Vincent Probst

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

BACKGROUNDnBrugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.nnnOBJECTIVEnThis study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.nnnMETHODSnMutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.nnnRESULTSnA total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.nnnCONCLUSIONnThis international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.

Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non–SCN5A-related patients☆

OBJECTIVESnWe have tested whether a genotype-phenotype relationship exists in Brugada syndrome (BS) by trying to distinguish BS patients with (carriers) and those without (non-carriers) a mutation in the gene encoding the cardiac sodium channel (SCN5A) using clinical parameters.nnnBACKGROUNDnBrugada syndrome is an inherited cardiac disease characterized by a varying degree of ST-segment elevation in the right precordial leads and (non)specific conduction disorders. In a minority of patients, SCN5A mutations can be found. Genetic heterogeneity has been demonstrated, but other causally related genes await identification. If a genotype-phenotype relationship exists, this might facilitate screening.nnnMETHODSnIn a multi-center study, we have collected data on demographics, clinical history, family history, electrocardiogram (ECG) parameters, His to ventricle interval (HV), and ECG parameters after pharmacologic challenge with I(Na) blocking drugs for BS patients with (n = 23), or those without (n = 54), an identified SCN5A mutation.nnnRESULTSnNo differences were found in demographics, clinical history, or family history. Carriers had a significantly longer PQ interval on the baseline ECG and a significantly longer HV time. A PQ interval of > or =210 ms and an HV interval > or =60 ms seem to be predictive for the presence of an SCN5A mutation. After I(Na) blocking drugs, carriers had significantly longer PQ and QRS intervals and more increase in QRS duration.nnnCONCLUSIONSnWe observed significantly longer conduction intervals on baseline ECG in patients with established SCN5A mutations (PQ and HV interval and, upon class I drugs, more QRS increase). These results concur with the observed loss of function of mutated BS-related sodium channels. Brugada syndrome patients with, and those without, an SCN5A mutation can be differentiated by phenotypical differences.

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans.

Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease.

The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases. In contrast, very little is known about the genetic and molecular mechanisms underlying human sinus node dysfunction (SND). Here, we report a genetic and molecular mechanism for human SND. We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous for AnkB phenocopy human SND displayed severe bradycardia and rate variability. AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters, and AnkB is required for physiological cardiac pacing. Finally, dysfunction in AnkB-based trafficking pathways causes abnormal sinoatrial node (SAN) electrical activity and SND. Together, our findings associate abnormal channel targeting with human SND and highlight the critical role of local membrane organization for sinoatrial node excitability.

Progressive Cardiac Conduction Defect is the Prevailing Phenotype in Carriers of a Brugada Syndrome SCN5A Mutation

Introduction: Loss‐of‐function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenègre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome.

Prevalence of early repolarization pattern in inferolateral leads in patients with Brugada syndrome

BACKGROUNDnRecent data have shown a high incidence of the early repolarization pattern confined in inferolateral leads in patients with idiopathic ventricular fibrillation.nnnOBJECTIVESnThe purpose of the present study was to investigate the prevalence and the prognostic significance of the early repolarization pattern in inferolateral leads in patients with Brugada syndrome.nnnMETHODSnClinical, genetic, and electrophysiologic data from 290 individuals (223 males, mean age 48.3 +/- 14.2 years) with a spontaneous or drug-induced type 1 electrocardiogram (ECG) pattern of Brugada syndrome and structurally normal hearts were analyzed. Twelve-lead ECGs were evaluated for the presence of early repolarization pattern, which was defined as J-point elevation of at least 0.1 mV from baseline in at least two inferior or lateral leads. Follow-up data were obtained for all subjects.nnnRESULTSnAn early repolarization pattern manifested as notched or slurred J-point elevation mainly in lateral leads was observed in 35 subjects (12%). The prevalence of the early repolarization pattern was significantly higher in male subjects (P = .004). During a mean follow-up period of 44.9 +/- 27.5 months, 22 subjects (8%) displayed an arrhythmic event including sudden cardiac death. There were no significant differences regarding spontaneous ECG type of Brugada syndrome, symptoms, family history of sudden cardiac death, and positive genetic test between subjects with and without the early repolarization pattern. The presence of early repolarization pattern was not associated with arrhythmic events during follow-up (Hazard ratio [HR] 1.090; 95% confidence interval 0.349-3.403; P = .882).nnnCONCLUSIONnThe early repolarization pattern in inferolateral leads is not an uncommon finding in Brugada syndrome. In our population, the early repolarization features were not associated with a worse outcome in subjects with Brugada syndrome.

Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy.

OBJECTIVESnThe aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease.nnnBACKGROUNDnMutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias.nnnMETHODSnThree unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified.nnnRESULTSnDilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine.nnnCONCLUSIONSnA new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine.

Identification of Large Families in Early Repolarization Syndrome

OBJECTIVESnThe aim of this study was to identify families affected by early repolarization syndrome (ERS) and to determine the mode of transmission of the disease.nnnBACKGROUNDnEarly repolarization (ER) has recently been linked to idiopathic ventricular fibrillation. Familial inheritance of the disease has been suggested but not demonstrated.nnnMETHODSnWe screened relatives of 4 families affected by ERS. ER was defined as a distinct J-wave in at least 2 consecutive leads and a 1-mm amplitude above baseline. The Valsalva maneuver was performed in affected and unaffected family members to decrease heart rate and thus increase or reveal an ER pattern.nnnRESULTSnTwenty-two sudden cardiac deaths occurred in the 4 families including 10 before 35 years of age. In the 4 families, the prevalence of ER was 56%, 34%, 61%, and 33% of, respectively, 30, 82, 29, and 30 screened relatives. In these families, transmission of an ER pattern is compatible with an autosomal dominant mode of inheritance. All probands were screened for genes identified in ERS, and no mutation was found. The Valsalva maneuver was performed in 80 relatives, resulting in increased J-wave amplitude for 17 of 20 affected patients and revealing an ER pattern in 17 relatives in whom 5 are obligate transmitters of an ER pattern.nnnCONCLUSIONSnERS can be inherited through autosomal dominant transmission and should be considered a real inherited arrhythmia syndrome. Familial investigation can be facilitated by using the Valsalva maneuver to reveal the electrocardiographic pattern in family members. The prognosis value of this test remains to be assessed.

Monomorphic Ventricular Tachycardia Due to Brugada Syndrome Successfully Treated by Hydroquinidine Therapy in a 3‐Year‐Old Child

Mutations in the SCN5A gene can cause Brugada syndrome, a genetically inherited form of idiopathic ventricular fibrillation. We describe the case of a 3‐year‐old child with a structurally normal heart presenting with monomorphic ventricular tachycardia. Her electrocardiogram suggested a Brugada syndrome and the diagnosis was confirmed by the identification of a Brugada syndrome in her mother and in two other family members. Genetic study led to the identification of a c.2516T→C SCN5A mutation. The child was treated with quinidine therapy without recurrence of arrhythmic events for a time period of 16 months.

Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome

BACKGROUNDnDespite isolated reports of Brugada syndrome (BrS) in the inferior or lateral leads, the prevalence and prognostic value of ST elevation in the peripheral electrocardiographic (ECG) leads in patients with BrS remain poorly known.nnnOBJECTIVEnTo study the prevalence, characteristics, and prognostic value of type 1 ST elevation and ST depression in the peripheral ECG leads in a large cohort of patients with BrS.nnnMETHODSnECGs from 323 patients with BrS (age 47 ± 13 years; 257 men) with spontaneous (n = 141) or drug-induced (n = 182) type 1 ECG were retrospectively reviewed. Two hundred twenty-five (70%) patients were asymptomatic, 72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients) at diagnosis or over a mean follow-up of 48 ± 34 months.nnnRESULTSnThirty (9%) patients presented with type 1 ST elevation in at least 1 peripheral lead (22 patients in the aVR leads, 2 in the inferior leads, 5 in both aVR and inferior leads, and 1 in the aVR and VL leads). Patients with type 1 ST elevation in the peripheral leads more often had mutations in the SCN5A gene, were more often inducible, had slower heart rate, and higher J-wave amplitude in the right precordial leads. Twenty-seven percent (8 of 30) of the patients with type 1 ST elevation in the peripheral leads experimented sudden death/appropriate implantable cardioverter-defibrillator therapy, whereas it occurred in only 6% (18 of 293) of other patients (P < .0001). In multivariate analysis, type 1 ECG in the peripheral leads was independently associated with malignant arrhythmic events (odds ratio 4.58; 95% confidence interval 1.7-12.32; P = .0025).nnnCONCLUSIONSnType 1 ST elevation in the peripheral ECG leads can be seen in 10% of the patients with BrS and is an independent predictor for a malignant arrhythmic event.