| Domain | Database-ready summary | Key ontology / identifiers | Evidence type | Key citations |
|---|---|---|---|---|
| Identity | Jervell and Lange-Nielsen syndrome 2 (JLNS2) is a rare cardio-auditory channelopathy defined by congenital profound bilateral sensorineural hearing loss plus long-QT syndrome with risk of ventricular arrhythmia and sudden death; it is distinct from JLNS1, which is caused by biallelic KCNQ1 variants. | OMIM: 612347; MONDO: disease-level JLNS available as MONDO_0002441; HPO candidates: congenital sensorineural hearing impairment, long QT interval | Human clinical families; disease-gene curation | (pqac-00000003, pqac-00000000) |
| Causal gene / inheritance | Cause: biallelic loss-of-function variants in KCNE1, encoding the potassium voltage-gated channel subfamily E regulatory subunit 1, an accessory subunit for KCNQ1/Kv7.1. Inheritance is autosomal recessive; heterozygous loss-of-function carriers may have normal hearing and normal QT, while some heterozygous missense alleles can cause Romano-Ward syndrome via dominant-negative effects. | Gene: KCNE1; HGNC-approved symbol: KCNE1; HPO candidate: autosomal recessive inheritance | Human clinical genetics; mechanistic interpretation | (pqac-00000003, pqac-00000002, pqac-00000001) |
| Cardinal phenotypes | Core phenotype is congenital, severe-to-profound, bilateral sensorineural deafness with prolonged QTc. Reported JLNS2 families had QTcF about 487-495 ms and QTcB about 503-518 ms; syncopal events may be absent in some genetically confirmed cases, so hearing-loss-first presentation is possible. | HPO candidates: profound sensorineural hearing impairment; bilateral hearing impairment; long QT interval; syncope; sudden cardiac death | Human clinical families | (pqac-00000002, pqac-00000003) |
| Mechanism / pathophysiology | Upstream defect: KCNE1 deficiency impairs the IKs channel complex with KCNQ1. In heart, reduced repolarizing current delays ventricular repolarization, prolonging QT and increasing torsades/ventricular arrhythmia risk. In inner ear stria vascularis, KCNE1/KCNQ1 dysfunction disrupts K+ secretion into endolymph and collapses the endocochlear potential required for hair-cell depolarization, causing deafness; paralog compensation appears insufficient in inner ear. | GO candidates: potassium ion transmembrane transport; regulation of cardiac action potential repolarization; sensory perception of sound; CL candidate: strial marginal cell; UBERON candidate: stria vascularis, cochlea, heart ventricle | Human molecular genetics; animal model; auditory cell biology | (pqac-00000001, pqac-00000004, pqac-00000014) |
| Diagnostic anchors | Diagnostic confirmation rests on syndromic phenotype plus ECG and molecular testing. Contemporary congenital LQTS anchors: QTc ≥480 ms, or modified Schwartz score >3; in symptomatic patients, QTc ≥460 ms can suffice. Because a proportion of gene-confirmed LQTS can have normal-range resting QTc, KCNE1-inclusive NGS panels/exome testing are important in deaf children or families with cardio-auditory findings. | HPO candidates: abnormal electrocardiogram, long QT interval; test concepts: ECG, molecular genetic testing | Human clinical guidelines/review; human genetic diagnosis | (pqac-00000009, pqac-00000006, pqac-00000016) |
| Standard management | Management is largely extrapolated from congenital LQTS/JLNS practice: nonselective beta-blockers (nadolol or propranolol) are first-line; avoidance of QT-prolonging drugs and trigger management are standard. ICD is recommended after cardiac arrest and considered for persistent symptoms despite beta-blockers; left cardiac sympathetic denervation is used when events recur or ICD is unsuitable. Cochlear implantation can improve hearing, but peri-anesthetic arrhythmia risk requires careful planning and monitoring. | NCIT candidates: Beta Adrenergic Receptor Blocking Agent Therapy; Implantable Cardioverter Defibrillator; Sympathectomy; Cochlear Implantation | Guidelines/review; case report real-world implementation | (pqac-00000006, pqac-00000005, pqac-00000015) |
| Emerging research / latest developments | Recent work emphasizes precision medicine in congenital LQTS using patient-specific iPSC-derived cardiomyocytes, CRISPR-enabled variant validation, and high-throughput drug testing. A completed 2024 phase 4 JLNS trial tested acute IV diltiazem effects on QT interval in 1 genetically confirmed adult participant; results were submitted for publication after trial completion. | Research concepts: iPSC disease modeling; CRISPR genome editing; ClinicalTrials.gov NCT06534671 | In vitro precision-medicine review; clinical trial | (pqac-00000007, pqac-00000010, pqac-00000013) |
| Major evidence gaps | JLNS2-specific epidemiology, penetrance, carrier frequency, founder-variant frequencies, longitudinal survival, quality-of-life metrics, and genotype-specific treatment outcomes remain sparse because published evidence is limited to few families/case-based data. No confident JLNS2-specific epigenomic, transcriptomic, proteomic, metabolomic, or large natural-history datasets were identified in the retrieved evidence. | No supported disease-specific ontology additions beyond above | Evidence-gap synthesis | (pqac-00000003, pqac-00000002, pqac-00000013) |


*Table: This table summarizes the most actionable database-ready facts for Jervell and Lange-Nielsen syndrome 2, including identity, gene, mechanism, diagnosis, management, recent research, and explicit evidence gaps. It is designed to support structured knowledge-base entry creation while avoiding unsupported identifiers.*