DiagnosisClinical DiagnosisThe diagnosis of Jervell and Lange-Nielsen syndrome (JLNS) is definitively established in individuals with all of the following:Congenital sensorineural deafness Long QT interval, often manifest as syncope, most often elicited by emotion or exercise Presence of two disease-causing mutations in either KCNQ1 or KCNE1 [Priori et al 1999] Hearing loss. All individuals with molecularly confirmed JLNS have profound congenital sensorineural deafness (see Deafness and Hereditary Hearing Loss Overview.)Long QTc. Based on existing diagnostic criteria, all individuals with JLNS have a QTc interval greater than 500 msec (average 550 msec), indicating increased time for ventricular depolarization and repolarization [Tyson et al 2000]. Generally, the upper limit of normal for the QTc is 440 msec for males and 460 msec for post-pubertal females [Priori et al 1999, Allan et al 2001]. Note: (1) In the "pre-molecular" era, diagnosis of JLNS relied on clinical criteria alone, and thus it is not currently known how many children with molecularly confirmed JLNS have a borderline QTc interval prolongation of 440 msec to 500 msec or how many children with molecularly confirmed JLNS have a QTc that falls within the "normal" range. This issue will be resolved as data on more affected individuals are gathered. A review by Schwartz et al [2006] gives a comprehensive summary of the natural history, molecular basis, and clinical characteristics of 186 affected individuals from 135 families, in whom mutations were identified in 63 (47%). (2) Hearing loss commonly occurs in the setting of familial long QT syndrome (LQTS) (see Romano-Ward Syndrome). In this situation, the hearing loss may be entirely unrelated to the etiology of the LQTS, particularly if the hearing loss is moderate.Molecular Genetic TestingGenes. JLNS is caused by mutations in either KCNQ1 or KCNE1 [Neyroud et al 1997, Splawski et al 1997, Duggal et al 1998, Chen et al 1999]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Jervell and Lange-Nielsen SyndromeView in own windowGene Symbol Proportion of JLNS Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityKCNQ190% ^{1Sequence analysis / mutation scanningSequence variants 2, 3ClinicalDeletion / duplication analysis 4Exonic or multiexonic deletion or duplication 5KCNE110% 6Sequence analysis / mutation scanningSequence variants 2, 3ClinicalDeletion / duplication analysis 4Partial- or whole-gene deletion; none reported 71. In a study of ten families, nine had mutations in KCNQ1 [Tyson et al 2000]. In a second study of 63 families, 57 (90.5%) had mutations in KCNQ1 [Schwartz et al 2006]. In a Norwegian study 12 out of 13 unrelated persons with JLNS had four different Norwegian founder mutations [Berge et al 2008]. See also Winbo et al [2012a]. In Sweden and Norway only KCNQ1 appear to be associated with JLNS [Tranebjaerg et al 1999, Tyson et al 2000, Winbo et al 2012a].2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Mutations have been found in either KCNQ1 or KCNE1 in 94% of individuals with clinical JLNS undergoing molecular testing [Schwartz et al 2006]. The mutations may be located in all coding exons. Current experience indicates that 33% are compound heterozygotes [Schwartz et al 2006]. 4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Both deletion and duplication of exon(s) of KCNQ1 are known to cause long QT syndrome [Zehelein et al 2006, Eddy et al 2008]; their frequency is unknown. 6. Of 63 families, six (9.5%) had mutations in KCNE1 [Schwartz et al 2006]. None of the Norwegian patients with JLNS have been shown to have KCNE1 mutations [Tranebjaerg et al 1999, Berge et al 2008, Siem et al 2008]. KCNE1 mutations account for fewer than 10% of all JLNS cases, and are not involved in Norwegian or Swedish cases [Tranebjaerg et al 1999, Winbo et al 2012a].7. No deletions or duplications of KCNE1 have been reported to cause JLNS. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.) Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. Two alternatives exist:1.Sequential gene testing. The most common strategy for molecular diagnosis of a proband suspected of having JLNS is sequence analysis of KCNQ1; if no mutation is identified, sequencing of KCNE1 is appropriate. In countries with KCNQ1 founder mutations, like Norway, particular mutations should be tested first [Tranebjaerg et al 1999, Tranebjaerg 2004, Berge et al 2008, Siem et al 2008].
OR2.Multi-gene testing. Consider using a long QT syndrome multi-gene panel that includes genes associated with JLNS. These panels vary by methods used and genes included; thus, the ability of a panel to detect the causative mutation(s) in any given individual also varies.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersHeterozygosity for mutations in KCNQ1 and KCNE1 has been observed in children without hearing loss who have long QT syndrome (LQTS) inherited in an autosomal dominant manner [Towbin et al 2001] (also called Romano-Ward syndrome) (see Differential Diagnosis).}

Natural HistoryHomozygotes. Deafness is congenital, bilateral, profound, and sensorineural in all individuals with molecularly confirmed Jervell and Lange-Nielsen syndrome (JLNS) (see Deafness and Hereditary Hearing Loss Overview). Abnormal cardiac depolarization and repolarization may result in prolongation of the QT interval and tachyarrhythmias (including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation), which may culminate in syncope or sudden death. The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright.In the Schwartz et al [2006] study of 135 families with JLNS, the QTc was markedly prolonged (557±65 msec); 50% of individuals had cardiac events before age three years, with emotions and exercise being the primary triggers. Note, however, that selection bias for severely affected individuals cannot be excluded: individuals with putative JLNS but no clinical manifestations other than deafness until adulthood (and to age 50 years in one case) have been described.QTc prolongation in JLNS, particularly when severe, appears to be associated with increased risk for death in infancy (SIDS). Although more than half of untreated children with JLNS die prior to age 15 years, some individuals are reported to have survived several syncopal episodes during adulthood.A high frequency of individuals with KCNQ1-related JLNS have iron deficiency anemia and hypergastrinemia [Winbo et al 2012b]. This may be due to loss of the KCNQ1 potassium channels and reduced gastric acid secretion. The study by Winbo et al [2012b] confirms previous anecdotal reports of anemia in individuals with JLNS in Norway [Tranebjaerg et al 1999]. The sex ratio among individuals with JLNS is even, but females are at lower risk for cardiac arrest/sudden death [Schwartz et al 2006].Physical examination is unremarkable except for deafness. Heterozygotes. Heterozygotes usually have normal hearing. In some individuals who are heterozygous for mutations associated with JLNS, QTc prolongation, fainting, and sudden death never occur. In contrast, some individuals heterozygous for mutations associated with JLNS may have QTc prolongation associated with fainting and death heritable in an autosomal dominant manner. This form of LQTS is called Romano-Ward syndrome (RWS). RWS can also be caused by mutations in several genes that do not cause deafness/JLNS in a homozygous form (see Differential Diagnosis.) These mutations may be associated with highly variable QTc intervals, from normal to markedly abnormal. Histopathology of temporal bone. Histologic examination of a few temporal bones was performed prior to the availability of molecular genetic testing, but not since. In a mouse model with knock-out for Kcnq1 (which can be considered an animal model for JLNS in humans), atrophy of the stria vascularis and collapse of the endolymphatic compartments and surrounding membranes are marked. Complete degeneration of the organ of Corti and associated degeneration of the spiral ganglion were found [Rivas & Francis 2005]. In one Norwegian individual with JLNS resulting from homozygosity for the c.572_576del mutation in KCNQ1, histopathologic examination of the temporal bones showed severe atrophy of the stria vascularis and the organ of Corti with absence of cochlear nerve fibers [Tranebjaerg L & Merchant SM, unpublished data 2012].

Genotype-Phenotype CorrelationsData to establish better predictors for a correlation between genotype and phenotype were provided from a large number of individuals with molecularly confirmed JLNS. Among 63 individuals who were genotyped, 33% were compound heterozygotes [Schwartz et al 2006]. No clinical difference was evident between persons with at least one inactivating mutation (insertion/deletion, splice mutation, truncation) and those with missense mutations.Among six asymptomatic individuals in the study of Schwartz et al [2006], two had KCNQ1 mutations and four had KCNE1 mutations, further confirming the milder presentation of JLNS associated with KCNE1 mutations compared to JLNS associated with KCNQ1 mutations.

Differential DiagnosisDeafness and prolonged QTc with or without long QT syndrome (LQTS) both have multiple etiologies, including genetic and environmental causes. In many individuals with both deafness and prolonged QTc (or LQTS), the deafness and prolonged QTc (or LQTS) have separate etiologies. All of these possibilities must be considered in each affected individual, particularly in the absence of parental consanguinity or an affected sib. The following considerations are relevant in an individual who has both deafness and prolonged QTc:Prior to the availability of molecular genetic testing, the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS) was based on clinical criteria alone. RWS was commonly diagnosed in persons with LQTS and normal hearing. Some children with JLNS may be misdiagnosed with epilepsy and incorrectly treated with antiepileptic drugs before the correct diagnosis of JLNS is established [Tranebjaerg et al 1999]. Long QT multi-gene panels may include testing for a number of the genes related to disorders discussed in this section. Note: The genes involved and methods used vary by laboratory. Romano-Ward syndrome (RWS, long QT syndrome). The diagnosis of Romano-Ward syndrome (RWS) is made on the basis of a prolonged QT interval on the ECG, clinical presentation, and family history; or identification of a mutation in KCNQ1 (locus name LQT1), KCNH2 (locus name LQT2), SCN5A (locus name LQT3), KCNE1 (locus name LQT5), or KCNE2 (locus name LQT6) in the absence of profound congenital sensorineural deafness (the presence of which is highly suggestive of Jervell and Lange-Nielsen syndrome). Individuals with mutations in KCNE1 may also have atrial fibrillation [Olesen et al 2012]. Mutations in two other genes, ANK2 and KCNJ2, have been proposed as causative of LQT4 and LQT7, respectively, but uncertainty exists as to whether the long QT syndrome (LQTS) designation is appropriate for these conditions and further study is underway. Diagnostic criteria have been established for the resting ECG QTc value in the absence of specific conditions known to lengthen the QTc interval. Table 2 summarizes the genes known to be associated with RWS. Only KCNQ1 and KCNE1 have been implicated in both RWS and JLNS. Three families with autosomal recessive Romano-Ward syndrome without hearing loss have been well studied [Larsen et al 1999].Table 2. Genes Associated with Autosomal Dominant Long QT Syndrome (Romano-Ward Syndrome)View in own windowLocus NameGeneProtein FunctionProportion of Individuals with RWSLQT1KCNQ1 I_Ks K+ channel α subunit 46% LQT2KCNH2 (HERG) I_Ks K+ channel α subunit 38%LQT3SCN5A I_Na Na+ channel α subunit 13%LQT4 ¹ Unknown Unknown LQT5KCNE1 I_Ks K+ β subunit 2%LQT6KCNE2I_Kr K+ channel β subunit 1%LQT7 ¹ UnknownUnknownLQT9CAV3RareLQT10SCN4BRareLQT11AKAP9RareLQT12SNTA1RareLQT13KCNJ5RareFrom Keating & Sanguinetti [2001] LQT = long QT I_Kr = rapidly activating delayed rectifier potassium current I_Ks = slowly activating delayed rectifier potassium channel1. From Romano-Ward Syndrome. Two other genes, ANK2 and KCNJ2, have been proposed to be associated with LQT4 and LQT7 respectively, but uncertainty exists as to whether the long QT syndrome (LQTS) designation is appropriate for these conditions; further study is underway.Other genetic disorders considered to be cardiac channelopathies associated with LQTS include the following [Ackerman 2005]:Timothy syndrome Andersen-Tawil syndrome Brugada syndrome Causes of hearing loss. The differential diagnosis for hearing loss includes consideration of other forms of syndromic and nonsyndromic disorders, as well as acquired disorders. For more information on hereditary hearing loss, see Deafness and Hereditary Hearing Loss Overview. One disorder that should be noted specifically is DFNB1, the most common autosomal recessive form of nonsyndromic hearing loss. DFNB1 is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment. No other associated medical findings are present. Diagnosis of DFNB1 depends on identification of deafness-causing mutations in GJB2 and/or GJB6, which alter the gap junction beta-2 protein (connexin 26) and the gap junction beta-6 protein (connexin 30), respectively. Molecular genetic testing detects more than 99% of mutations in these genes. JLNS should be suspected in any infant who has profound bilateral sensorineural hearing loss, no identifiable GJB2 or GJB6 mutations, and a normal physical examination.Acquired causes of LQTS Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia Malnutrition or liquid protein diet Drugs: vasodilators, tricyclic antidepressants, organophosphates, antihistamines, phenothiazines, procainamide, disopyramide, quinidine, and many others. For a complete, updated list see www.azcert.org. Primary myocardial problems: cardiomyopathy, myocarditis, ischemia Central nervous or autonomic system injury; subarachnoid hemorrhage; stellate ganglion blockade Sudden infant death syndrome (SIDS). Recent data from multicenter studies indicate that 9.5% of sudden infant death syndrome (SIDS) cases may be heterozygous for functionally significant mutations in one of the seven known LQTS-related genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CAV3) [Arnestad et al 2007, Berul & Perry 2007, Wang et al 2007]. Sudden arrhythmic death may thus be an important contributor to SIDS, and it is unknown which proportion of such cases have or would develop profound hearing impairment. Recent implementation of universal neonatal hearing screening, supplemented with early electrocardiography, may have the potential to identify high-risk children. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).LQT1LQT5

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Jervell and Lange-Nielsen syndrome (JLNS), the following evaluations are recommended:Formal audiologic evaluation for extent of hearing loss Cardiac examination including calculation of QTc A three-generation thorough family history on cardiac disease, syncope, and hearing Complete blood count to screen for anemia. If anemia is present, screening for iron deficiency is recommended. Medical genetics consultationTreatment of ManifestationsHearing loss in JLNS may be treated successfully with cochlear implantation (CI), an intervention that does not interfere with bipolar pacemakers [Green et al 2000, Chorbachi et al 2002] (see Deafness and Hereditary Hearing Loss Overview). To date, the cumulative published experience includes approximately 20 individuals with JLNS who have received cochlear implantation. Of note, the diagnosis of JLNS was only verified with molecular genetic testing in four Norwegian individuals, all of whom had mutations in KCNQ1. Note: Although cochlear implantation seems safe, special precautions are necessary during anesthesia because of the increased risk for cardiac arrhythmia [Daneshi et al 2008, Siem et al 2008, Yanmei et al 2008]. One affected individual died during a perioperative cardiac arrest [Broomfield et al 2010]. The main goal in management of JLNS is prevention of syncope, cardiac arrest, and sudden death. Note that efficacy of beta-blocker treatment is only partial: 51% of treated individuals had cardiac events and 27% had cardiac arrest or sudden death. Even with additional therapies (e.g., pacemaker, implantable cardioverter/defibrillator, left sympathetic denervation), 18 (56%) of 32 individuals experienced additional symptoms, including sudden death in seven [Schwartz et al 2006].Administration of beta-adrenergic blockers has been the traditional first-line medical therapy for cardiac events, but more aggressive immediate treatment may be appropriate. In contrast to Romano-Ward syndrome (RWS), cardiac events in JLNS frequently occur despite beta blockade [Schwartz et al 2006]. Goldenberg et al [2006] demonstrated markedly increased mortality in individuals with JLNS treated exclusively with beta blockers in comparison with individuals with RWS. A mortality rate of 35% over five years was observed for individuals receiving beta blockers exclusively; 86% of individuals treated exclusively with beta blockers experienced a cardiac event. The interactions of beta blockers with other medical conditions (e.g., asthma, diabetes mellitus, depression) should also be considered. Implantable cardioverter defibrillators (ICDs) should be considered in individuals with a history of cardiac arrest or failure to respond to other treatments [Goel et al 2004]. More recent recommendations have strongly urged ICD placement for high-risk individuals, defined by the following criteria [Schwartz et al 2006]:
• QTc interval >550 msec
• Syncope before age 5 years
• Male gender, age >20 years with KCNQ1 mutation
The risk of sudden cardiac death appears to be low in individuals younger than age five years, but medical therapy should be administered early on in these high-risk individuals and ICD placement should be considered after age five years [Richter & Brugada 2006].In certain cases, the availability of automated external defibrillators in the home, workplace, or school may be applicable, as is appropriate CPR training of family members and those who have regular contact with individuals with JLNS. Left cardiac sympathetic denervation has been used with effect for some patients. The treatment of iron deficiency anemia should follow standard guidelines. Prevention of Primary ManifestationsSee Treatment of Manifestations regarding prevention of syncope, cardiac arrest, and sudden death.Prevention of Secondary Complications Special precautions during anesthesia are necessary because of the increased risk for cardiac arrhythmia [Daneshi et al 2008, Siem et al 2008, Yanmei et al 2008].SurveillanceBeta-blocker dose should be regularly assessed for efficacy and adverse effects; doses should be altered as needed. Because dose adjustment is especially important in growing children, evaluation is appropriate every three to six months during rapid growth phases.Affected individuals should have regular, periodic evaluations of implantable cardioverter defibrillators (ICDs) for inappropriate shocks and pocket or lead complications.Agents/Circumstances to AvoidThe following should be avoided:Drugs that cause further prolongation of the QT interval or provoke torsade de pointes; see www.azcert.org for a complete and updated list. Triggers for intense or sudden emotion; activities that are known to precipitate syncopal events in individuals with long QT syndrome, including: Competitive sports Amusement park rides Frightening movies Jumping into cold water A cardiologist should make recommendations for activity restrictions based on the effectiveness of medical intervention. Evaluation of Relatives at RiskStandard newborn screening programs are sufficient to identify hearing loss in children with JLNS.Because of the relationship between JLNS and Romano-Ward syndrome, electrocardiogram should be considered for relatives at risk for JLNS even if they have normal hearing.If the JLNS disease-causing mutations in an affected family member are known, molecular genetic testing of a relative with congenital profound sensorineural hearing loss is recommended to confirm the diagnosis of JLNS.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherFamily members of individuals with JLNS should be trained in cardiopulmonary resuscitation (CPR) as up to 95% of individuals with JLNS have a cardiac event before adulthood [Schwartz et al 2006].Affected individuals should wear an ID bracelet explaining their diagnosis.It is appropriate to notify local Emergency Medical Services (EMS) of high-risk persons such as those with JLNS [Hazinski et al 2004].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Jervell and Lange-Nielsen Syndrome: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLQT1KCNQ111p15​.5-p15.4Potassium voltage-gated channel subfamily KQT member 1Deafness Gene Mutation Database
Gene Connection for the Heart - KCNQ1 (KVLQT1)
KCNQ1 @ LOVD
KCNQ1 @ ZAC-GGMKCNQ1LQT5KCNE121q22​.12Potassium voltage-gated channel subfamily E member 1Deafness Gene Mutation Database
Gene Connection for the Heart - Long QT syndrome type 5 mutation database
CCHMC - Human Genetics Mutation Database
KCNE1 @ LOVD
KCNE1 @ ZAC-GGMKCNE1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Jervell and Lange-Nielsen Syndrome (View All in OMIM) View in own window 176261POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 1; KCNE1 220400JERVELL AND LANGE-NIELSEN SYNDROME 1; JLNS1 607542POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1 612347JERVELL AND LANGE-NIELSEN SYNDROME 2; JLNS2Molecular Genetic PathogenesisJervell and Lange-Nielsen syndrome (JLNS) is caused by an aberration in a potassium channel found in the stria vascularis of the cochlea (inner ear) and the heart.KCNQ1 and KCNE1 encode the alpha and beta subunit proteins (K_VLQT1/minK) for the slow potassium current, I_Ks of the cochlea and the heart. When stimulated by sound, potassium from the scala media of the cochlea passes through the apex of the hair cells, depolarizing the hair cells and causing a calcium-channel-induced release of neurotransmitter onto the auditory nerve. Depolarizations of the auditory nerve are sent centrally where they are perceived as sound. The maintenance of high potassium concentration in the endolymphatic fluid of the inner ear is required for normal hearing. The potassium-rich fluid of the scala media is created by the I_Ks potassium channels (exclusively K_VLQT1/minK) in the stria vascularis. Malfunction in these channels in the cochlea causes deafness. Malfunction in these channels in the heart results in abnormal ventricular electrical activity and LQTS. KCNQ1 Normal allelic variants. KCNQ1 is located at chromosome 11p15 and consists of 16 exons spanning approximately 400 kb. The reference sequence for the cDNA is NM_000218.2. Pathologic allelic variants. At least 13 JLNS-causing mutations in KCNQ1 are known, ten resulting in frameshift and premature truncation [Tyson et al 2000, Wang et al 2002, Ning et al 2003, Zehelein et al 2006, Zhang et al 2008, Bhuiyan et al 2008, Ohno et al 2008, Baek et al 2010, Wang et al 2011, Gao et al 2012]. Normal gene product. The gene product is potassium voltage-gated channel subfamily KQT member 1 (also known as voltage-gated potassium channel protein KvLQT1); this alpha subunit has six transmembrane regions. It coassembles with the protein encoded by KCNE1 to form the functional channel I_Ks.Abnormal gene product. Mutations in the gene result in premature truncation and inability to coassemble with the protein encoded by KCNE1 to form the functional channel I_Ks. In a mouse model, recessive mutations may exhibit a dominant-negative effect that is not clinically observed in affected individuals, suggesting post-translational processing effects in vivo [Thomas et al 2007, Hothi et al 2009]KCNE1 Normal allelic variants. KCNE1 is located at chromosome 21q22.12 and consists of three exons spanning approximately 40 kb. Pathologic allelic variants. Four JLNS-causing mutations have been identified in KCNE1, all of which are missense (see Table A).Normal gene product. Potassium voltage-gated channel subfamily E member 1 (also known as minK potassium channel protein beta subunit) is a protein of 130 amino acids with one transmembrane region. It coassembles with the protein encoded by KCNQ1 to form the functional channel I_Ks. Abnormal gene product. The specific effect of each mutation differs in the manner in which it impairs potassium channel function.