SCN5A Mutation Research Articles

Phenotypic spectrum of the SCN1A mutation (from febrile seizures to Dravet syndrome).

with the Dravet's syndrome phenotype are associated with the detection of a sequence variant in the SCN1A gene (alpha 1 subunit of the voltage-gated sodium channel) (2). However, sequence variants in the SCN1A gene are associated with a very broad clinical spectrum, from asymptomatic carriers to the severe myoclonic epilepsy phenotype with severe disease (3).In the presented work, we retrospectively evaluated a group of 6 patients of the Department of Pediatric Neurology of the Medical Faculty of Masaryk University and the University Hospital in Brno with a proven missense mutation. Based on the specific pathogenic sequence variant, we correlated the patient's phenotype with the location of the sequence variant in the SCN1A gene. The aim of the analysis was to verify the extent, to which the storage of a pathogenic sequence variant in the SCN1A gene corresponds to the clinical picture of the patient (Tab. 2, Fig. 2, Ref. 10). Keywords: Dravet's syndrome, sodium channel, functional analysis, prognosis.

Epilepsy surgery in patient with monogenic epilepsy related to SCN8A mutation.

Epilepsy surgery is superior to prolonged medical therapy in patients with drug-resistant focal epilepsy, but reports on epilepsy surgery outcomes for patients with a genetic etiology are limited, especially in adults. This is the first documented report of a stereoelectroencephalography (SEEG) evaluation and resective surgery outcome in an adult patient with epilepsy related to SCN8A mutation. We describe a patient with epilepsy related to SCN8A mutation which was reported as a variant of uncertain significance at time of his pre-surgical evaluation and reclassified as likely pathogenic about 3years after resective epilepsy surgery. Most of his pre-surgical evaluation results suggested right temporal lobe epilepsy, but few reported semiological symptoms, ictal SPECT, and neuropsychology results were discordant, and brain MRI was non-lesional. Therefore, SEEG was recommended; ultimately, seizures were localized to the right hippocampus. He was seizure-free for 1.5years after right anterior temporal lobectomy, then reported three focal to bilateral tonic-clonic (FBTC) seizures in the subsequent 12months (preoperatively, 6 focal impaired awareness seizures and 4-6 FBTC per year). This case demonstrates that epilepsy surgery reduced seizure burden in a patient with SCN8A-related epilepsy granting him short-term seizure freedom after resection, and then decreased seizure frequency after relapse compared to the preoperative baseline.

Genetic Screening of Patients with Thyrotoxic Hypokalemic Periodic Paralysis: An Experience from a Tertiary Care Hospital in the Northeast of Brazil.

Thyrotoxic Hypokalemic Periodic Paralysis (THPP) is a rare neuromuscular disease characterized by recurrent episodes of skeletal muscle weakness associated with hypokalemia. Alterations in protein-encoding genes that are part of ion channels seem to be related to the development of this disease. However, the pathogenic potential of some variants in these genomic regions is not yet fully understood. The aim of this study was to screen genetic alterations in regions coding for calcium (cav1.1), sodium (nav1.4), and potassium (Kir2.6) channels, evaluating its impact on the phenotype of patients with THPP. Four patients with a diagnosis of THPP followed by the Endocrinology Service of the University Hospital of the Federal University of Maranhão (Brazil) were investigated for the presence of molecular abnormalities in CACNA1S, SCN4A, and KCNJ18 genes. The KCNJ18 analysis revealed at least one polymorphic variant in each patient. Considering the haplotypic classification of R39Q, R40H, A56E, and I249V variants, two cases were named Kir2.6_RRAI and the other two patients were named Kir2.6_QHEV. No patient had point mutations in the regions evaluated for CACNA1S and SCN4A genes. The identification of the Kir2.6_RRAI and Kir2.6_QHEV haplotypes reinforces the existence of two main haplotypes involving these four loci of the KCNJ18gene. On the other hand, point mutations in CACNA1S, SCN4A, and KCNJ18 genes do not seem to be the main mechanism of pathogenesis of THPP, indicating that many questions about this topic still remain unclear. So, the diagnosis of this rare disorder should still be based on clinical and biochemical aspects presented by the patient.

Genetic aspects of pain and its variability in the human population

The sensation of pain is common to both animals and human beings. Its threshold, intensity, tolerability, and characteristics are variable and depend on ethnicity, gender, stress exposure, co-existing mental disorders, such as depression or anxiety, social and economical background, as well as on genetic factors. It is estimated that about 5 and 20 percent of population suffer from acute and chronic pain, respectively, which results in the search for medical advice in healthcare facilities, and causes great expenses in health care budgets worldwide. Research aimed at identifying the causative agents of pain syndromes include single nucleotidepolymorphism (SNP), family history studies, twin siblings' genetic diversity studies, and recently, also a genome-wide association study (GWAS). Clinical syndromes of derangement of pain sensation are generally caused by single gene mutations (e.g. erythromelalgia and paroxysmal extreme pain disorder caused by mutations of SCN9A), but can also be associated with multiple gene mutations, as happens in migraine, fibromyalgia or hereditary sensory and autonomic neuropathies. Structural changes of proteins caused by gene mutations involve various cellular element, such as ion channels, receptors, scaffolding proteins, enzymes, transporting proteins, eventually leading to numerous clinical entities in which pain or its lack remain the leading symptoms. The sensation of pain is initiated by a stimulus, which activates the free nerve endings via chemical mediators, and the mechanical stimuli is then transmitted to the brain along the neurons and spinal tracts. Synaptic neurotransmitters and cell structures take part in this process and eventually affect the intensity of pain sensation.

SCN1A Mutation-Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis.

Background: SCN1A is one of the most common epilepsy genes. About 80% of SCN1A gene mutations cause Dravet syndrome (DS), which is a severe and catastrophic epileptic encephalopathy. More than 1,800 mutations have been identified in SCN1A. Although it is known that SCN1A is the main cause of DS and genetic epilepsy with febrile seizures plus (GEFS+), there is a dearth of information on the other related diseases caused by mutations of SCN1A.Objective: The aim of this study is to systematically review the literature associated with SCN1A and other non-DS-related disorders.Methods: We searched PubMed and SCOPUS for all the published cases related to gene mutations of SCN1A until October 20, 2021. The results reported by each study were summarized narratively.Results: The PubMed and SCOPUS search yielded 2,889 items. A total of 453 studies published between 2005 and 2020 met the final inclusion criteria. Overall, 303 studies on DS, 93 on GEFS+, three on Doose syndrome, nine on the epilepsy of infancy with migrating focal seizures (EIMFS), six on the West syndrome, two on the Lennox–Gastaut syndrome (LGS), one on the Rett syndrome, seven on the nonsyndromic epileptic encephalopathy (NEE), 19 on hemiplegia migraine, six on autism spectrum disorder (ASD), two on nonepileptic SCN1A-related sudden deaths, and two on the arthrogryposis multiplex congenital were included.Conclusion: Aside from DS, SCN1A also causes other epileptic encephalopathies, such as GEFS+, Doose syndrome, EIMFS, West syndrome, LGS, Rett syndrome, and NEE. In addition to epilepsy, hemiplegic migraine, ASD, sudden death, and arthrogryposis multiplex congenital can also be caused by mutations of SCN1A.

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts.

Sodium voltage-gated channel α subunit 5 (SCN5A)-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with SCN5A-disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one SCN5A pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives. Fifteen patients (88.2%) were male, and sixteen independent variants were found (twelve missense, three truncating and one complex inframe deletion/insertion). The frequency of compound heterozygosity was remarkably high (3/17, 17.6%), with early childhood onset and severe disease. Overall, 70.6% of pediatric patients presented with overlap syndrome, 11.8% with isolated sick sinus syndrome, 11.8% with isolated Brugada syndrome (BrS) and 5.9% with isolated type 3 long QT syndrome (LQTS). A total of 24/45 SCN5A mutation carriers were affected (overall penetrance 53.3%), and penetrance was higher in males (63.3%, 19 affected/30 mutation carriers) than in females (33.3%, 5 affected/15 carriers). In conclusion, pediatric patients with SCNA-disease causing variants presented mainly as overlap syndrome, with predominant loss-of-function phenotypes of sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD) and ventricular arrhythmias.

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder.

Rare mutations associated with schizophrenia (SZ) and bipolar disorder (BD) usually have high clinical penetrance; however, they are highly heterogeneous and personalized. Identifying rare mutations is instrumental in making the molecular diagnosis, understanding the pathogenesis, and providing genetic counseling for the affected individuals and families. We conducted whole-genome sequencing analysis in two multiplex families with the dominant inheritance of SZ and BD. We detected a G327E mutation of SCN9A and an A654V mutation of DPP4 cosegregating with SZ and BD in one three-generation multiplex family. We also identified three mutations cosegregating with SZ and BD in another two-generation multiplex family, including L711S of SCN9A, M4554I of ABCA13, and P159L of SYT14. These five missense mutations were rare and deleterious. Mutations of SCN9A have initially been reported to cause congenital insensitivity to pain and neuropathic pain syndromes. Further studies showed that rare mutations of SCN9A were associated with seizure and autism spectrum disorders. Our findings suggest that SZ and BD might also be part of the clinical phenotype spectra of SCN9A mutations. Our study also indicates the oligogenic involvement in SZ and BD and supports the multiple-hit model of SZ and BD.

Familial Dilated Cardiomyopathy and Sudden Cardiac Arrest: New Association with a SCN5A Mutation.

Dilated cardiomyopathy (DCM) has significant morbidity and mortality. Familial transmission is reported in 20–35% of cases, highlighting the role of genetics in this disorder. We present an interesting family in which the index case is a 64-year-old woman who survived a sudden cardiac arrest. She presented left ventricular dilatation and dysfunction, which indicated the presence of DCM, as well as a history of DCM and sudden arrest in her family (mother and sister). Genetic testing identified a heterozygous mutation c.74A > G missense change that causes an amino acid, p.Glu25Gly, change in the N-terminal domain of the SCN5A protein. After performing an exhaustive family medical history, we found that this previously not described mutation segregated within the family. All relatives with the DCM phenotype were carriers, whereas none of the noncarriers showed signs of heart disease, so this mutation is the most likely cause of the disease. This is the first time that a variant in the N-terminal domain of SCN5A has been associated with DCM.

Generation of two induced pluripotent stem cell lines from Brugada syndrome affected patients carrying SCN5A mutations

SCN5A gene loss-of-function mutations are commonly associated with Brugada syndrome, which represents a risk of lethal arrhythmias and sudden cardiac death. The present report describes the generation of two human induced pluripotent stem cell (iPSC) lines reprogrammed from two Brugada syndrome affected patients carrying SCN5A mutations, c.53506 G>A and c.2102 C>T, respectively. Pluripotency markers, karyotype stability, and differentiation capability into derivatives of the three germ layers were assessed and described in the present report. These lines can be used as a reliable cell model for Brugada syndrome investigations and characterization of leading cellular mechanisms.

Spectrum of mutations and their phenotypic manifestations in children and adults with long QT syndrome

Aim. To determine the spectrum of mutations in the genes responsible for the long QT syndrome (LQTS) and study their phenotypic manifestations in patients with LQTS in different age groups.Materials and methods. The study included 35 unrelated probands with a clinical diagnosis of LQTS: 23 adults (8 men) and 12 children (9 boys). There were following clinical features: syncope — 54%, positive family history for SCD — 29%, implanted cardioverter defibrillator (ICD) — 46%. All participants underwent 12-lead electrocardiography (ECG), 24-hour Holter monitoring, genealogical analysis, echocardiography and cardiac MRI. The genetic study was performed by nextgeneration sequencing (NGS) using the MiSeq system (Illumina). The quantitative comparison of two unrelated groups was carried out using the nonparametric MannWhitney U-test. The differences were considered significant at p&lt;0,05.Results. In the examined group of 35 probands, 23 genetic variants of pathogenicity class IV and V (hereinafter referred to as) were identified. The molecular genetic variant of the disease was verified in 66% of probands. At the same time, the detection of mutations in the group with early manifestation (children) was significantly higher: 83% (10 out of 12 children) vs 57% in adults (13 out of 23). Rare genetic variants of uncertain significance (VUS, class III pathogenicity) were detected in 4 probands (11%). In the groups of children and adults with LQT1, LQT2 and LQT3, the sex distribution deviated from the 1:1 ratio. Among children, two-thirds were boys, among adults — the same proportion was represented by women. Disease manifestation time, QTc duration and adverse events risk depended on the genetic type of LQTS, intragenic localization of mutations and sex. In children, all 4 missense mutations in the KCNQ1 gene were located in transmembrane domain, and in adults, 4 mutations were in the transmembrane domain and three — in the C-terminal domain of the protein. LQT1 in boys was characterized by early manifestation, while QTc did not exceed 500 ms and there were no adverse outcomes. Two women out of 7 adults with LQT1 with mutations in the transmembrane domain had na ICD (QTc &gt;520 ms). All patients with LQT2 (4 children, 4 adults) had QTc &gt;500 ms. At the same time, 2 children and 3 women had an ICD. LQT3 was diagnosed only in the children subgroup (2 boys, with QTc of 510 ms and QTc of 610 ms); one of them died suddenly despite beta-blocker therapy. Four adult patients, carriers of class III pathogenicity variants, had QTc &lt;500 ms and delayed disease manifestation (after 30 years). Three of them had episodes of clinical death with subsequent resuscitation and implantation of cardioverter defibrillator.Conclusion. The average diagnostic efficiency of mutation identification using NGS in patients with clinically manifest LQTS was 66%. At the same time, mutations were more common in the children’s group. In genotype-positive probands, the risk of adverse outcomes correlated with sex, age and the genetic variant of disease. The greatest number of adverse outcomes was observed in carriers of mutations in both KCNH2 (LQT2) and SCN5A (LQT3) genes. Variants with unknown clinical significance were identified in 4 probands (11%), which potentially allowed to confirm the diagnosis after functional tests.

Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease.

Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.

Abstract 14243: The Apelin Mimetic Peptide (2Nal) Partially Inhibits the Transient Outward Potassium Current (Ito) in Rat Cardiomyocytes; a Potential Pharmacological Agent Against Brugada Syndrome

Introduction: Brugada syndrome (BrS) is an inherited disease characterized by ventricular cardiac arrhythmias leading to sudden cardiac death. One potential cause for arrhythmias is a disruption of the balance between the depolarizing fast sodium inward current (I Na ) and its opposing transient outward currents (I to ) favoring a faster repolarization during phase one of the action potential (AP). Hypothesis: BrS is mainly associated with a reduction in I Na amplitude caused by dominant mutations in the gene SCN5A encoding cardiac sodium channels. However, recent studies have shown that gain-of-function mutations in KCND3, the gene encoding Kv4.3 channels, increase I to amplitude. Therefore, targeting I to to modulate the balance of current during phase one of the AP represents a promising therapeutic approach to BrS, Methods: We used Patch-Clamp technique to test the effect of 2Nal, a newly synthesized peptide derived from apelin, on I to in rat ventricular cardiomyocytes. Apelin is an endogenous neurotransmitter with strong inotropic effects on cardiac cells. Results: We found that apelin had no effect on I to . In contrast, 2Nal maximally inhibited 46.9% ± 3.4 (n=9) of I to with an IC 50 =0.29 nM but did not change its kinetics, thus indicating that 2Nal acts as a partial blocker. The voltage dependence of potassium channels availability was not modified, suggesting that 2Nal simply reduced the conductance of each channel contributing to I to . Conclusions: Because of its partial antagonist effect on ITo, 2Nal provide a safety margin that could be potentially useful for the treatment of Brugada syndrome.

Abstract 12672: A New Genetic Model Organism for Primate-Specific Cardiac Function and Disease

Introduction: Due to differences in cardiac structure and function, it has become increasingly clear that many aspects of cardiovascular disease are not well modeled in mice. This has spurred a search for new model organisms with the practical advantages of mice but that more closely mimic human biology. This study examines mouse lemur (Microcebus species) - the world’s smallest, most prolific, and among the most abundant non-human primates - and the cheapest and easiest to maintain, as such a model. Methods: This study characterizes the normal cardiac anatomy and histology, and baseline values for heart rate, cholesterol, and cardiac waveform by ECG (a point-of-care blood assay and a portable 3-lead monitoring device were used to screen ~400 animals). It also describes the development of a whole genome and single cell RNA-sequencing and analysis pipeline for Microcebus murinus. Results: Transcriptomic analysis identified 6000 cardiac cells, including all major and many minor cardiac cell types, including several exceedingly rare cell types. The lipid profiles of these animals more closely resembled that of humans, with an average LDL level of 81 mg/dL, with several obese animals having values &gt;200. 20 naturally-occurring ECG variants were identified, all resembling known human ECG variants including 8 major cardiac arrhythmias. The screen uncovered the first cases of heart disease in lemurs. One is atrial fibrillation; Another is sick sinus syndrome (SSS), whose human familial form arises from mutations in ion channel genes, HCN4 or SCN5A. Both arrythmias show familial clustering, with the SSS pedigree exhibiting an autosomal dominant inheritance pattern. SNP/variant analysis revealed 30 million variants in the SSS animals, and ongoing work has narrowed these to just a handful of high impact, functional variants in SCN5A, suggesting that the underlying mouse lemur SSS disease gene and causative mutation are the same as in humans. Conclusions: The results establish the mouse lemur as the first systematic, high-throughput primate genetic model for cardiovascular physiology and disease, and reveal human-like cardiac cell types and diseases. The approach uncovered naturally-occurring cardiac diseases that have not been found in mice.

Digenic heterozygous mutations of KCNH2 and SCN5A induced young and early-onset long QT syndrome and sinoatrial node dysfunction.

IntroductionLong QT syndrome (LQTS) is a life‐threatening inherited channelopathy, and prolonged QT intervals easily trigger malignant arrhythmias, especially torsades de pointes and ventricular fibrillation.Materials and methodsThe proband with overlapped phenotypes of LQTS and sinoatrial node dysfunction underwent some necessary examinations, including echocardiography, electrocardiogram (ECG), and Holter monitoring. Next, whole‐exome sequencing was performed, and candidate genes were validated by Sanger sequencing. RNA secondary structure and protein physical‐chemical parameter analyses were used to predict the possible structural change of the proteins induced by the mutations.ResultsWe identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, c.921_923del) and SCN5A p.R1865H (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter‐defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 p.307_308del as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav1.5 protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index.ConclusionsThe digenic heterozygous KCNH2 and SCN5A mutations were associated with young early‐onset long QT syndrome and sinoatrial node dysfunction.

Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model.

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+ currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD.

Pregnancy in women with Brugada syndrome: Is there an increased arrhythmia risk? A case-series report.

In some rare arrhythmia syndromes, arrhythmia risk in female patients increases during pregnancy, necessitating extra controls. We wanted to evaluate if the increased risk for arrhythmia during pregnancy applies in women with Brugada syndrome and their potentially affected fetuses. A comprehensive literature search was performed on PubMed (MeSH search terms "Brugada syndrome,""pregnancy,""parturition,""labor,""delivery,""fetal death," and "stillbirth"). Overall, six case reports with a total of six patients were identified. Of these six patients (three carriers of an SCN5A variant, three not tested), two women (both with unknown SCN5A status), developed severe cardiac events during pregnancy. The first patient, with a previous history of aborted sudden cardiac arrest at the age of 12 years, developed ventricular fibrillation(VF), while the other was diagnosed with Brugada syndrome postpartum because of nocturnal agonal respiration during pregnancy. These (limited, heterogenous) cases suggest that women with Brugada syndrome (and their possibly affected fetuses), might have an overall low tendency to develop arrhythmias during pregnancy, but important data on risk factors (SCN5A status) are lacking. Arrhythmia risk during pregnancy seems to increase in probands and those who have previously experienced cardiac events. We suggest the use of risk stratification in these women to improve patient care, lower the emotional stress and physical burden for the pregnant mother, and lower health costs. Furthermore, we plead for SCN5A analysis in all these women for use of risk stratification and to enable cascade screening especially for specialized care in children carrying an SCN5A mutation.

Reprogramming of a human induced pluripotent stem cell line from a long QT syndrome patient harboring a heterozygous mutation of c.1537C > T in SCN5A gene

Long QT syndrome (LQTS) often causes malignant arrhythmia and syncope. Mutations in the SCN5A gene are the main cause of type 3 LQTS. In this study, we generated a human induced pluripotent stem cell line ZJYYPHi001-A from a female LQTS patient harboring a heterozygous mutation in SCN5A using non-integrative Sendai virus. This cell line expressed pluripotency markers, had the normal karyotype and could differentiate into three germ layers in vitro.

New insights into risk stratification of Brugada syndrome from high density epicardial electroanatomic mapping

Abstract Background/Introduction Brugada syndrome (BrS) has been initially described as a channelopathy with no structural heart disease but a growing body of evidence points towards structural anomalies in the epicardium of right ventricle outflow tract (RVOT-EPI). Since its first description the electrical substrate of BrS has been thought to be a fractionation of the electrograms (EGMs) in the RVOT-EPI. Also there is recent evidence that SCN5A mutation BrS patients might be at increased risk of sudden cardiac death (SCD). No studies correlated high-density mapping substrate with clinical outcomes. Purpose The aim of the current study was to compare clinical characteristics of BRS patients with EGMs characteristics from high-density epicardial mapping with Advisor HD-Grid mapping catheter. Methods All consecutive patients with BrS who underwent hybrid RVOT-EPI substrate ablation at our University Hospital between April 2018 and March 2021 were retrospectively included in the study. Genetic analysis was performed in all patients and clinical data were collected. BrS was diagnosed following current recommendations. Inclusion criteria were: 1) use of Advisor HD-Grid mapping catheter and 3D-electroanatomical (EAM) mapping system EnSite Precision; 2) acquisition of EAM before and after ajmaline infusion at standard protocol (1 mg/kg in 5 minutes). Bipolar EGMs were considered abnormal (aEGMs) if they met at least 1 of the following: prolonged duration (&amp;gt;80 ms), fragmented components (at least 2 distinct peaks), and/or late potentials extending beyond the end of the QRS complex. aEGMs duration (Ed) was defined as the time from surface QRS onset in D2 to bipolar EGM offset. Results Fifteen patients were included in the study. Six patients (40%) had history of SCD or inducible ventricular arrhythmias (VAs) at electrophysiological study and 5 patients (33.3%) had a mutation of SCN5A. The mean number of points of EAMs was 1020±500. Patients with history of SCD or VAs compared with patients without history had similar Ed before ajmaline [117.5 ms (100.6–132.5) vs 110.5 ms (106.8–114.8), p=0.72] but longer Ed after ajmaline [247.5 ms (231.6–273.9) vs 188.0 ms (178.0, 211.5), p=0.034]. The best cutoff of Ed after ajmaline to predict VAs history was 233 msec (AUC of the model 0.83, sensitivity: 0.98, specificity: 0.66). Patients with SCN5A mutation compared with patients without had similar Ed before ajmaline [125.2 ms (117.9–132.6) vs 105.0 ms (103.0–119.0), p=0.24] but longer Ed after ajmaline [270.0 ms (259.0–280.5) vs 200.8 ms (181.2–224.2), p=0.037], figure 1. The best cutoff of Ed after ajmaline to predict SCN5A mutation was 256.5 ms (AUC of the model 0.84, sensitivity: 0.80, specificity: 0.98), figure 2. Conclusions High density RVOT epicardial mapping provides data of clinical meaning in risk stratification of BrS patients. These data should be interpreted in the context of a population undergone RVOT-EPI substrate ablation. Funding Acknowledgement Type of funding sources: None. aEGM duration and SCD/VA or SCN5AROC curves for EGM derived prediction

Arrhythmias caused by mutations in SCN5A in children

Abstract Pathogenic genetic variants of the sodium channel alpha-subunit gene (SCN5A) is the leading cause of familial bradyarrhythmias. These diseases often manifest with syncope, have family segregation, and needs antiarrhythmic devices implantation, even in children. However, phenotypically these mutations can manifest as sick sinus syndrome (SSS), atrial fibrillation (AF), Brugada syndrome, and long QT syndrome. There are no studies on the prevalence of SCN5A mutations in children with arrhythmias. The aim is to study phenotypic and electrocardiographic manifestations of SCN5A-mutations in children with bradyarrhythmias. Methods We analyzed the data of 26 patients with bradyarrhythmias, who underwent genetic testing, from the database of the Russian Pediatric Arrhythmia Center. Seventeen were the probands, and nine - family members. The average age was 15.4±4.5 (from 2 to 17). Whole-exome sequencing was performed for 18 patients, cardiovascular panels for others. Results Variants of the sodium channel gene were detected in 3 family cases of arrhythmias and one sporadic case. In total, variants in SCN5A gene were found in 9 patients out of 26 (35%). In the first family, two sisters aged 6 and 17 have two biallelic variants of unknown significance in SCN5A gene. Both girls periodically have a Brugada marker on their ECG. The sisters both had syncope before the implantation of defibrillators. The girls' parents and older sister are clinically healthy, but the father previously had syncope. In the second family, a boy with a binodal disease, syncope, and an implanted pacemaker has two biallelic likely pathogenic variants in SCN5A gene. The boy's sister inherited only the mother's of SCN5A variant, showed a normal ECG in the first year of life, but then developed bradycardia within one year, and then joined the AVB of the 1st degree. Both parents had no clinical manifestations and no complaints. The third family included a mother and daughter with SSS and the heterozygous missense variant of unknown significance in SCN5A gene. Both of them do not need pacemaker implantation. The 12-year-old girl with two heterozygous variants of unknown significance in SCN5A gene had SSS, AF and underwent pacemaker implantation. Conclusion Genetic variants of SCN5A were detected in 35% of patients with bradyarrhythmias. Electrocardiographic manifestations of arrhythmias in our patients with SCN5A variants are diverse – SSS, Brugada syndrome, atrial fibrillation. Phenotypic variability in the manifestation of the SCN5A mutation requires a more thorough study of bradyarrhythmias' genetic causes in children. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Clinical Research Institute of Pediatrics named after acad. Y.E.Veltishev at the Pirogov Russian National Research Medical University, Moscow, Russia

The utility of the implantable loop recorder in patients with a diagnosis or family history of long QT syndrome

Abstract Background There is limited published data on the use of implantable loop recorders (ILRs) in patients with long QT syndrome (LQTS). Purpose We sought to evaluate the utility of the ILR in patients who had a diagnosis of LQTS or who had a family history of LQTS. Methods We carried out a retrospective analysis of patients attending an Inherited Cardiac Conditions Clinic who had an active ILR and who had a diagnosis or family history of LQTS. Patient demographics, indications for ILR implantation and clinical outcomes were compiled. Results Nine patients with a diagnosis of LQTS and an active ILR were identified with an average age of 37 years. Genetic results were available for seven patients. Four patients had a confirmed pathogenic mutation (one KCNQ1 and three KCNH2), one patient had a variant of uncertain significance in SCN5A and two patients had negative genetic testing. Indications for implantation were syncope (n=4), recurrent altered consciousness episodes (n=1), assessment of occult arrhythmia or beta blocker complications (n=2), palpitations and dizziness (n=1) and nocturnal dyspnoea and palpitations (n=1). Mean follow-up was 706 days and average age at ILR implant was 35 years. The ILR for three patients was a second device, implanted after end of battery life of the initial ILR. ILR recordings led to a change in management in three patients: finding of paroxysmal atrial fibrillation (n=1), finding of nocturnal QTc of 511ms with a change in medications (n=1) and a pause leading to cessation of beta blocker (n=1). Eleven patients with a family history of LQTS and active ILR were identified. Nine patients were female, and the average age was 44.4 years. Genetic test results were available for five patients. Three patients had a pathogenic mutation in SCN5A, and two patients had negative genetic testing for common LQTS genes. Indications for implantation included syncope (n=5), lightheaded episodes (n=3) and risk assessment in gene carriers (n=3). The mean duration of ILR follow-up was 680 days and average age at ILR implant was 42.5 years. Five patients had no arrhythmia detected during ILR recording, two patients had supraventricular tachycardia identified, in two patients ILR data outruled a sinister cause for a symptomatic episode, one patient had documentation of SVT and brief NSVT which led to referral for electrophysiology study and one patient had no recurrence of symptoms and a second ILR was implanted. Conclusion ILRs were inserted in selected patients with a diagnosis of LQTS or in patients with a family history of LQTS or who were gene carriers. Rationale for ILR implantation included risk stratification, monitoring for occult arrhythmia and rhythm-symptom correlation in symptomatic patients. The ILR impacted management in almost 50% of patients and is considered an important tool in selected patients attending Inherited Cardiac Condition Clinics. Funding Acknowledgement Type of funding sources: None. Table 1