Jervell And Lange-Nielsen Syndrome Patients Research Articles

Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients.

KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous KCNQ1 mutations cause type 1 Jervell and Lange-Nielsen syndrome (JLNS) with deafness and higher sudden cardiac death risk. KCNQ1 variants causing JLNS or LQT1 might have distinct phenotypic expressions in heterozygous patients. The aim of this study is to evaluate QTc duration and incidence of long QT syndrome-related cardiac events according to genetic presentation. We enrolled LQT1 or JLNS patients with class IV/V KCNQ1 variants from our inherited arrhythmia clinic (September 1993 to January 2023). Medical history, ECG, and follow-up were collected. Additionally, we conducted a thorough literature review for JLNS variants. Survival curves were compared between groups, and multivariate Cox regression models identified genetic and clinical risk factors. Among the 789 KCNQ1 variant carriers, 3 groups were identified: 30 JLNS, 161 heterozygous carriers of JLNS variants (HTZ-JLNS), and 550 LQT1 heterozygous carriers of non-JLNS variants (HTZ-Non-JLNS). At diagnosis, mean age was 3.4 ± 4.7 years for JLNS, 26.7 ± 21 years for HTZ-JLNS, and 26 ± 21 years for HTZ-non-JLNS; 55.3% were female; and the mean QTc was 551 ± 54 ms for JLNS, 441 ± 32 ms for HTZ-JLNS, and 467 ± 36 ms for HTZ-Non-JLNS. Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of heterozygous KCNQ1 variant carriers and had a lower risk of cardiac events than heterozygous non-JLNS variant carriers (HTZ-Non-JLNS) [hazard ratio (HR) = 0.34 (0.22-0.54); P < 0.01]. After multivariate analysis, four genetic parameters were independently associated with events: haploinsufficiency [HR = 0.60 (0.37-0.97); P = 0.04], pore localization [HR = 1.61 (1.14-1.2.26); P < 0.01], C-terminal localization [HR = 0.67 (0.46-0.98); P = 0.04], and group [HR = 0.43 (0.27-0.69); P < 0.01]. Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other LQT1 patients.

Mutation Screening of KCNQ1 and KCNE1 Genes in Iranian Patients With Jervell and Lange-Nielsen Syndrome

Background: Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive genetic disease with deafness and QT prolongation. Mutations in KCNQ1 and KCNE1 genes are a cause of JLNS. Our objective was to perform mutational analysis of the KCNQ1 and KCNE1 genes to determine the frequency of mutations in the Iranian population. Material and methods: Fourteen patients and their families were investigated. Mutational screening of the KCNQ1 and KCNE1 genes was performed by a polymerase chain reaction (PCR) followed by direct Sanger sequencing. Results: We identified two frameshift mutations in the KCNQ1 gene, including a novel mutation, c.1356 1356delG, and a known mutation, c.1534_1534delG. A common single nucleotide polymorphism (SNP), c.112G > A, was also found in KCNE1 in seven probands. Conclusion: A novel mutation in the KCNQ1 gene is described. There may be less frequency of mutations in the KCNQ1 and of KCNE1 genes in Iranian JLNS patients compared with other populations.

Autosomal recessive long QT syndrome, type 1 in eight families from Saudi Arabia.

BackgroundOne of the most common primary cardiac arrhythmia syndromes is autosomal dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono‐allelic mutations in the KCNQ1 gene. Bi‐allelic mutations in the KCNQ1 gene are causal to Jervell and Lange‐Nielsen syndrome (JLNS), characterized by severe and early‐onset arrhythmias with prolonged QTc interval on surface ECG and sensorineural deafness. Occasionally, bi‐allelic mutations in KCNQ1 are also found in patients without any deafness, referred to as autosomal recessive long QT syndrome, type 1 (AR LQT1).MethodsWe used Sanger sequencing to detect the pathogenic mutations in KCNQ1 gene in eight families from Saudi Arabia with autosomal recessive LQT1.ResultsWe have detected pathogenic mutations in all eight families, two of the mutations are founder mutations, which are c.387‐5T>A and p.Val172Met/p.Arg293Cys (in cis). QTc and cardiac phenotype was found to be pronounced in all the probands comparable to the cardiac phenotype in JLNS patients. Heterozygous carriers for these mutations did not exhibit any clinical phenotype, but a significant number of them have sinus bradycardia.ConclusionTo the best of our knowledge, this is the first description of a large series of patients with familial autosomal recessive LQT, type 1. These mutations could be used for targeted screening in cardiac arrhythmia patients in Saudi Arabia and in people of Arabic ancestry.

The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?

Patients with Jervell and Lange-Nielsen syndrome (JLNS) exhibit severe phenotypes that are characterized by congenital deafness, very long QT intervals, and high risk of life-threatening arrhythmias. Current treatment strategies include high doses of beta-blocker medication, left cardiac sympathetic denervation, and ICD placement, which is challenging in young children. The purpose of this study was to evaluate the safety and effect of pacing in addition to beta-blocker treatment in children with JLNS. All genetically confirmed patients with JLNS born since 1999 in Norway were included in the study. Data on history of long QT syndrome-related symptoms, QT interval, and beta-blocker and pacemaker treatment were recorded. A total of 9 patients with QT intervals ranging from 510 to 660 ms were identified. Eight patients developed long QT syndrome-related symptoms, and 1 patient died before diagnosis. The survivors received beta-blocker medication. Seven patients also received a pacemaker; 1 had a ventricular lead and 6 had atrial leads. The patient with the ventricular lead died during follow-up. The 6 patients with atrial leads survived without events at a mean follow-up of 6.9 years after pacemaker implantation. Two patients received prophylactic upgrade to a 2-chamber ICD. 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. If confirmed in additional patients, 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.

Genotype-phenotype analysis of Jervell and Lange-Nielsen syndrome in six families from Saudi Arabia

We sought to explore the genotype-phenotype of Jervell and Lange-Nielsen syndrome (JLNS) patients in Saudi Arabia. We have also assessed the plausible effect of consanguinity into the pathology of JLNS. Six families with at least one JLNS-affected member attended our clinic between 2011 and 2013. Retrospective and prospective clinical data were collected and genetic investigation was performed. Pathogenic mutations in the KCNQ1 gene were detected in all JLNS patients. The homozygous mutations detected were Leu273Phe, Asp202Asn, Ile567Thr, and c.1486_1487delCT and compound heterozygous mutations were c.820_ 830del and c.1251+1G>T. All living JLNS patients except one had a QTc of >500 ms and a history of recurrent syncope. β-Blockers abolished the cardiac-related events in all patients except two siblings with homozygous Ile567Thr mutation. Four of the six mutations were originally reported in autosomal dominant long QT syndrome (LQTS) patients. Eighty percent of the heterozygote mutation carriers showed prolongation of QTc, but majority of these reported no symptoms attributable to arrhythmias. Mutations detected in this study will be advantageous in tribe and region-specific cascade screening of LQTS in Saudi Arabia.

De novo mutation in the KCNQ1 gene causal to Jervell and Lange‐Nielsen syndrome

Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive disorder, clinically characterized by severe cardiac arrhythmias [due to prolonged QTc interval in electrocardiogram (ECG)] and bilateral sensory neural deafness. Molecular defects causal to JLNS are either homozygous or compound heterozygous mutations, predominantly in the KCNQ1 gene and occasionally in the KCNE1 gene. As the molecular defect is bi-allelic, JLNS patients inherit one pathogenic mutation causal to the disorder from each parent. In this report, we show for the first time that such a disorder could also occur due to a spontaneous de novo mutation in the affected individual, not inherited from the parent, which makes this case unique unlike the previously reported JLNS cases.

Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome

Background:Long QT syndrome (LQTS) is characterized by QT prolongation, syncope and sudden death. This study aims to explore the causes, clinical manifestations and therapeutic outcomes of Jervell and Lange-Nielsen syndrome (JLNS), a rare form of LQTS with congenital sensorineural deafness, in Chinese individuals.Materials and Methods:Three JLNS kindreds from the Chinese National LQTS Registry were investigated. Mutational screening of KCNQ1 and KCNE1 genes was performed by polymerase chain reaction and direct DNA sequence analysis. LQTS phenotype and therapeutic outcomes were evaluated for all probands and family members.Results:We identified 7 KCNQ1 mutations. c.1032_1117dup (p.Ser373TrpfsX10) and c.1319delT (p.Val440AlafsX26) were novel, causing JLNS in a 16-year-old boy with a QTc (QT interval corrected for heart rate) of 620 ms and recurrent syncope. c.605-2A>G and c.815G>A (p.Gly272Asp) caused JLNS in a 12-year-old girl and her 5-year-old brother, showing QTc of 590 to 600 ms and recurrent syncope. The fourth JLNS case, a 46-year-old man carrying c.1032G>A (p.Ala344Alasp) and c.569G>A (p.Arg190Gln) and with QTc of 460 ms, has been syncope-free since age 30. His 16-year-old daughter carries novel missense mutation c.574C>T (p.Arg192Cys) and c.1032G>A(p.Ala344Alasp) and displayed a severe phenotype of Romano-Ward syndrome (RWS) characterized by a QTc of 530 ms and recurrent syncope with normal hearing. Both the father and daughter also carried c.253G>A (p.Asp85Asn; rs1805128), a rare single nucleotide polymorphism (SNP) on KCNE1. Bizarre T waves were seen in 3/4 JLNS patients. Symptoms were improved and T wave abnormalities became less abnormal after appropriate treatment.Conclusion:This study broadens the mutation and phenotype spectrums of JLNS. Compound heterozygous KCNQ1 mutations can result in both JLNS and severe forms of RWS in Chinese individuals.

Genotype phenotypic analysis in three Chinese Jervell and Lange–Nielsen syndrome families

Background and purposeLong QT syndrome (LQTS) is an inherited cardiac disorder characterised by QT interval prolongation on ECG, ventricular arrhythmias and sudden death. Two forms of LQTS have been identified:...

E0020 Compound heterozygous novel splicing mutation D202sp and missence mutation G272D on KCNQ1 caused Jervel and Lange-Nielsen syndrome in a Chinese family

BackgroundLong QT syndrome (LQTS) is an inherited cardiac disorder characterised by QT interval prolongation on ECG, ventricular arrhythmias and sudden death. Two forms have been identified: autosomal dominant Romamo-Ward syndrome...

Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family

BackgroundLong QT syndrome (LQTS) is a cardiac disorder characterized by prolonged QT intervals on electrocardiograms (ECG), ventricular arrhythmias, and sudden death. Clinically, two inherited forms of LQTS have been defined: autosomal dominant LQTS or Romano-Ward syndrome (RWS) not associated with deafness and autosomal recessive LQTS or Jervell and Lange-Nielsen syndrome (JLNS) associated with deafness.MethodsA Chinese family with both RWS and JLNS was identified. Family members were diagnosed based on the presence of a prolonged QT interval as seen on a 12-lead ECG and a medical history of syncope, palpitation, and deafness. Mutational studies in the KCNQ1 potassium channel gene were performed using direct DNA sequence analysis and restriction length polymorphism analysis.ResultsThe proband in the Chinese family and her brother had previously been diagnosed with JLNS, and two other members were affected with RWS. The proband was also affected with atrial fibrillation. A single nucleotide substitution of C to T at nucleotide 965 of KCNQ1 was identified, and the mutation resulted in the substitution of a threonine residue at codon 322 by a methionine residue (T322M). The novel heterozygous T322M mutation was identified in two patients with RWS, one member with borderline QTc, and two normal family members. The two JLNS patients in the family carried the homozygous T322M mutation. The T322M mutation was not found in 200 Chinese normal controls.ConclusionOur results suggest that T322M is a novel mutation that caused RWS with high intrafamilial variability in the heterozygous carriers and typical JLNS in the homozygous carriers within this Chinese family. The T322M mutation is the first mutation identified for JLNS in the Chinese population.

Jervell and Lange-Nielsen Syndrome in Norwegian Children: Aspects Around Cochlear Implantation, Hearing, and Balance

Jervell and Lange-Nielsen syndrome (JLNS) is a rare cause of autosomal recessive inherited deafness. JLNS patients are candidates for cochlear implantation, and represent a group that needs special attention and precautions. The aim of this article is to draw some guidelines for dealing with these patients, and to emphasize the importance of electrocardiography (ECG) screening of congenitally deaf patients. A probable vestibular dysfunction is also discussed. Eight of 273 implanted children (2.9%) at Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway have been diagnosed with JLNS. All the children were evaluated with ECG, six of them before cochlear implantation. Auditory perception was evaluated with the littlEARS Auditory Questionnaire, or with a test battery developed at Rikshospitalet-Radiumhospitalet Medical Center. DNA sequencing was used to screen for mutations in the genes KCNQ1 and KCNE1. The cases are presented and discussed in a retrospective case review. Two of the children are dead. The corrected QT (QTc) interval in the ECG was markedly prolonged in all the children (median QTc, 0.59 sec; range, 0.53-0.65). Six children have more than 1 yr experience with their cochlear implant. Four of them are performing average or above compared with the other implanted children. All the children have mutations in the KCNQ1 gene. Six of our patients have delayed gross motor development, and the remaining two are markedly delayed compared with their older siblings. Cochlear implantation can be performed safely and with good results in children with JLNS, but requires knowledge of the diagnosis and necessary precautions have to be taken. ECG should be taken for all children with congenital deafness, preferably before exposure to strong sound stimuli. Vestibular dysfunction seems to be a part of JLNS, but this needs further investigation.

Clinical Course and Risk Stratification of Patients Affected with the Jervell and Lange‐Nielsen Syndrome

Data regarding risk factors and clinical course of patients affected with Jervell and Lange-Nielsen syndrome (JLNS), an autosomal recessive form of the congenital long-QT syndrome (LQTS), are limited to several reported cases and a retrospective analysis. We prospectively followed-up 44 JLNS patients from the U.S. portion of the International LQTS Registry and compared their clinical course with 2,174 patients with the phenotypically determined dominant form of LQTS (Romano-Ward syndrome [RWS]) and a subgroup of 285 patients with type 1 LQTS (LQT1). Mean (+/-SD) corrected QT interval (QTc) in the JLNS, RWS, and LQT1 groups were 548 +/- 73, 500 +/- 48, and 502 +/- 46 msec, respectively (P < 0.001). 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). The JLNS:RWS and JLNS:LQT1 adjusted hazard ratios (HR) for cardiac events were highest among patients with a baseline QTc > or = 550 msec (HR = 15.83 [P < 0.001] and 13.80 [P < 0.001], respectively). 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. Patients with JLNS experience a high rate of cardiac and fatal events from early childhood despite medical therapy. Defibrillator therapy appears to improve outcome in this high-risk population, although longer follow-up is needed to establish its long-term efficacy.