Europace Advance Access originally published online on December 21, 2007
Europace 2008 10(1):79-85; doi:10.1093/europace/eum271
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BRUGADA SYNDROME
The occurrence of Brugada syndrome and isolated cardiac conductive disease in the same family could be due to a single SCN5A mutation or to the accidental association of both diseases
1 INSERM ERI 12, Amiens, France; 2 Department of Cardiology, Amiens-Picardie University Hospital, 80054 Amiens Cedex 1, France; 3 Research Center, Laval Hospital and Department of Medicine, Laval University, Québec, Canada; 4 INSERM U582, Institut de Myologie, IFR 14, Pitié-Salpêtrière Hospital, Paris, France; 5 Pierre et Marie Curie University, Paris, France; 6 UF Cardiogénétique et Myogénétique, Service de Biochimie B, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France; 7 Department of Cardiology, Lariboisière Hospital, Paris, France
Manuscript submitted 10 September 2007. Accepted after revision 15 November 2007.
* Corresponding author. Tel: +33 3 22 45 58 75; fax: +33 3 22 45 56 61.E-mail address: hermida.jean-sylvain{at}chu-amiens.fr
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Abstract |
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Aims: The distinct cardiac arrhythmia diseases, Brugada syndrome (BS) and isolated cardiac conduction disease (ICCD) are caused by heterozygous mutations in the SCN5A gene. Previous studies have demonstrated an intriguing association between ICCD and BS with the same mutation in the SCN5A gene.
Methods and results: The proband of a multigenerational family presented BS and a familial history of sudden death. We performed clinical evaluations in family members including drug testing and screening for SCN5A mutations. Based on electrocardiogram features, we identified four individuals with BS, two with ICCD and one compatible with both. For five individuals, one with BS and ICCD, three with BS and one with ICCD, we characterized a heterozygous C- to T- mutation at position 4313 (P1438L) in the SCN5A gene. Expression studies of the P1438L mutation showed non-functional channels. The proband’s father with the BS phenotype was not a carrier of the new SCN5A mutation.
Conclusion: We report the case of a family with BS and/or ICCD and describe a novel mutation, the P1438L SCN5A mutation. In this family, the occurrence of BS and ICCD could be due to this single mutation but also to the accidental association of both diseases.
Key Words: Arrhythmia, Cardiac conduction disease, Genetics
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Introduction |
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Three distinct inherited cardiac arrhythmia diseases, Brugada syndrome (BS), isolated cardiac conduction disease (ICCD) and long QT syndrome variant type 3 (LQT3) are associated with heterozygous mutations in the SCN5A gene.1
–4 This gene encodes for the 
subunit of the cardiac voltage-gated sodium channels that initiate cardiac action potentials.5
BS is characterized by episodes of syncope, ventricular fibrillation or sudden cardiac death in patients with structurally normal hearts. Patients with BS have a peculiar electrocardiogram (ECG) with ST segment elevation in the right precordial leads V1–V3 and a pattern mimicking a right bundle branch block.6,7 Several studies confirm the existence of malignant forms in this syndrome.8 Mutations responsible for BS lead to loss of function of the sodium channel. A decrease in the depolarizing inward sodium current is thought to lead to early repolarization in the right ventricular epicardium, where the transient outward potassium current (Ito) is more prominent than in the endocardium. This would cause a voltage gradient from endocardium to epicardium, ST elevation on the ECG, and susceptibility to arrhythmias caused by phase 2 re-entry.9–11 An alternative hypotheses focus on right ventricle conduction delay. Sodium channel blocking agents unmask the ECG phenotype and are used clinically for the diagnosis of BS.12
ICCD is characterized by a progressive worsening of cardiac conduction through the His–Purkinje system, eventually leading to complete atrioventricular (AV) block, causing syncope and sudden death. Long PR interval, right bundle branch block and broadening of the QRS complex are commonly observed but also 1–3 AV block, complete or incomplete right bundle branch block, left posterior hemiblock, left anterior hemiblock, parietal block, left bundle branch block and SA block. This syndrome, linked to an SCN5A mutation, may be transmitted as an autosomal dominant trait.13,14 The pathophysiology sequence of ICCD is unclear but most likely results from a loss of function of the cardiac sodium channel.
Clinically, common features exist between the two syndromes, as both exhibit a relatively high incidence of sudden cardiac death without prior symptoms.5 An intriguing association between ICCD and BS has been documented by Kyndt et al.15 who identified an SCN5A mutation which could lead either to BS or to an ICCD. In the present study, we report a French family with BS and/or ICCD and describe a novel P1438L SCN5A mutation that exhibit no current and thus a complete loss of function.
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Clinical investigation
The study was conducted according to the French guidelines for genetic research and was approved by the Amiens-Picardie University Hospital Ethics Committee. A detailed pedigree of the family was assembled. Permission and informed written consent were obtained from relatives who agreed to participate in the study. Investigation included a review of medical history, a complete physical examination, and a 12-lead ECG (GE Marquette Mac 5000, USA). BS was defined by the presence of a coved ST segment elevation
0.2 mV in at least two of the right precordial leads before or after Na channel blocker administration. In 15 family members, a Na channel blockage challenge was conducted with IV ajmaline (1 mg/kg) or flecainide (2 mg/kg). When some individuals were suspected of having conduction disease or BS, we performed flecainide/ajmaline tests with previously inserted temporary pacemaker electrodes. An echocardiography was performed in all the affected patients. The conduction defects were defined using conventional classification.16 During follow-up, patients who had clinical manifestations of BS or ICCD were assessed every 6 months for 4 years by clinical examination, ECG, and 24-h ambulatory ECG.
Mutation analysis of SCN5A
Blood samples were obtained from participating family members and spouses. Genomic DNA was prepared by standard method phenol chloroform extraction from peripheral blood lymphocytes. All SCN5A coding exons and intronic flanking sequences were amplified by polymerase chain reaction as described previously.14 Molecular screening was performed on DNA amplification products by denaturing high performance liquid chromatography (DHPLC; Transgenomics, Crewe, UK). All abnormal profiles were analysed by sequencing on ABI prism 310 (Applied Biosystems, Foster City, USA).
Genetic analysis of SCN5A polymorphisms
Fluorescence resonance energy transfer and probe melting curve
Three SCN5A polymorphisms, 1141-3 C > A in intron 9, 1673 A > G in exon 11 and 5457 C > T in exon 28 were analysed as previously described.17
Functional study
Mutagenesis
Mutant Nav1.5/P1438L, was generated using the QuickChange TM site-directed mutagenesis kit (Stratagene, La Jolla, CA, USA). The mutants Nav1.5/P1438L were constructed using the following 33 nucleotides mutagenic sense 5'-GGGTATGAAGAGCAGCTTCAGTGGGAATACAAC-3' and antisense primers 5'-GTTGTATTCCCACTGAAGCTGCTCTTCATACCC-3'. The pcDNA1 mutant (Nav1.5/P1438L) and wild-type (Nav1.5/WT) constructs were purified using Qiagen columns (Qiagen Inc., Chatsworth, CA, USA).
Transfection of the tsA201 cell line
TsA201 is a mammalian cell line derived from human embryonic kidney HEK 293 cells by stable transfection with SV40 large T antigen.18 Cells were transfected using calcium phosphate method and cotransfected with an expression plasmid for a lymphocyte surface antigen (CD8-a) to facilitate identification of individual transfected cells.19 The human sodium channel β1 subunit and CD8 were constructed in a piRES vector (piRES/CD8/β1). Transfected cells that bind beads expressed the β1-subunit. The cDNA coding for Nav1.5/WT or mutant Nav1.5/P1438L and piERS/CD8/β1 were used. For patch clamp experiments, cells were incubated in a medium containing anti-CD8-a coated beads (Dynabeads M-450 CD8-a) to distinguished transfected cells by light microscopy.
Patch clamp method
Macroscopic sodium currents from tsA201 transfected cells were recorded using the whole-cell configuration of the patch clamp technique.20 Voltage-clamp command pulses were generated by microcomputer using pCLAMP software v8.0 (Axon Instruments, Foster City, CA, USA). Sodium currents were filtered at 5 kHz, digitized at 10 kHz and stored on a microcomputer equipped with an AD converter (Digidata 1300, Axon Instruments). Data analysis was performed using a combination of pCLAMP software v9.0 (Axon Instruments), Microsoft Excel and SigmaPlot 2001 (SPSS Inc., Chicago, IL, USA).
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Clinical results
A partial pedigree of this family is presented in Figure 1. The family consisted of 24 members (41.7% men; age ranged from 4 to 82 years). Three family members were symptomatic (Table 1).
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Proband
The proband (patient III-9) was referred to our institution because of an unexplained syncope. His ECG was compatible with both ICCD and BS. The patient appeared to be otherwise, very healthy and active. Physical examination was normal. ECG recordings demonstrated an ST-segment elevation with a prolonged PR interval and a pseudo aspect of RBBB (QRS duration 120 ms) (Figure 1A, Table 1). Invasive electrophysiological testing demonstrated a slightly prolonged HV interval (60 ms). Programmed electrical stimulation triggered, at a basic cycle length of 600 ms, a sustained polymorphic ventricular tachycardia degenerating into ventricular fibrillation requiring electrical cardioversion, in response to two extra stimuli. Patient III-9 was given an implantable cardiac-defibrillator (ICD). During follow-up, no ICD discharge and no recurrence of syncope were observed.
The proband’s brothers and sister
The proband’s brother (patient III-6) ECG showed spontaneously ST-segment elevations (Table 1). The other proband’s brother (patient III-8) ECG, exhibited no sign of BS or ICCD (Table 1). Although asymptomatic, the proband’s sister (patient III-10) exhibited type 2 ECG signs of BS. After ajmaline or flecainide administration, patients III-6, III-8, and III-10 exhibited typical ECG patterns of BS (Figure 1B, C and D, respectively, Table 1). Invasive electrophysiological testing results showed that the proband’s two brothers (patients III-6 and III-10) were negative. They had never presented syncope and remained untreated. An ECG performed 2 months ago in the proband’s sister (patient III-8), showed a spontaneous type 1 pattern of BS with an ST-segment elevation of 0.2 mV. Invasive electrophysiological testing results showed that the proband’s sister was negative.
The proband’s parents
The proband’s father (patient II-6) ECG showed a type-2 ECG pattern of BS with a normal PR interval and QRS duration of 90 ms (Figure 2A, Table 1). The ajmaline challenge revealed a typical ECG pattern of BS (Figure 2C, Table 1).
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The proband’s mother (patient II-7) ECG showed a complete RBBB without ST-segment elevation (Figure 2B, Table 1). The ajmaline challenge induced a marked prolongation of the QRS duration (200 ms) but without any ST segment elevation. A negative T-wave was observed in the V2 ECG lead placed in the second and fourth intercostal space (Figure 2D, Table 1). This patient had never developed paroxymal AV block during ajmaline challenge. She remained without treatment until March 2004 when she experienced an unexplained syncope. In an electrophysiological study, her HV interval of 52 ms at baseline, increased to 108 ms after ajmaline injection. No ST segment elevation was observed. The programmed ventricular stimulation induced a VF in response to two extrastimuli during ventricular pacing at 400 ms cycle length. Subsequently, an ICD was inserted. During the follow-up no recurrence of syncope or ICD shock were recorded.
The paternal branch
The ECGs performed in the father's family (nine members) were normal even after ajmaline challenge.
The maternal branch
The ECGs performed in the mother's family (seven members) were normal except for subject II-8 who died suddenly at 61 years. The ECG performed 6 months before his death had revealed atrial fibrillation, a complete RBBB, left anterior hemiblock and a QRS duration of 200 ms suggestive of ICCD (Figure 2E). The cause of the sudden death remains unknown. For all the other members of the mother's family (six members) the ECGs were normal even after ajmaline administration.
Mutation analysis of SCN5A
The proband
Proband DNA was screened to identify an SCN5A mutation. An aberrant profile was detected for exon 25 resulting from a heterozygous C to T substitution in position 4313 (Figure 3A and B). This variation changed a proline to a leucine at position 1438 (P1438L) in the extra cellular linker S5–S6 of domain III. The proline residue at position 1438 is conserved in the voltage-dependent sodium channels of different species and in all sodium channel family members.
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The family
The SCN5A P1438L mutation was identified in the proband’s brothers and sister but was not found in the father who presented a BS phenotype. The father's DNA was screened but no other SCN5A mutation was found. The proband’s mother ECG that showed an ICCD but not BS harboured the P1438L mutation. No other family members were found with the mutation.
SCN5A polymorphisms
Known polymorphisms1673 A > G and 5457 C > T lead, respectively, to the non-synonymous H558R and to the synonymous D1819D variation. They were all informative and the haplotypes are shown in Figure 1. The father was a homozygous carrier of the rarest alleles (1141–3A and 1673 G corresponding to R558) while the mother carried the most frequent ones. A haplotype C–A–C carrying the SCN5A P1438L mutation was transmitted by the mother to her four affected children, while a distinct A–G–C haplotype was inherited by the three sons but not by the daughter from the father.
Functional study
The resulting sodium currents show normal fast activation and inactivation kinetics for the wild-type (Nav1.5/WT), whereas mutant channels (Nav1.5/P1438L) did not elicit any currents. Cells transfected with the P1438 mutant exhibited no inward current (Figure 3C).
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Discussion |
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We report a case of a French family with BS and/or ICCD and we describe a novel P1438L SCN5A mutation. Expression studies of the P1438L mutation showed non-functional channels. The P1438L SCN5A mutation could be a new mutation responsible for ICCD and BS. However, this study reports also the possibility for ICCD and BS to co-exist in the same.
ICCD is characterized by a progressive worsening of cardiac conduction through the His–Purkinje system. The patients with ICCD had a negative sodium channel blockers challenge, a test that has been reported to identify BS patients with a normal ST segment.12 Previous studies have demonstrated that ICCD, linked to SCN5A mutation, may be transmitted as an autosomal dominant trait.14–16 The pathophysiology sequence of ICCD is unclear but most likely results from a loss of function of the cardiac sodium channel. The proband’s mother, who presented an ICCD, carries the P1438L SCN5A mutation. The P1438L mutation induces a loss of function of the Na channel. The voltage clamp experiments demonstrated that cells expressing the mutant channel did not show any activation of inward current with or without β subunit. Other studies have demonstrated the loss of Na current with SCN5A mutations inducing ICCD15,21 or BS.22 BS is characterized by episodes of syncope, ventricular fibrillation or sudden cardiac death in patients with structurally normal hearts. Patients with BS have a peculiar ECG with ST segment elevation and a pattern mimicking a right bundle branch block. SCN5A mutations are identified in a small number of patients with BS and account for<20% of BS cases. Weiss et al.23 identified a novel BS gene locus on chromosome 3.
The proband’s ECG was compatible with both BS and ICCD. The proband’s mother ECG was compatible with ICCD and the invasive electrophysiological testing was positive in this patient. At this time we have no study concerning the results of invasive electrophysiological testing in patient with ICCD. The proband’s father presented a BS phenotype but the involvement of an SCN5A mutation was excluded by a direct investigation, suggesting that he was probably carrier of a mutation in a yet unidentified gene. A recent study has demonstrated the role of HERG (KCNH2), which encodes the -subunit of the rapid delayed rectifier K+ channel (IKr), in BS.24 Haplotype analysis of SCN5A polymorphisms shows that the father did not transmit the same allele for the SCN5A locus to his four children, which is compatible with a paternal mutation in another gene. In vitro, the rare allele R558 has been shown to attenuate the effect of a given SCN5A mutation.25 Nevertheless in this family, the four children are all heterozygous R558H carriers. So, the potential interaction of SCN5A polymorphisms with the mutation in this family and a potential explanation for phenotype variation remains obscure. An intriguing association between ICCD and BS has been documented by Kyndt et al.,15 Rossenbacker et al.26 and Smits et al.27 One explanation of this association would be those as-yet unidentified modifier genes and/or environmental factors might influence the occurrence of the ECG phenotype. However, structural abnormalities were excluded by echocardiography.
In the present study, two hypotheses could explain the association of BS and ICCD in the same family.
Hypothesis 1: the P1438L SCN5A mutation is responsible for the ICCD and BS phenotypes. The proband’s father has a BS phenotype due to some other cause like a false positive response to ajmaline test. The proband’s mother carries the P1438L SCN5A mutation responsible for her ICCD phenotype. All the children have the P1438L mutation. For the proband, this mutation is associated with a phenotype compatible with BS and ICCD. In the other children, the P1438L is associated with a BS phenotype. This suggests that factors such as other genetic anomalies or environmental background may play a role in determining phenotype and can result in different syndromes. In addition, the gender of patients may also play a role in determining the phenotype as suggested in the study by Kyndt et al.15 The same mutation can lead to BS phenotype in male carriers and conduction disease in female carriers.15 In our study two out three male patients carrying the SCN5A mutation had a BS phenotype, the other male has a BS and ICCD phenotypes. One out of two female patients has a BS phenotype and the other one has an ICCD phenotype.
Hypothesis 2: two phenotypic expression segregate in this family. The P1438L SCN5A mutation is responsible for ICCD phenotypes. The proband’s father has BS not related to an SCN5A mutation. The children have the P1438L SCN5A mutation but their BS phenotype is due to other mutation inherited from the father. The probability of one child having both mutations is 25%. The low but not negligible probability of the four children having both mutations is 6.25%. Interestingly, in families where an association between BS and ICCD was reported, no data was available from the parents.15,26,27 The possibility of two different mutations is considered by Smits et al.27 to explain that one patient presented a BS phenotype without SCN5A mutation. In our study, the presence of an SCN5A mutation in one parent and the BS phenotype in the other without identified SCN5A mutation open the hypothesis of an as yet unidentified second gene responsible for the BS in this family. The prevalence of an SCN5A mutation remains unknown but that of latent forms of BS ECG reaches 0.5% in the healthy population.28 The possibility of having such a confounding situation with an SCN5A mutation independent of the BS phenotype is not negligible.
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Conclusion |
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Since the late 1990s, genetics had helped to establish a diagnosis of BS by identifying the SCN5A mutations responsible for it. However, only 20% of the patients with BS present an SCN5A mutation. Moreover, different mutations in the SCN5A gene could be linked to multiple arrhythmic diseases such as ICCD or long QT syndrome. Genetic studies have demonstrated the association between ICCD and BS but a fortuitous association between BS and ICCD cannot be excluded, depending on the hereditary transmission of these two diseases.
Conflict of interest: none declared.
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This work was supported by funds from the Programme Hospitalier de Recherche Clinique of Amiens Picardie University Hospital and the GIS-Institut des Maladies Rares (Network on BS).
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References |
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