Compound Heterozygous SCN5A Mutations in a Toddler - Are they Associated with a More Severe Phenotype?

Sacilotto, Luciana; Epifanio, Hindalis Ballesteros; Darrieux, Francisco; Wulkan, Fanny; Oliveira, Théo Gremen Mimary de; Hachul, Denise Tessariol; Pereira, Alexandre da Costa; Scanavacca, Maurício

doi:10.5935/abc.20170006

Cited by 7 publications

(9 citation statements)

References 10 publications

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“…Brugada syndrome clinical expression varies from totally asymptomatic to life-threatening arrhythmias. BrS patients harboring a compound heterozygous mutation of the SCN5A gene seem to be affected by the worst clinical picture (Sacilotto et al, 2017). However, a possible rescue effect due to the different contributions of two mutations in the same gene has been reported (Nunez et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Novel SCN5A Frameshift Mutation in Brugada Syndrome Associated With Complex Arrhythmic Phenotype

et al. 2019

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In this case report, we characterize a novel inherited frameshift mutation c.4700_4701del (p.Phe1567Cysfs * 221) in a single copy of the SCN5A gene and its association with Brugada syndrome (BrS). The proband experienced a life-threatening ventricular arrhythmia successfully treated with DC-shock and he also suffered from supraventricular tachycardia. Ajmaline test confirmed the BrS diagnosis. No other mutation nor low frequency variants in the other 23 analyzed genes were detected. The same mutation was found in the father and sister, who were both diagnosed with BrS. We hypothesize that this mutation could be responsible for BrS and potentially linked to supraventricular tachycardias. Further studies are needed to confirm this observation and to assess the clinical relevance of this mutation, in terms of risk-stratification.

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Section: Discussionmentioning

confidence: 99%

Novel SCN5A Frameshift Mutation in Brugada Syndrome Associated With Complex Arrhythmic Phenotype

et al. 2019

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“…Single heterozygous loss-of-function variants in SCN5A can cause BrS, cardiac conduction disease, sick sinus syndrome, dilated cardiomyopathy, and familial atrial fibrillation or manifest as an ‘overlap syndrome’ of these entities ( 22 ). When SCN5A is affected by two compound variants, this can result in a significant aggravation of the disease severity and/or earlier disease onset ( 5 , 23 – 26 ). This was also observed in our proband who experienced his first syncope during physical activity at around the age of 2 years, probably caused by brady-arrhythmia in the setting of atrial standstill.…”

Section: Discussionmentioning

confidence: 99%

“…This was also observed in our proband who experienced his first syncope during physical activity at around the age of 2 years, probably caused by brady-arrhythmia in the setting of atrial standstill. Most of the similarly published patients presented with sinus node dysfunction ( 5 , 23 , 24 , 26 ). Only Sacilotto et al reported a patient presenting initially with atrial flutter and recurrent syncopes without spontaneous ventricular arrhythmia and who, similarly to our case, presented a spontaneous BrS type-1 ECG pattern during follow-up ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…Only Sacilotto et al reported a patient presenting initially with atrial flutter and recurrent syncopes without spontaneous ventricular arrhythmia and who, similarly to our case, presented a spontaneous BrS type-1 ECG pattern during follow-up ( 24 ). Clinical interventions mostly encompass the implantation of a pacemaker ( 5 , 23 , 24 , 26 ), with additional low-dose aspirin ( 24 ) or oral quinidine ( 23 ), and single patient received β-blockers without pacemaker implantation ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

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Compound Heterozygous SCN5A Mutations in Severe Sodium Channelopathy With Brugada Syndrome: A Case Report

Nijak

Labro

Wilde

et al. 2020

Front. Cardiovasc. Med.

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Aims: Brugada syndrome (BrS) is an inherited cardiac arrhythmia with an increased risk for sudden cardiac death (SCD). About 20% of BrS cases are explained by mutations in the SCN5A gene, encoding the main cardiac sodium Na v 1.5 channel. Here we present a severe case of cardiac sodium channelopathy with BrS caused by SCN5A compound heterozygous mutations. We performed a genetic analysis of SCN5A in a male proband who collapsed during cycling at the age of 2 years. Because of atrial standstill, he received a pacemaker, and at the age of 3 years, he experienced a collapse anew with left-sided brain stroke. A later ECG taken during a fever unmasked a characteristic BrS type-1 pattern. The functional effect of the detected genetic variants was investigated. Methods and Results: Next-generation sequencing allowed the detection of two SCN5A variants in trans: c.4813+3_4813+6dupGGGT-a Belgian founder mutation-and c.4711 T>C, p.Phe1571Leu. A familial segregation analysis showed the presence of the founder mutation in the proband's affected father and paternal aunt and the de novo occurrence of the p.Phe1571Leu. The functional effect of the founder mutation was previously described as a loss-of-function. We performed a functional analysis of the p.Phe571Leu variant in HEK293 cells alone or co-expressed with the β 1-subunit. Compared to the SCN5A wild type, p.Phe1571Leu displayed a hyperpolarizing shift in the voltage dependence of inactivation (loss-of-function), while the activation parameters were unaffected. Using the peptide toxin nemertide α-1, the variant's loss-of-function effect could be restored due to a toxin-dependent reduction of channel inactivation. Nijak et al. Functional Characterization of p.Phe1571Leu in SCN5A Conclusion: This is the first report providing support for the pathogenicity of the p.Phe1571Leu SCN5A variant which, together with the c.4813+3_4813+6dupGGGT founder mutation, explains the severity of the phenotype of cardiac sodium channelopathy with BrS in the presented case.

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“…Rare compound alterations suggest that single variants in SCN5A are not sufficient to cause BrS [ 28 ]. Genetic background may therefore be a powerful modulator of disease expression [ 29 ], and compound variants may be associated with more severe BrS phenotypes [ 30 ], although nothing conclusive has been reported so far. Further genotype–phenotype studies in large cohorts supported by functional analysis (in vitro/in vivo) are needed to clarify the true pathogenic roles of the various genetic alterations in BrS.…”

Section: Genetic Alterationsmentioning

confidence: 99%

Update on Genetic Basis of Brugada Syndrome: Monogenic, Polygenic or Oligogenic?

Campuzano

Sarquella‐Brugada

César

et al. 2020

IJMS

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Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the SCN5A gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.

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Compound Heterozygous SCN5A Mutations in a Toddler - Are they Associated with a More Severe Phenotype?

Cited by 7 publications

References 10 publications

Novel SCN5A Frameshift Mutation in Brugada Syndrome Associated With Complex Arrhythmic Phenotype

Novel SCN5A Frameshift Mutation in Brugada Syndrome Associated With Complex Arrhythmic Phenotype

Compound Heterozygous SCN5A Mutations in Severe Sodium Channelopathy With Brugada Syndrome: A Case Report

Update on Genetic Basis of Brugada Syndrome: Monogenic, Polygenic or Oligogenic?

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