott-Warren et al. — CI care pathway	Perioperative death → evidence-based pathway
39210075	Syndromic CI cohort	JLNS common CI indication; no inner-ear malformation
31518351	KCNQ1 structural models	IKs assembly; destabilization as dysfunction mechanism
33040543	Ablation of triggering PVC in JLNS2	Niche cardiac option; documents KCNE1 missense JLNS2
29037160	Turkish JLNS families	Oligogenic modifiers (RYR2, NKX2-5); panel utility
18606002	Congenital LQTS review	Treatment framework (beta-blockers, LCSD, ICD)

Limitations and Knowledge Gaps

No human molecular-profiling data. No JLNS2-specific transcriptomic, proteomic, metabolomic, or epigenomic patient datasets were identified. Mechanistic evidence rests on electrophysiology, structural modeling, and animal models.
JLNS2-specific epidemiology is imprecise. Published prevalence figures aggregate JLNS1+JLNS2; the specific incidence/carrier frequency of KCNE1-only JLNS2 is not well quantified.
Mouse cardiac model limitation. Species differences in dominant repolarizing currents mean Kcne1⁻/⁻ mice under-represent the human cardiac arrhythmia phenotype [PMID: 19148726]; human iPSC-cardiomyocyte data for JLNS2 specifically are sparse.
gnomAD LoF constraint uncertainty. KCNE1's single short coding exon yields very few expected LoF events, producing a wide confidence interval around the observed/expected LoF ratio; the "LoF-tolerant" inference should be read with that caveat (though it is congruent with recessive inheritance).
No JLNS2-specific QoL or pharmacogenomic instruments were identified.

Proposed Follow-up Experiments / Actions

Genotype-stratified natural history. Analyze registry data to isolate JLNS2 (KCNE1) from JLNS1 (KCNQ1) and compare event rates, QTc, and treatment response — does the β-subunit subtype modify prognosis?
Patient iPSC-cardiomyocytes. Generate JLNS2 iPSC-CMs (biallelic KCNE1 null) to directly measure IKs loss, action-potential prolongation, and drug responses in a human cardiac context, overcoming mouse limitations.
Inner-ear gene therapy translation. Advance canalostomy Kcne1 gene delivery [PMID: 33514733] toward larger-animal safety/efficacy and define the developmental window for hearing/vestibular rescue.
Modifier-gene mapping. Systematically test whether RYR2, NKX2-5, and common LQTS-modifier polymorphisms explain variable cardiac severity among biallelic KCNE1 patients [PMID: 29037160].
Standardize perioperative CI protocols. Prospectively validate a multidisciplinary CI care pathway for JLNS (prophylactic beta-blockade, ICD/pacing standby, avoidance of QT-prolonging anesthetics) across centers to reduce perioperative mortality [PMID: 30227792; PMID: 31846911].
Population screening cost-effectiveness. Evaluate ECG screening of all congenitally deaf children (especially in consanguineous populations) as a prevention strategy for sentinel sudden death [PMID: 34308870; PMID: 22830134].

Report compiled from primary literature and aggregated genomic resources across a five-iteration autonomous investigation (6 confirmed findings; 27 papers reviewed). Evidence types are noted throughout as human clinical, model organism, in vitro, or computational.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	19
On topic	14
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	22
Resolved	20
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	9
Terms named correctly	6
Terms named as a different term	3

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:0012871 (2 mentions) - the report calls it "MONDO"; MONDO calls it Jervell and Lange-Nielsen syndrome 2
UBERON:0002282 (1 mention) - the report calls it "organ of Corti"; UBERON calls it stria vascularis of cochlear duct
UBERON:0002295 (1 mention) - the report calls it "stria vascularis"; UBERON calls it scala media

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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Classifications

Mappings

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Progression

Prevalence

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Jervell and Lange-Nielsen Syndrome 2 (JLNS2): Disease Characteristics Report

Executive summary

1. Disease information

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

Risk factors

Protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment and real-world implementation

13. Prevention

14. Other species and natural disease

15. Model organisms and advanced research

Evidence limitations

Artifacts

Reference Validation

Quotes that could not be checked

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver

Jervell and Lange-Nielsen Syndrome Type 2 (JLNS2): Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else