| Domain | JLNS1 (KCNQ1) summary | JLNS2 distinction / caveat | Key supported numbers | Ontology suggestions | Evidence |
|---|---|---|---|---|---|
| Identity / identifiers | Jervell and Lange-Nielsen syndrome 1 is the KCNQ1-related form of autosomal-recessive cardioauditory long-QT syndrome with congenital sensorineural deafness and marked QT prolongation; disease-level resources support MONDO:0024540 for JLNS1, while the broader syndrome is MONDO:0002441. | JLNS2 is the KCNE1-related subtype; do not merge subtype-specific assertions when a source discusses broader JLNS. | None subtype-specific beyond MONDO assignment in retrieved evidence. | MONDO:0024540; MeSH: Jervell-Lange Nielsen Syndrome; HP:0000365; HP:0001649 | (pqac-00000000, pqac-00000003, pqac-00000005, pqac-00000007) |
| Causal gene and inheritance | Primary causal gene is KCNQ1; inheritance is autosomal recessive / biallelic with loss-of-function mechanism. Both truncating and missense variants leading to loss of function are relevant for LQTS/JLNS. | KCNE1 causes JLNS2; KCNE1 cases appear less common and may have a less severe clinical course than KCNQ1-associated JLNS. | Approximately 90% of JLNS cases are due to KCNQ1 mutations in one review/case-based source. | HGNC:6294 (KCNQ1); GO:0006813; GO:0005267 | (pqac-00000008, pqac-00000011, pqac-00000012, pqac-00000017) |
| Cardinal phenotypes and frequencies | Core phenotype is profound congenital bilateral sensorineural hearing loss plus prolonged QTc, often with syncope/seizures and risk of torsades/ventricular fibrillation/sudden death. Onset is often congenital/early childhood. | Severity appears worse in JLNS1/KCNQ1 than JLNS2/KCNE1 in cohort/review evidence. | In a cooperative study of 187 J-LN patients, almost 90% had cardiac events, 50% were symptomatic by age 3 years, mean QTc was 557 ± 65 ms; JLNS is commonly defined by QTc >500 ms. | HP:0000365; HP:0001649; HP:0001279; HP:0002133; HP:0011675 | (pqac-00000004, pqac-00000012, pqac-00000017) |
| Triggers / natural history | Events are precipitated by adrenergic or physiologic stressors; misdiagnosis as epilepsy can occur because arrhythmic syncope may present with seizure-like episodes. | Trigger data are largely reported for broader JLNS rather than subtype-exclusive JLNS1 cohorts. | Reported triggers include exercise, emotion, swimming, auditory stimuli, anesthesia, and fever; >25% sudden cardiac death reported in one review/case-based source. | HP:0001250; NCIT:C50595 (Syncope) | (pqac-00000006, pqac-00000008, pqac-00000012, pqac-00000013) |
| Molecular mechanism | KCNQ1 encodes Kv7.1, which with KCNE1 forms the IKs channel. In heart, loss of IKs delays repolarization and prolongs action potential duration/QT. In inner ear stria vascularis, impaired K+ secretion/endocochlear potential disrupts potassium homeostasis causing deafness; severe loss can also associate with vestibular dysfunction and hair-cell loss in models. Residual function may explain atypical recessive LQT1 without deafness. | JLNS2 shares pathway logic through KCNE1 but subtype-specific gene/protein defect differs. | One mechanistic review notes JLNS can occur when KCNQ1 protein level falls below about 10% of normal. | GO:0002027; GO:1903779; GO:0060088; UBERON:0002046; CL:0000586 | (pqac-00000003, pqac-00000007, pqac-00000012, pqac-00000013) |
| Pathogenic variant spectrum / modifiers | Reported JLNS1 variants include homozygous missense, nonsense/frameshift, splice-site, and compound heterozygous combinations; examples include p.Arg243His, c.477+1G>A, p.Arg174Cys, p.Arg366Gln, c.1741A>T (p.Lys581Ter), and c.477+5G>A. Additional variants in other arrhythmia genes (for example RYR2, NKX2-5 in one case) were proposed as possible severity modifiers. | Modifier evidence is limited and case-based, not established as routine causal annotation. | Exact example QTc values in case reports included 520 ms and 530 ms. | SO:0001583; SO:0001587; SO:0001627; SO:0001578 | (pqac-00000001, pqac-00000002, pqac-00000004, pqac-00000013) |
| Diagnostics | Diagnosis is based on ECG plus congenital deafness phenotype and confirmatory molecular testing. Suggested workup: 12-lead ECG/QTc, hearing evaluation/audiology, family history, and targeted sequencing/panel testing; exome/genome sequencing can support diagnosis in rare disease workflows. | Subtype resolution requires genetic testing because both KCNQ1 and KCNE1 can cause JLNS. | QTc >500 ms is a common diagnostic clue; one report used a 127-gene deafness panel/NGS, and another emphasized broad targeted cardiac panels. | LOINC/ECG concept; HP:0001649; HP:0000365; NCIT:C47891 (Genetic Testing) | (pqac-00000004, pqac-00000006, pqac-00000012, pqac-00000016) |
| Treatment / real-world management | First-line therapy is beta-blockade, with non-selective agents such as nadolol or propranolol generally preferred in LQTS guidance. ICD is used for cardiac arrest survivors or persistent breakthrough events; LCSD is used in refractory/intolerant high-risk cases. Cochlear implantation can substantially improve hearing but requires peri-anesthetic arrhythmia precautions. | JLNS1 often has particularly high arrhythmic risk, so escalation beyond beta-blockers is common; KCNE1-associated JLNS may be milder. | In general LQTS guidance, arrhythmic recurrence after cardiac arrest is about 14% within 5 years despite therapy; one review states LCSD can reduce cardiac events by about 90% in high-risk LQTS; in a JLNS cohort/review, beta-blockers had limited efficacy and LCSD appeared ineffective. | NCIT:C945 (Beta Adrenergic Receptor Blocker Therapy); NCIT:C27996 (Implantable Cardioverter Defibrillator); NCIT:C80466 (Sympathectomy); NCIT:C15220 (Cochlear Implantation) | (pqac-00000002, pqac-00000006, pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000017) |
| Prognosis | Prognosis remains guarded relative to many other LQTS forms because events begin early and treatment may be less protective; however outcomes improve with recognition, arrhythmia prevention, and hearing intervention. | Worse prognosis is particularly associated with KCNQ1-mutant J-LN in expert review. | Untreated LQTS mortality within 1 year was cited as 21% in one case-based review; >25% sudden cardiac death reported for JLNS in another source. | HP:0001699; NCIT:C28554 (Sudden Cardiac Death) | (pqac-00000002, pqac-00000008, pqac-00000017) |
| Model organisms / systems | Kcnq1-null mice recapitulate major JLNS traits including deafness, vestibular dysfunction, altered cardiac repolarization, collapsed Reissner membrane, and massive hair-cell loss. Human iPSC-cardiomyocyte models are being used to study KCNQ1-related LQTS/JLNS mechanisms and therapeutic screening; CRISPR correction and gene-replacement concepts are preclinical. | No established naturally occurring veterinary JLNS1 model was identified in retrieved evidence. | None beyond qualitative recapitulation. | NCBITaxon:10090; CL:0000746 (cardiomyocyte); UBERON:0001851 (stria vascularis) | (pqac-00000008, pqac-00000012, pqac-00000016) |
| 2023-2024 developments | 2023 CardiacG2P provided structured curation that specifically states both PTCs and missense KCNQ1 loss-of-function variants are relevant to LQTS/JLNS and improves variant prioritization. 2023-2024 reviews highlight patient-specific iPSC models, CRISPR-enabled precision-medicine workflows, and updated pediatric/ESC-aligned management. A phase 4 single-subject trial tested acute IV diltiazem QT effects in genetically confirmed JLNS (NCT06534671; first posted 2024-08-02; completed 2024-10-23). | These are emerging or platform-level advances; none constitute an approved JLNS1 molecular therapy. | CardiacG2P sensitivity for retained P/LP variants was 281/285 (98.6%) in benchmark testing; the diltiazem study enrolled 1 participant. | NCIT:C15206 (Clinical Trial); NCIT:C129000 (Induced Pluripotent Stem Cell) | (pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000014, pqac-00000015, pqac-00000016) |


*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.*