title: Complex genetic background in a large family with Brugada syndrome.
abstract: The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST-segment elevation in V1-V3 leads and negative T wave on standard ECG. BrS patients are at risk of sudden cardiac death (SCD) due to ventricular tachyarrhythmia. At least 17 genes have been proposed to be linked to BrS, although recent findings suggested a polygenic background. Mutations in SCN5A, the gene coding for the cardiac sodium channel Nav1.5, have been found in 15-30% of index cases. Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) in SCN5A. By performing whole-cell patch-clamp experiments using HEK293 cells expressing wild-type (WT) or p.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant-induced alterations lead to a loss of function of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation. Additional next generation sequencing analyses revealed the p.R25W mutation in KCNH2 gene in SCN5A-negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN5A genetic variant.
authors: I. M. Sechenov First Moscow State Medical University, Moscow, Russia.
authors: Siamak
authors: S
authors: Saber
authors: Environment & Natural Substances Team, University of Sidi Mohamed Ben Abdellah-Fes, Multidisciplinary Faculty of Taza, Taza, Morocco.
authors: Mohamed-Yassine
authors: MY
authors: Amarouch
authors: Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors: Amir-Farjam
authors: AF
authors: Fazelifar
authors: Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors: Majid
authors: M
authors: Haghjoo
authors: Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors: Zahra
authors: Z
authors: Emkanjoo
authors: Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors: Abolfath
authors: A
authors: Alizadeh
authors: Medical Genetics Department, National Institute for Genetic Engineering & Biotechnology, Tehran, Iran.
authors: Massoud
authors: M
authors: Houshmand
authors: I. M. Sechenov First Moscow State Medical University, Moscow, Russia Petrovsky Russian Research Center of Surgery, RAMS, Moscow, Russia.
authors: Alexander V
authors: AV
authors: Gavrilenko
authors: Department of Clinical Research, Ion Channels and Channelopathies, University of Bern, Bern, Switzerland.
authors: Hugues
authors: H
authors: Abriel
authors: I. M. Sechenov First Moscow State Medical University, Moscow, Russia Petrovsky Russian Research Center of Surgery, RAMS, Moscow, Russia.
authors: Elena V
authors: EV
authors: Zaklyazminskaya
keywords: Brugada syndrome; KCNH2; Nav1.5; SCN5A; inherited channelopathy
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