Jervell and Lange-Nielsen Syndrome 1: Disease Characteristics Report

Scope and evidence conventions

Jervell and Lange-Nielsen syndrome 1 (JLNS1) is specifically the biallelic KCNQ1-related disorder. It must be distinguished from JLNS2, caused by biallelic KCNE1 variants, and from broader congenital long-QT syndrome (LQTS) evidence. Where subtype-specific data are unavailable, this report labels evidence as applying to all JLNS or general LQTS rather than assuming it is JLNS1-specific. Most available information is aggregated from disease resources, cohorts, and published families—not individual electronic health records.

A knowledge-base-ready summary is provided below.

Table: This table condenses subtype-specific knowledge for Jervell and Lange-Nielsen syndrome 1 into knowledge-base-ready rows covering identity, mechanism, phenotypes, diagnosis, treatment, prognosis, models, and recent developments. It emphasizes the distinction between KCNQ1-related JLNS1 and KCNE1-related JLNS2 and includes ontology suggestions for downstream annotation.

1. Disease information

Definition

JLNS1 is a rare, severe, congenital cardioauditory ion-channel disorder characterized by profound bilateral sensorineural hearing loss and markedly prolonged ventricular repolarization, usually QTc >500 ms, with susceptibility to torsades de pointes, ventricular fibrillation, syncope, seizure-like episodes, cardiac arrest, and sudden death. It results from two pathogenic alleles in KCNQ1, whereas JLNS2 is attributable to KCNE1. Open Targets associates JLNS1 (MONDO:0024540) most strongly with KCNQ1; its weaker KCNE1 association likely reflects cross-mapping of the broader JLNS concept and should not redefine subtype 1. (OpenTargets Search: Jervell and Lange-Nielsen syndrome-KCNQ1, oertli2021molecularmechanismof pages 1-2, qiu2020jervellandlangenielsen pages 1-2)

Exact abstract wording: “JLNS is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds).” Qiu et al., published 16 May 2020, DOI: 10.1155/2020/3569359. (qiu2020jervellandlangenielsen pages 1-2)

Identifiers and synonyms

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

2. Etiology

Causal factors and genetic risk

JLNS1 is a Mendelian autosomal-recessive disorder caused by germline biallelic loss-of-function KCNQ1 variants, either homozygous or compound heterozygous. Disease-relevant classes include missense variants that impair channel function or trafficking, nonsense and frameshift variants, splice-altering variants, and less commonly exon-level copy-number changes. A 2023 expert-curated CardiacG2P analysis explicitly concluded that both protein-truncating and missense loss-of-function KCNQ1 variants cause LQTS/JLNS. (josephs2023beyondgenediseasevalidity pages 1-2, josephs2023beyondgenediseasevalidity pages 9-10)

Reported JLNS1 genotypes include:

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

These examples are not a substitute for current ClinVar assertions. Variant classification should use ACMG/AMP criteria, segregation, population frequency, phenotype specificity, RNA evidence for splice variants, and functional electrophysiology. Pathogenic alleles are expected to be individually rare in gnomAD; no universal allele-frequency value applies. The variants are germline, not somatic.

Modifiers and protective factors

Residual Kv7.1/IKs activity is a major biological modifier: severe reduction tends to produce cardioauditory disease, whereas partial function can produce recessive LQT1 without deafness. In vitro work on homozygous c.1892_1893insC (p.Pro631fs*20) showed loss of IKs only in homomeric mutant complexes, while wild-type-containing complexes were rescued by KCNE1, explaining unaffected heterozygotes and atypical recessive LQTS. (oertli2021molecularmechanismof pages 1-2, oertli2021molecularmechanismof pages 2-4)

One severe case also carried RYR2 p.Ile449Arg and NKX2-5 p.Cys270Tyr, proposed as modifiers; this remains a single-family hypothesis, not a validated modifier panel. (uysal2017“homozygousandcompound pages 2-5, uysal2017“homozygousandcompound pages 1-2)

No reproducible protective allele, diet, supplement, or environmental exposure preventing JLNS1 occurrence has been established. Clinically protective measures instead reduce arrhythmic risk after disease is present.

Gene–environment interaction

The genotype creates reduced repolarization reserve. Adrenergic stimulation and physiological stress—exercise, swimming, emotion, sudden sound, fever—and peri-anesthetic factors can then trigger ventricular arrhythmia. QT-prolonging drugs, hypokalemia, hypomagnesemia, bradycardia, and poor medication adherence can further erode repolarization reserve. A KCNQ1-JLNS child developed life-threatening arrhythmia after cochlear-implant anesthesia, directly illustrating this interaction. (qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7)

Smoking, alcohol, diet, infection, occupation, pollution, and toxins are not causal factors for this Mendelian syndrome. Fever or electrolyte loss can nevertheless act as event triggers.

3. Phenotypes

Cohort evidence indicates a severe early course: almost 90% of 187 JLNS patients had cardiac events, 50% were symptomatic by age three, and mean QTc was 557±65 ms. This cohort combined KCNQ1- and KCNE1-related JLNS, but KCNQ1 disease had the more severe course. (crotti2008congenitallongqt pages 4-5)

Quality-of-life burdens include communication and educational disability from deafness, activity restrictions, medication burden, anxiety concerning sudden death, recurrent hospitalization, ICD shocks, and family/caregiver stress. No JLNS1-specific EQ-5D, SF-36, or PROMIS dataset was identified.

4. Genetic and molecular information

Gene and protein

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

Functional consequences

Pathogenic variants can cause defective voltage sensing/gating, pore conductance, tetramer assembly, KCNE1 interaction, protein stability, trafficking, or cell-surface expression. The p.Lys581Ter variant removes part of the C-terminal A-domain needed for normal channel trafficking/assembly. (qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7)

The predominant mechanism is loss of function, not gain of function. Dominant-negative effects may occur for particular alleles, but JLNS1 requires a disease-causing allele on each homolog. Large chromosomal abnormalities are not the usual mechanism; deletion/duplication analysis remains relevant when sequencing finds only one allele. No consistent disease-specific DNA-methylation, histone, or chromatin signature is established. KCNQ1 resides within an imprinted region, but JLNS1 itself is not ordinarily classified as an imprinting disorder.

5. Environmental information

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

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

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

6. Mechanism and pathophysiology

Cardiac causal chain

Biallelic KCNQ1 loss of function → reduced Kv7.1/KCNE1 IKs → impaired phase-3 repolarizing K+ current and reduced adaptation to faster heart rates → prolonged cardiomyocyte action-potential duration → prolonged QTc and increased dispersion of repolarization → early afterdepolarizations/torsades de pointes → syncope, anoxic seizure, ventricular fibrillation, or sudden death. (oertli2021molecularmechanismof pages 1-2, oertli2021molecularmechanismof pages 2-4, yu2023precisionmedicinefor pages 1-2)

Relevant cell type: ventricular cardiomyocyte (CL:0000746). Suggested GO terms include potassium-ion transmembrane transport (GO:0071805), regulation of cardiac muscle-cell action potential (GO:0098901), cardiac muscle-cell action-potential repolarization (GO:0086009), and voltage-gated potassium-channel complex (GO:0008076).

Auditory/vestibular causal chain

Loss of Kv7.1/KCNE1 in stria-vascularis marginal cells → impaired K+ secretion into endolymph → loss of endocochlear potential and endolymph homeostasis → collapse of cochlear structures and secondary sensory-hair-cell degeneration → congenital severe-to-profound sensorineural deafness. Vestibular dark-cell dysfunction can similarly disturb vestibular endolymph. Kcnq1-null mice show collapsed Reissner membrane, massive hair-cell loss, and malformed saccule, utricle, and semicircular ducts. (qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7)

Suggested terms: sensory epithelial cell of cochlea/hair cell (CL:0000202), marginal cell of stria vascularis, potassium-ion homeostasis (GO:0055075), sensory perception of sound (GO:0007605), cochlea (UBERON:0001844), stria vascularis (UBERON:0001851), and vestibular apparatus (UBERON:0004681).

Other molecular profiling

No validated JLNS1-specific clinical transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic signature was identified. Patient-specific iPSC-cardiomyocytes are increasingly used for mechanistic phenotyping and drug testing, but their immaturity and cellular heterogeneity limit direct clinical extrapolation. (yu2023precisionmedicinefor pages 1-2)

7. Anatomical structures affected

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

Suggested anatomy terms include heart (UBERON:0000948), myocardium (UBERON:0002349), cochlea (UBERON:0001844), stria vascularis (UBERON:0001851), organ of Corti (UBERON:0002227), and plasma membrane (GO:0005886). Hearing loss is bilateral; cardiac disease has no meaningful lateralization.

8. Temporal development

JLNS1 is congenital and lifelong. Hearing loss is present at birth or recognized in infancy; cardiac manifestations may begin prenatally with bradycardia or during early childhood with syncope/seizures. Half of patients in the mixed-JLNS cohort were symptomatic by age three. (crotti2008congenitallongqt pages 4-5)

The course is chronic with episodic acute arrhythmias, not conventionally staged and not relapsing-remitting. Deafness generally does not remit spontaneously. Arrhythmic risk persists lifelong but is modifiable by treatment and avoidance of triggers. Critical windows include fetal/neonatal detection, infancy before a first cardiac event, cochlear-implant timing for language acquisition, medication initiation, and all anesthetic procedures.

9. Inheritance and population

Epidemiology

Worldwide prevalence has been estimated at approximately 1 per 1,000,000 to 1 per 200,000. Approximately 90% of all JLNS was attributed to KCNQ1 in the 2020 report, making JLNS1 the major molecular subtype. These estimates are uncertain because the disorder is exceptionally rare, can be misdiagnosed as epilepsy, and may be enriched in founder or consanguineous populations. (qiu2020jervellandlangenielsen pages 1-2)

No robust annual incidence, sex ratio, or age-stratified population estimate was identified. Both sexes are genetically affected equally; sex and hormonal state can modify arrhythmic risk in LQTS generally.

Recurrence and penetrance

For two heterozygous carrier parents, each pregnancy has a theoretical 25% affected, 50% carrier, and 25% non-carrier probability. Penetrance of the classic cardioauditory phenotype is high but not absolute: residual-function biallelic genotypes can cause recessive LQTS without deafness, demonstrating variable expressivity. Heterozygous relatives may be asymptomatic or manifest dominant LQT1 depending on the allele’s functional effect. (uysal2017“homozygousandcompound pages 5-6, oertli2021molecularmechanismof pages 1-2)

Consanguinity increases the probability that both parents carry the same rare allele. Founder effects are reported in Scandinavian populations, but no precise founder-variant frequency was adequately retrieved. Anticipation is not expected; germline mosaicism is theoretically possible but not a recognized major mechanism.

10. Diagnostics

Clinical and functional evaluation

Recommended evaluation comprises:

1. 12-lead ECG with manually verified QT/QTc; repeat ECGs because measurement and rate correction can vary.
2. Holter monitoring and exercise testing where useful for rhythm burden and repolarization behavior.
3. Detailed history of exertional/emotional syncope, seizures, cardiac arrest, medications, and sudden deaths.
4. Formal audiology—auditory brainstem response in infants and age-appropriate pure-tone/speech testing.
5. Serum potassium, magnesium, calcium, and thyroid assessment to identify acquired aggravators, not to diagnose the genetic disease.
6. Device interrogation where an ICD/pacemaker is present.

Profound congenital deafness plus QTc >500 ms is highly suggestive, but molecular confirmation is required to assign JLNS1 rather than JLNS2. (uysal2017“homozygousandcompound pages 1-2, qiu2020jervellandlangenielsen pages 1-2)

Genetic testing

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

Differential diagnosis

Differentials include Romano-Ward LQT1; JLNS2/KCNE1; acquired long QT; Timothy syndrome; Andersen-Tawil syndrome; catecholaminergic polymorphic ventricular tachycardia; epilepsy; vasovagal syncope; and nonsyndromic congenital deafness such as GJB2- or SLC26A4-related disease. The combination of profound congenital deafness, marked QT prolongation, and biallelic KCNQ1 variants distinguishes JLNS1.

Screening

All first-degree relatives should receive ECG and targeted familial-variant testing. Hearing screening alone is insufficient because a child can pass newborn screening and later be recognized as hearing impaired, as occurred in the reported KCNQ1 family. (qiu2020jervellandlangenielsen pages 1-2)

Population ECG/genomic newborn screening remains investigational; cascade screening is the established high-yield approach.

11. Outcome and prognosis

JLNS is among the most malignant LQTS forms. In the 187-patient cohort, almost 90% experienced cardiac events and half were symptomatic by age three. KCNQ1-associated disease had a substantially more severe course than KCNE1-associated disease. (crotti2008congenitallongqt pages 4-5)

A separate review reported sudden cardiac death in >25%, although this is historical/mixed-management evidence and should not be interpreted as a contemporary treated JLNS1 mortality rate. (qiu2020jervellandlangenielsen pages 1-2)

Poor prognostic factors include very long QTc, early symptoms, prior cardiac arrest, recurrent events despite β-blockade, KCNQ1 rather than KCNE1 etiology, nonadherence, and exposure to avoidable triggers. No validated JLNS1-specific five- or ten-year survival estimate or prognostic molecular biomarker was identified.

Hearing generally does not recover medically, but cochlear implantation can produce good auditory performance. ICD shocks and activity restrictions may cause substantial psychosocial morbidity. Recovery from the genetic disorder is not expected; risk management is lifelong.

12. Treatment

Standard strategy

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

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

Experimental therapy and trials

No gene, RNA, or cell therapy is approved for JLNS1. Preclinical approaches include KCNQ1 gene replacement, CRISPR correction, patient-specific iPSC drug screening, and suppression-and-replacement constructs. Kcnq1 replacement in immature mouse scala media improved hearing, cochlear morphology, and vestibular function, but this has not established human safety or efficacy. (qiu2020jervellandlangenielsen pages 1-2, yu2023precisionmedicinefor pages 1-2)

NCT06534671, first posted 2 August 2024, was a completed phase-4, open-label, single-group study of acute IV diltiazem in genetically confirmed adult JLNS. It enrolled one participant and measured short-term QT effects after 0.25 mg/kg, with a possible 0.35 mg/kg second dose. This is exploratory single-subject evidence and does not support routine diltiazem treatment. ClinicalTrials.gov record. (NCT06534671 chunk 1)

13. Prevention

Primary prevention of de novo disease in an individual is not possible after conception, but reproductive options include carrier testing, partner testing, prenatal diagnosis, and preimplantation genetic testing when familial variants are known.

Secondary prevention consists of early ECG/genetic diagnosis in deaf infants, cascade testing, and immediate treatment before a first arrhythmia. Tertiary prevention includes strict β-blocker adherence; avoidance of QT-prolonging drugs; prompt correction of potassium, magnesium, and calcium abnormalities; fever/dehydration management; individualized exercise/swimming precautions; supervised anesthesia; and ICD/LCSD escalation when indicated. There is no JLNS-specific vaccine or infectious prophylaxis.

14. Other species and natural disease

No well-established naturally occurring companion-animal or wildlife disease directly equivalent to human KCNQ1-JLNS1 was identified. Therefore, breed ontology, veterinary prevalence, transmission, and zoonotic potential are not applicable/unknown. The disorder is genetic and noncommunicable.

Orthologous Kcnq1/Kcne1 channel biology is evolutionarily conserved in mammals. Relevant taxa include human (NCBI Taxon 9606) and laboratory mouse (NCBI Taxon 10090).

15. Model organisms and experimental systems

Mouse

Kcnq1-null mice reproduce major disease components: deafness, vestibular dysfunction, and abnormal cardiac repolarization. Their inner ears show collapsed Reissner membrane, extensive hair-cell loss, and abnormalities of the saccule, utricle, and semicircular ducts. This provides strong mechanistic support for KCNQ1-dependent endolymph homeostasis. Limitations include species-specific cardiac electrophysiology and differences in developmental timing and arrhythmic susceptibility. (qiu2020jervellandlangenielsen pages 1-2)

Heterologous cellular models

Xenopus oocytes and mammalian expression systems permit voltage-clamp measurement of IKs, trafficking, assembly, and dominant-negative or recessive behavior. Such work demonstrated that KCNE1 could rescue function in complexes containing wild-type KCNQ1 for an atypical recessive variant. (oertli2021molecularmechanismof pages 1-2)

Human iPSC models

Patient-specific iPSC-derived cardiomyocytes reproduce prolonged action potentials and allow isogenic CRISPR correction, mechanistic study, and high-throughput drug testing. A 2023 review described WGS, CRISPR editing, machine learning, and iPSC cardiomyocytes as converging platforms for LQTS precision medicine. These remain research systems because iPSC cardiomyocytes are relatively immature and do not fully reproduce whole-heart autonomic, conduction, pharmacokinetic, or developmental physiology. (yu2023precisionmedicinefor pages 1-2)

Recent developments and expert assessment

The most consequential 2023–2024 developments were not new approved treatments but improvements in variant interpretation, risk-adapted management, and human disease modeling. CardiacG2P formally encoded biallelic requirement and KCNQ1 loss-of-function variant classes for scalable genomic interpretation; across its benchmark set it retained 281/285 pathogenic/likely pathogenic variants (98.6% sensitivity), although that benchmark was not JLNS1-specific. (josephs2023beyondgenediseasevalidity pages 1-2, josephs2023beyondgenediseasevalidity pages 9-10)

The 2024 pediatric synthesis of ESC guidance reinforced nonselective β-blockade, selective use of ICD and LCSD, and careful reassessment of risk after therapy. Meanwhile, iPSC/CRISPR work supports eventual genotype-specific treatment but remains preclinical. (balestra2024congenitallongqt pages 8-9, yu2023precisionmedicinefor pages 1-2)

Overall expert interpretation

JLNS1 should be treated as a medical emergency in genetic deafness evaluation: every child with severe congenital sensorineural hearing loss should have a careful history for syncope/seizures and consideration of ECG, especially before anesthesia. Molecular confirmation matters because KCNQ1-related JLNS has greater arrhythmic severity than KCNE1-related disease. The strongest current intervention is coordinated early care—expert β-blockade, trigger avoidance, rapid escalation to device or denervation therapy when warranted, and cochlear rehabilitation—not an experimental molecular therapy. (qiu2020jervellandlangenielsen pages 1-2, qiu2020jervellandlangenielsen pages 5-7, crotti2008congenitallongqt pages 4-5)

Evidence gaps

Reliable JLNS1-specific estimates remain unavailable for annual incidence, modern treated survival, sex ratio, individual phenotype frequencies, quantitative quality-of-life scores, carrier frequency, penetrance by variant class, validated modifier genes, epigenomic or multi-omic signatures, and naturally occurring veterinary disease. Many published outcome statistics combine JLNS1 and JLNS2 or derive from historical cohorts; database ingestion should preserve those evidence-scope qualifiers.

References

1. (OpenTargets Search: Jervell and Lange-Nielsen syndrome-KCNQ1): Open Targets Query (Jervell and Lange-Nielsen syndrome-KCNQ1, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (oertli2021molecularmechanismof pages 1-2): Annemarie Oertli, Susanne Rinné, Robin Moss, Stefan Kääb, Gunnar Seemann, Britt-Maria Beckmann, and Niels Decher. Molecular mechanism of autosomal recessive long qt-syndrome 1 without deafness. International Journal of Molecular Sciences, 22:1112, Jan 2021. URL: https://doi.org/10.3390/ijms22031112, doi:10.3390/ijms22031112. This article has 13 citations.

3. (oertli2021molecularmechanismof pages 12-13): Annemarie Oertli, Susanne Rinné, Robin Moss, Stefan Kääb, Gunnar Seemann, Britt-Maria Beckmann, and Niels Decher. Molecular mechanism of autosomal recessive long qt-syndrome 1 without deafness. International Journal of Molecular Sciences, 22:1112, Jan 2021. URL: https://doi.org/10.3390/ijms22031112, doi:10.3390/ijms22031112. This article has 13 citations.

4. (oertli2021molecularmechanismof pages 2-4): Annemarie Oertli, Susanne Rinné, Robin Moss, Stefan Kääb, Gunnar Seemann, Britt-Maria Beckmann, and Niels Decher. Molecular mechanism of autosomal recessive long qt-syndrome 1 without deafness. International Journal of Molecular Sciences, 22:1112, Jan 2021. URL: https://doi.org/10.3390/ijms22031112, doi:10.3390/ijms22031112. This article has 13 citations.

5. (qiu2020jervellandlangenielsen pages 1-2): Yue Qiu, Sen Chen, Xia Wu, Wen-Juan Zhang, Wen Xie, Yuan Jin, Le Xie, Kai Xu, Xue Bai, Hui-Min Zhang, Xiao-Zhou Liu, Xiao-Hui Wang, Yu Sun, and Wei-Jia Kong. Jervell and lange-nielsen syndrome due to a novel compound heterozygous kcnq1 mutation in a chinese family. Neural Plasticity, 2020:1-8, May 2020. URL: https://doi.org/10.1155/2020/3569359, doi:10.1155/2020/3569359. This article has 14 citations and is from a peer-reviewed journal.

6. (josephs2023beyondgenediseasevalidity pages 9-10): Katherine S. Josephs, Angharad M. Roberts, Pantazis Theotokis, Roddy Walsh, Philip J. Ostrowski, Matthew Edwards, Andrew Fleming, Courtney Thaxton, Jason D. Roberts, Melanie Care, Wojciech Zareba, Arnon Adler, Amy C. Sturm, Rafik Tadros, Valeria Novelli, Emma Owens, Lucas Bronicki, Olga Jarinova, Bert Callewaert, Stacey Peters, Tom Lumbers, Elizabeth Jordan, Babken Asatryan, Neesha Krishnan, Ray E. Hershberger, C. Anwar A. Chahal, Andrew P. Landstrom, Cynthia James, Elizabeth M. McNally, Daniel P. Judge, Peter van Tintelen, Arthur Wilde, Michael Gollob, Jodie Ingles, and James S. Ware. Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions. Genome Medicine, Oct 2023. URL: https://doi.org/10.1186/s13073-023-01246-8, doi:10.1186/s13073-023-01246-8. This article has 35 citations and is from a highest quality peer-reviewed journal.

7. (crotti2008congenitallongqt pages 4-5): Lia Crotti, Giuseppe Celano, Federica Dagradi, and Peter J Schwartz. Congenital long qt syndrome. Orphanet Journal of Rare Diseases, Jul 2008. URL: https://doi.org/10.1186/1750-1172-3-18, doi:10.1186/1750-1172-3-18. This article has 457 citations and is from a peer-reviewed journal.

8. (uysal2017“homozygousandcompound pages 1-2): Fahrettin Uysal, Burcu Turkgenc, Guven Toksoy, Ozlem M. Bostan, Elif Evke, Oya Uyguner, Cengiz Yakicier, Hulya Kayserili, Ergun Cil, and Sehime G. Temel. “homozygous, and compound heterozygous mutation in 3 turkish family with jervell and lange-nielsen syndrome: case reports”. BMC Medical Genetics, Oct 2017. URL: https://doi.org/10.1186/s12881-017-0474-8, doi:10.1186/s12881-017-0474-8. This article has 11 citations and is from a peer-reviewed journal.

9. (uysal2017“homozygousandcompound pages 6-7): Fahrettin Uysal, Burcu Turkgenc, Guven Toksoy, Ozlem M. Bostan, Elif Evke, Oya Uyguner, Cengiz Yakicier, Hulya Kayserili, Ergun Cil, and Sehime G. Temel. “homozygous, and compound heterozygous mutation in 3 turkish family with jervell and lange-nielsen syndrome: case reports”. BMC Medical Genetics, Oct 2017. URL: https://doi.org/10.1186/s12881-017-0474-8, doi:10.1186/s12881-017-0474-8. This article has 11 citations and is from a peer-reviewed journal.

10. (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.

11. (uysal2017“homozygousandcompound pages 2-5): Fahrettin Uysal, Burcu Turkgenc, Guven Toksoy, Ozlem M. Bostan, Elif Evke, Oya Uyguner, Cengiz Yakicier, Hulya Kayserili, Ergun Cil, and Sehime G. Temel. “homozygous, and compound heterozygous mutation in 3 turkish family with jervell and lange-nielsen syndrome: case reports”. BMC Medical Genetics, Oct 2017. URL: https://doi.org/10.1186/s12881-017-0474-8, doi:10.1186/s12881-017-0474-8. This article has 11 citations and is from a peer-reviewed journal.

12. (uysal2017“homozygousandcompound pages 5-6): Fahrettin Uysal, Burcu Turkgenc, Guven Toksoy, Ozlem M. Bostan, Elif Evke, Oya Uyguner, Cengiz Yakicier, Hulya Kayserili, Ergun Cil, and Sehime G. Temel. “homozygous, and compound heterozygous mutation in 3 turkish family with jervell and lange-nielsen syndrome: case reports”. BMC Medical Genetics, Oct 2017. URL: https://doi.org/10.1186/s12881-017-0474-8, doi:10.1186/s12881-017-0474-8. This article has 11 citations and is from a peer-reviewed journal.

13. (yu2023precisionmedicinefor pages 1-2): Yang Yu, Isabelle Deschenes, and Ming-Tao Zhao. Precision medicine for long qt syndrome: patient-specific ipscs take the lead. Expert Reviews in Molecular Medicine, Jan 2023. URL: https://doi.org/10.1017/erm.2022.43, doi:10.1017/erm.2022.43. This article has 23 citations and is from a peer-reviewed journal.

14. (balestra2024congenitallongqt pages 8-9): Elia Balestra, Marco Bobbo, Marco Cittar, Daniela Chicco, Biancamaria D’Agata Mottolese, Egidio Barbi, and Thomas Caiffa. Congenital long qt syndrome in children and adolescents: a general overview. Children, 11:582, May 2024. URL: https://doi.org/10.3390/children11050582, doi:10.3390/children11050582. This article has 20 citations.

15. (hauwanga2024managementoflong pages 5-6): Wilhelmina N Hauwanga, Ryan Chun Chien Yau, Kang Suen Goh, Jose Ittay Castro Ceron, Berley Alphonse, Gurinder Singh, Sara Elamin, Vaishnavi Jamched, Aaron A Abraham, Joshi Purvil, Jeshua N Devan, Gabriella Valentim, Billy McBenedict, Bruno Lima Pessôa, and Evandro T Mesquita. Management of long qt syndrome: a systematic review. Cureus, Jun 2024. URL: https://doi.org/10.7759/cureus.62592, doi:10.7759/cureus.62592. This article has 10 citations.

16. (NCT06534671 chunk 1): Prince Joseph Kannankeril. Diltiazem in Jervell and Lange-Nielsen Syndrome. Vanderbilt University Medical Center. 2024. ClinicalTrials.gov Identifier: NCT06534671

17. (josephs2023beyondgenediseasevalidity pages 1-2): Katherine S. Josephs, Angharad M. Roberts, Pantazis Theotokis, Roddy Walsh, Philip J. Ostrowski, Matthew Edwards, Andrew Fleming, Courtney Thaxton, Jason D. Roberts, Melanie Care, Wojciech Zareba, Arnon Adler, Amy C. Sturm, Rafik Tadros, Valeria Novelli, Emma Owens, Lucas Bronicki, Olga Jarinova, Bert Callewaert, Stacey Peters, Tom Lumbers, Elizabeth Jordan, Babken Asatryan, Neesha Krishnan, Ray E. Hershberger, C. Anwar A. Chahal, Andrew P. Landstrom, Cynthia James, Elizabeth M. McNally, Daniel P. Judge, Peter van Tintelen, Arthur Wilde, Michael Gollob, Jodie Ingles, and James S. Ware. Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions. Genome Medicine, Oct 2023. URL: https://doi.org/10.1186/s13073-023-01246-8, doi:10.1186/s13073-023-01246-8. This article has 35 citations and is from a highest quality peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.