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Brugada Syndrome: Causes, Diagnosis, and Treatment-2nd Edition
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Brugada Syndrome: Causes, Diagnosis, and Treatment-2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 5088

Special Issue Editors

Prof. Carlo Pappone

E-Mail Website
Guest Editor
IRCCS Policlinico San Donato, San Donato Milanese MI, Italy
Interests: electrophysiology; catheter ablation of cardiac arrhythmias; ablation of atrial fibrillation; nonfluoroscopic mapping; cardiac pacing; biventricular pacing; nonexcitatory cardiac contractility modulation
Special Issues, Collections and Topics in MDPI journals
Dr. Michelle Monasky

E-Mail Website
Guest Editor
IRCCS Policlinico San Donato, San Donato Milanese MI, Italy
Interests: Brugada syndrome; sudden cardiac death; ventricular arrhythmias; cardiac cellular physiology; genetic testing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brugada syndrome (BrS) is characterized by a coved elevation of the ST-segment (type 1 BrS pattern) on the electrocardiogram, which may occur spontaneously or after a drug challenge. This syndrome is associated with an increased risk of sudden cardiac death (SCD) due to ventricular arrhythmias caused by an arrhythmogenic substrate. Diagnosis of BrS is challenging, since the first clinical manifestation of the syndrome may be SCD (or aborted SCD), which often occurs in early adulthood during sleep. Variants in the SCN5A gene seem to account for less than one-third of clinically-confirmed cases, while the genetics of the remaining cases remain unknown, or disputed, at best. Identifying asymptomatic individuals at risk of SCD is imperative. However, as current genetic testing is limited in the majority of cases, alternative tests must be developed to identify these individuals. This Special Issue will feature a selection of original research, review articles, and commentaries related to the current understanding of molecular genetics and cellular physiology, as well as diastolic and therapeutic options, in BrS.

Prof. Carlo Pappone
Dr. Michelle Monasky
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Brugada syndrome
  • Sudden cardiac death
  • Genetic testing
  • Arrhythmia
  • Ventricular arrhythmias
  • SCN5A
  • Channelopathy
  • Variant
  • Mutation
  • Segregation analysis
  • Functional studies
  • Calcium channel
  • Potassium channel
  • Polymorphism
  • Syncope
  • Mortality
  • Arrhythmogenic substrate
  • Ablation

Published Papers (2 papers)

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Research

17 pages, 3420 KiB  
Article
Functional Characterization of Two Novel Mutations in SCN5A Associated with Brugada Syndrome Identified in Italian Patients
by Cristina Balla, Elena Conte, Rita Selvatici, Renè Massimiliano Marsano, Andrea Gerbino, Marianna Farnè, Rikard Blunck, Francesco Vitali, Annarita Armaroli, Alessandro Brieda, Antonella Liantonio, Annamaria De Luca, Alessandra Ferlini, Claudio Rapezzi, Matteo Bertini, Francesca Gualandi and Paola Imbrici
Int. J. Mol. Sci. 2021, 22(12), 6513; https://doi.org/10.3390/ijms22126513 - 17 Jun 2021
Cited by 4 | Viewed by 2608
Abstract
Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated [...] Read more.
Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20–30% of BrS cases and is considered clinically relevant. Methods. Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel SCN5A mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. Results. Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. Conclusions. Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention. Full article
(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment-2nd Edition)
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13 pages, 3829 KiB  
Article
Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths
by Michelle M. Monasky, Emanuele Micaglio, Giuseppe Ciconte, Ilaria Rivolta, Valeria Borrelli, Andrea Ghiroldi, Sara D’Imperio, Anna Binda, Dario Melgari, Sara Benedetti, Predrag Mitrovic, Luigi Anastasia, Valerio Mecarocci, Žarko Ćalović, Giorgio Casari and Carlo Pappone
Int. J. Mol. Sci. 2021, 22(9), 4700; https://doi.org/10.3390/ijms22094700 - 29 Apr 2021
Cited by 5 | Viewed by 1961
Abstract
Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is [...] Read more.
Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants. Full article
(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment-2nd Edition)
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