Jervell And Lange-Nielsen Syndrome Research Articles

Abstract 17871: Heterozygous Carriers of KCNQ1 Variants Associated With the Jervell-Lange-Nielsen Syndrome Have a Better Outcome When Compared to Other Type 1 LQTS Patients

Background: KCNQ1 mutations are associated with a risk of life-threatening torsade de Pointes. In the most common presentation, the mutation is heterozygous (type 1 LQTS). The homozygous expression causes type 1 Jervell-Lange-Nielsen syndrome (JLNS) with deafness and higher risk of sudden cardiac death. Hypothesis: Heterozygous carriers of JLN mutations would have different phenotype expression than patients carrying other KCNQ1 variants. Aims: To evaluate QTc duration and incidence of LQTS-related cardiac events according to genetic presentation. Methods: All patients with class 4 or 5 KCNQ1 variants for LQT1 or JLNS followed in our center (September 1993 to January 2023) were included. Lifelong Severe Cardiac events (ACA, SCD, appropriate shocks) and cardiac events (severe event + cardiac syncope) were collected.Quantitative data were compared between groups by ANOVA. Kaplan-Meier survival curves with the log-rank test were used to compare survival between the groups. Results: Three groups were identified among 741 LQT1 patients (55.3% female, age at diagnosis 25.2 years); 30 JLNS (group 1), 557 LQT1 carrying heterozygous mutations not found in the JLNS population (group 2), and 154 heterozygous carriers of mutations found in the JLNS population (group 3). QTc interval duration was different between groups (548±60ms, 467±36ms and 450±31ms in group 1, 2, 3 respectively, p<0.001).Patients carrying heterozygous JLN mutations (group 3) had a lower risk for cardiac events than patients with heterozygous non JLN mutations (group2) (HR 0.36 [0.23-0.57]; p<0.01) (Figure). Four parameters were independently associated with cardiac events: QTc (HR 1.01 [1.01-1.01]; p<0.01, haploinsufficiency (HR 0.57 [0.36-0.92]; p<0.05), pore localization (HR 1.63 [1.16-2.30]; p<0.01), and group (HR 0.50 [0.32-0.81]; p<0.01). Conclusion: Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events that other type 1 LQTS patients.

Left cardiac sympathetic denervation in children with Jervell Lange-Nielsen syndrome and drug refractory torsades - A case series.

Long QT syndrome is an inherited malignant channelopathy which leads to life-threatening arrhythmia, with multiple genotypes. Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive subtype of this disease, characterized by congenital sensorineural deafness and a high incidence of sudden cardiac death (SCD). We prospectively followed up six children who underwent left cardiac sympathetic denervation (LCSD) for JLNS in view of high-risk features despite being on maximally tolerated doses of oral propranolol. Mean age at diagnosis was 2.75±0.39 years, with a significant delay between onset of symptoms and diagnosis (mean 7.2±3.5 months). All had sensorineural hearing loss, conforming to the JLNS phenotype. Mean QTc interval was 603±93ms, with T wave alternans (TWA) seen in all cases. All were started on propranolol and subsequently subjected to LCSD, and 3 underwent AAI permanent pacemaker implantation. Over a mean follow-up of 20 months, there was a significant reduction in QTc (603±93ms to 501±33ms, p=.04), which was persistent on follow-up (525±41ms) and only two out of six had persistent T wave alternans on ECG (p<.01). None of these children had presyncope, syncope, seizures, torsades de pointes, cardiac arrest or death on follow up following LCSD. Jervell Lange-Nielsen syndrome is a subtype of LQTS with high-risk features. LCSD, an effective therapeutic option for those having symptoms despite being on propranolol, results in significant reduction of QTc interval and amelioration of symptoms.

Novel combinations of variations in KCNQ1 were associated with patients with long QT syndrome or Jervell and Lange-Nielsen syndrome

ObjectivesLong QT syndrome (LQTS) is one of the primary causes of sudden cardiac death (SCD) in youth. Studies have identified mutations in ion channel genes as key players in the pathogenesis of LQTS. However, the specific etiology in individual families remains unknown.MethodsThree unrelated Chinese pedigrees diagnosed with LQTS or Jervell and Lange-Nielsen syndrome (JLNS) were recruited clinically. Whole exome sequencing (WES) was performed and further validated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing.ResultsAll of the probands in our study experienced syncope episodes and featured typically prolonged QTc-intervals. Two probands also presented with congenital hearing loss and iron-deficiency anemia and thus were diagnosed with JLNS. A total of five different variants in KCNQ1, encoding a subunit of the voltage-gated potassium channel, were identified in 3 probands. The heterozygous variants, KCNQ1 c.749T > C was responsible for LQTS in Case 1, transmitting in an autosomal dominant pattern. Two patterns of compound heterozygous variants were responsible for JLNS, including a large deletion causing loss of the exon 16 and missense variant c.1663 C > T in Case 2, and splicing variant c.605-2 A > G and frame-shift variant c.1265del in Case 3. To our knowledge, the compound heterozygous mutations containing a large deletion and missense variant were first reported in patients with JLNS.ConclusionOur study expanded the LQTS genetic spectrum, thus favoring disease screening and diagnosis, personalized treatment, and genetic consultation.

Computational Study on Effect of KCNQ1 P535T Mutation in a Cardiac Ventricular Tissue.

Heart diseases such as arrhythmia are the main causes of sudden death. Arrhythmias are typically caused by mutations in specific genes, damage in the cardiac tissue, or due to some chemical exposure. Arrhythmias caused due to mutation is called inherited arrhythmia. Induced arrhythmias are caused due to tissue damage or chemical exposure. Mutations in genes that encode ion channels of the cardiac cells usually result in (dysfunction) improper functioning of the channel. Improper functioning of the ion channel may lead to major changes in the action potential (AP) of the cardiac cells. This further leads to distorted electrical activity of the heart. Distorted electrical activity will affect the ECG that results in arrhythmia. KCNQ1 P535T mutation is one such gene mutation that encodes the potassium ion channel (KV7.1) of the cardiac ventricular tissue. Its clinical significance is not known. This study aims to perform a simulation study on P535T mutation in the KCNQ1 gene that encodes the potassium ion channel KV7.1 in the ventricular tissue grid. The effect of P535T mutation on transmural tissue grids for three genotypes (wild type, heterozygous, and homozygous) of cells are studied and the generated pseudo-ECGs are compared. Results show the delayed repolarization in the cells of ventricular tissue grid. Slower propagation of action potential in the transmural tissue grid is observed in the mutated (heterozygous and homozygous) genotypes. Longer QT interval is also observed in the pseudo-ECG of heterozygous and homozygous genotype tissue grids. From the pseudo-ECGs, it is observed that KCNQ1 P535T mutation leads to Long QT Syndrome (LQTS) which may result in life-threatening arrhythmias, such as Torsade de Pointes (TdP), Jervell and Lange-Nielsen syndrome (JLNS), and Romano-Ward syndrome (RWS).

Left cardiac sympathetic denervation in children with Jervell Lange-Nielsen syndrome and drug refractory torsades - A case series

Left cardiac sympathetic denervation in children with Jervell Lange-Nielsen syndrome and drug refractory torsades - A case series

The hERG PAS domain: A major regulator of IKr and a promising anti-arrhythmic drug target.

The hERG1 potassium channel conducts the critical cardiac repolarizing current IKr. Given its role in mediating electrical excitability, several groups have investigated the antiarrhythmic capacity of hERG1 activators in cardiac diseases marked by prolonged action potential duration (APD), such as long QT Syndrome. hERG1 activators have had limited success due to their off-target effects. We recently generated a single chain variable fragment (scFv) antibody, scFv2.10, that selectively binds the hERG1 Per-Arnt-Sim (PAS) domain. The PAS domain binds to the C-terminal cyclic nucleotide binding homology domain (CNBHD) and slows channel activation and promotes inactivation. scFv2.10 disrupts the PAS-CNBHD interaction, which in turn causes a two-fold increase in the time course of hERG1 activation and inactivation recovery, thereby increasing hERG1 current in HEK293 cells. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), disrupting the PAS-CNBHD interaction with scFv2.10 increases IKr and shortens APD. We hypothesized that the hERG1 PAS domain could represent a novel therapeutic target for diseases of impaired cardiac repolarization. To test this, we measured the antiarrhythmic capacity of scFv2.10 on a novel hiPSC-CM line derived from a patient with Jervell and Lange Nielsen syndrome (JLN). JLN syndrome is a severe form of long QT Syndrome Type 1 characterized by increased APD and incidence of sudden cardiac death. Compared to hiPSC-CMs derived from a healthy genetic background, JLN hiPSC-CMs display hallmarks of pro-arrhythmia including prolonged APD, increased action potential variability, and early afterdepolarizations. scFv2.10 reduced APD, action potential variability, and the incidence of early afterdepolarizations in JLN hiPSC-CMs, compared to GFP controls. These data demonstrate that the hERG1 PAS domain is a potential therapeutic target to treat disorders of electrical excitability.

Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome KCNQ1 Variants.

The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.

Genetics of Sudden Cardiac Death, the Channelopathies: Today's Perspective and the Future

Channelopathy constitute significant proportion of SCD worldwide (around 10% or 370000 deaths annually). Besides LQTS, the channelopathies include Brugada syndrome (BrS), short QT syndrome, Early Repolarization Syndrome (ERS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and congenital sick sinus syndrome. It was constituting a mysterious group of disease until the second half of the last century when Anton Jervell and Fred Lange-Nielsen described Jervell Lange-Nielsen syndrome in 1957.It was late until 1995 where genetic characterization commenced. Later on, the massive genetic information obtained in the field with discovery of genetic heterogeneity and allelic heterogeneity were all part of our new understanding and clues to solve the historical conundrum of channelopathies. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels. Diving deep into the genetic details of those syndromes enable us to improve our knowdelege and decode the pathophysiology of those malignant arrhythmias. The ultimate ambition is prevention of channelopathy based sudden cardiac death and associated disorders in human.

Compound heterozygote KCNQ1 mutation causing Jervell Lange Neilson syndrome: a case report of genotype-phenotype correlation

Congenital sensorineural hearing loss (SNHL) is a common phenomenon with several genetic and non-genetic associations that require early diagnosis and work-up to prompt appropriate interventions. Of the genetic associations, Jervell and Lange-Nielsen syndrome (JLNS) remains a rare monogenic disease that is characterized by SNHL, prolongation of QT interval, syncopal attacks due to ventricular arrhythmias and sudden cardiac death from very early in life. We hereby report a 5 years old girl with SNHL and recurrent blackout episodes in early childhood with significant family history, admitted for cochlear implant who developed ventricular arrhythmias requiring multiple interventions with further investigations revealing a prolonged QT interval on electrocardiography (ECG) with metabolic abnormalities (hypomagnesemia and hypokalemia). Her clinical exome study showed a compound heterozygous KCNQ1 mutation, a more sporadic form of JLNS managed using oral beta-blocker. This experience illustrates the relevance of a detailed systemic evaluation with an elaborate cardiac assessment in children with SNHL, more so in the presence of frequent unexplained acute life-threatening episodes.

Establishment of iPSC line from a Chinese infant (XACHi012-A) with Jervell and Lange-Nielsen syndrome carrying combined KCNQ1 frameshift c.431delC(p.I145Sfs*92) and nonsense c.1175G > A (p.W392X) variants and two iPSC lines from the parents (XACHi013-A, XACHi014-A)

Induced pluripotent stem cell lines (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the peripheral blood of a two month-old boy and the parents. Jervell and Lange-Nielsen syndrome (JLNS) was diagnosed in the boy carrying combined KCNQ1 frameshift c.431delC (p.I145Sfs*92) and nonsense c.1175G > A(p.W392X) variants inherited from his mother and father respectively. PBMCs were reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, SOX2, KLF4 and C-MYC. IPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carrying identified KCNQ1 variants with corresponding PBMC, and have a normal karyotype. Thus we established three iPSC lines as useful tools for studying the pathophysiological mechanism of JLNS and drug testing.

A cryptic splice-altering KCNQ1 variant in trans with R259L leading to Jervell and Lange-Nielsen syndrome

Here we report an infant with clinical findings suggestive of Jervell and Lange-Nielsen syndrome (JLNS), including a prolonged QT interval (LQTS) and chronic bilateral sensorineural deafness. NGS analysis revealed one known heterozygous pathogenic missense variant, KCNQ1 p.R259L, previously associated with LQTS but insufficient to explain the cardioauditory disorder. In a screening of proximal intronic regions, we found a heterozygous variant, KCNQ1 c.1686−9 T > C, absent from controls and previously undescribed. Several splicing prediction tools returned low scores for this intronic variant. Driven by the proband’s phenotype rather than the neutral predictions, we have characterized this rare intronic variant. Family analysis has shown that the proband inherited the missense and the intronic variants from his mother and father, respectively. A minigene splicing assay revealed that the intronic variant induced an additional transcript, arising from skipping of exon 14, which was translated into a truncated protein in transfected cells. The splice-out of exon 14 creates a frameshift in exon 15 and a stop codon in exon 16, which is the last exon of KCNQ1. This mis-spliced transcript is expected to escape nonsense-mediated decay and predicted to encode a truncated loss-of-function protein, KCNQ1 p.L563Kfs*73. The analysis of endogenous KCNQ1 expression in the blood of the proband’s parents detected the aberrant transcript only in the patient’s father. Taken together, these analyses confirmed the proband’s diagnosis of JLNS1 and indicated that c.1686−9 T > C is a cryptic splice-altering variant, expanding the known genetic spectrum of biallelic KCNQ1 variant combinations leading to JLNS1.

Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness.

KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current IKs, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in KCNQ1 result in long QT syndrome, called Romano–Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous KCNQ1 mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in Xenopus laevis oocytes, are in agreement with an autosomal recessive disorder, since the IKs reduction was only observed in homomeric mutants, but not in heteromeric IKs channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant IKs channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment.

Outcomes of Cochlear Implantation in Patients with Jervell and Lange-Nielsen Syndrome: A Systematic Review and Narrative Synthesis.

Establish outcomes following cochlear implantation (CI) in patients with Jervell and Lange-Nielsen Syndrome (JLNS). Methods Systematic review and narrative synthesis. Databases searched on Medline, Pubmed, Embase, Web of Science, Cochrane Collection and ClinicalTrials.gov. No limits placed on language or year of publication. Review conducted in accordance with the PRISMA statement. Searches identified 63 abstracts and 19 full texts. Of these, 9 studies met inclusion criteria reporting outcomes in 66 patients with at least 72 implants. Hearing outcomes were generally good. Mortality secondary to cardiac complications within the follow up period occurred in at least five cases (7.6%), though three of these were thought to be unrelated to surgery. Potentially dangerous arrhythmias without associated morbidity were also noted in at least five patients. The methodological quality of included studies was modest, predominantly consisting of case reports and non-controlled case series with small numbers of patients. All studies were OCEBM grade IV. One study contributed 41/66 patients (62%). Hearing outcomes following CI in JLNS are generally good with the majority of patients experiencing useful hearing improvement. Significant peri-operative cardiac risks exist and should be discussed with the patient and family during pre-operative counselling and prompt thorough investigation, pre-operative optimisation and peri-operative monitoring.

Jervell and Lange-Nielsen syndrome with novel KCNQ1 and additional gene mutations

We encountered a boy with Jervell and Lange-Nielsen syndrome (JLNS) with compound heterozygous KCNQ1 mutations, maternal Trp248Phe and a novel paternal mutation, Leu347Arg. His father showed long QT (LQT) and arrhythmia. His mother was asymptomatic with no ECG abnormalities. The proband and his father had an additional mutation (SNTA1 Thr372Met), which is reportedly related to SIDS. These results suggest that multiple gene mutations influence the phenotype of KCNQ1 mutation-related arrhythmia.

The combined novel KCNQ1 frameshift I145Sfs*92 and nonsense W392X variants caused Jervell and Lange-Nielsen syndrome in a Chinese infant presenting with sustained foetal bradycardia.

We report clinical and molecular analysis of an infant presenting with foetal bradycardia and clinical outcome of Jervell and Lange-Nielsen syndrome (JLNS). Clinical, electrocardiogram (ECG), and echocardiographic data were collected from members in a three-generation family. Whole exomes were amplified and sequenced for proband. The identified variants were verified in the remaining members. The pathogenicity of candidate variants was predicted using multiple software programmes. A 28-year-old non-consanguineous Chinese woman at 23 weeks' gestation presenting with sustained foetal bradycardia of 100 b.p.m. Immunological disorders and infection were excluded. The infant was delivered at 37 weeks' gestation with 2700-g birthweight. QTc was prolonged in both ECG and Holter recording. Hearing tests confirmed bilateral sensorineural hearing loss. Genetic testing demonstrated that the infant carried a novel frameshift c.431delC (p.I145Sfs*92) and a novel nonsense c.1175G>A (p.W392X) compound variants of KCNQ1 inherited from mother and father, respectively, in autosomal recessive inheritance. Only relative II-5 carrying heterozygous KCNQ1-I145Sfs*92 variant had prolonged QTc, while the other carriers did not have prolonged QT, suggesting an autosomal dominant inheritance of LQT1 phenotype with incomplete penetrance in the family. We report the novel frameshift KCNQ1-I145Sfs*92 and nonsense KCNQ1-W392X compound variants in autosomal recessive inheritance that caused JLNS presenting as sustained foetal bradycardia for the first time. Meanwhile, KCNQ1-I145Sfs*92 heterozygous variant demonstrated LQT1 phenotype in autosomal dominant inheritance with incomplete penetrance.

Jervell and Lange-Nielsen syndrome

Summary Jervell and Lange-Nielsen syndrome（JLNS） is an autosomal recessive hereditary disease characterized by congenital severe sensorineural hearing loss in both ears and severe arrhythmias with QT interval prolongation. Children with JLNS often exhibit sensorineural hearing loss and are easily misdiagnosed as non-syndromic hearing loss before attack of cardiac event. When a cochlear implant is performed, a fatal arrhythmia is likely to occur during the perioperative period, which seriously threatens the life of the child. It is currently found that the pathogenic genes of JLNS are mainly KCNQ1 and KCNE1. This article reviews the clinical manifestations, pathogenic genes, diagnosis and differential diagnosis, intervention measures of JLNS to further draw the attention to the disease, reduce misdiagnosis, improve the survival rate and quality of life of children with JLNS.

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.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi002-A from a patient affected by the Jervell and Lange-Nielsen syndrome and carrier of two compound heterozygous mutations on the KCNQ1 gene

We report the generation of human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a female patient carrier of the two compound heterozygous mutations c.568 C>T p.R190W (maternal allele), and c.1781 G>A p.R594Q (paternal allele) on the KCNQ1 gene, causing Jervell and Lange-Nielsen Syndrome (JLNS). To obtain hiPSCs, we used the classical approach of the four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC. The obtained hiPSC clones display pluripotent stem cell characteristics, and differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs).

Cochlear implant function in a patient with Jervell and Lange-Nielsen syndrome after defibrillation by countershock

Jervell and Lange-Nielsen syndrome (JLNS), a rare autosomal recessive congenital QT prolongation syndrome, is characterized by cardiac arrhythmias, syncopal episodes, and profound deafness. A cochlear implant (CI) for patients with JLNS is expected to result in hearing improvement. Sometimes, defibrillation is required if a patient experiences lethal arrhythmia. In this paper, we report a pediatric patient with JLNS who received defibrillation after CI surgery in his right ear at the age of 2 years. With intensive care, the post-operative course was uneventful, and the patient acquired satisfactory speech and hearing abilities. Five years after the surgery, he underwent defibrillation because of the incidence of syncopal attack. Thereafter, arrhythmic syncope recurred three times, which necessitated defibrillation therapy. To prevent recurrence of cardiac arrhythmia, he underwent ICD (implantable cardioverter-defibrillator) implantation at the age of 11 years. At present, CI works well and provides good hearing, while syncopal attack is prevented by ICD. From the experience of this case, electronic circuit of CI is thought to tolerate emergency countershock if the speech processor is removed.

Common founder effects of hereditary hemochromatosis, Wilson\xb4s disease, the long QT syndrome and autosomal recessive deafness caused by two novel mutations in the WHRN and TMC1 genes

BackgroundGenealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p.C282Y mutation is inherited with other recessive disorders such as Wilson´s disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation (KCNQ1/p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL).Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree.MethodsLQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing.ResultsOf nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder ( b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjällsjö river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of the late 16th century. One was of Swedish origin carrying the WHRN, c.1977delC, (p.S660Afs*30) mutation, the other was a TMC1(NM_138691),c.1814T>C,(p.L605P) mutation, possibly of Finnish origin.ConclusionsDeep human HFE genealogies show HFE to be associated with other genetic disorders like Wilson´s disease, LQTS, JLNS, and autosomal recessive hearing loss. Two new homozygous HL mutations in WHRN/p.S660Afs*30 and TMC1/p.L605P were identified,none of them previously reported from Scandinavia. The rarity of JLNS was possibly caused by miscarriage or intrauterine death. Most hearing loss (81.7%) was seen after 1844 when first cousin marriages were permitted. However, only 10 (10.3%) came from 1st cousin unions and only 2 (2.0 %) was born out of wedlock.