Complex genetic background in a large family with Brugada syndrome

Physiological Reports

Siamak Saber¹  Mohamed-Yassine Amarouch⁴  Amir-Farjam Fazelifar⁵  Majid Haghjoo⁵  Zahra Emkanjoo⁵  Abolfath Alizadeh⁵  Massoud Houshmand³  Alexander V. Gavrilenko¹  Hugues Abriel² 

[1] I. M. Sechenov First Moscow State Medical University, Moscow, Russia;Department of Clinical Research, Ion Channels and Channelopathies, University of Bern, Bern, Switzerland;Medical Genetics Department, National Institute for Genetic Engineering & Biotechnology, Tehran, Iran;Environment & Natural Substances Team, University of Sidi Mohamed Ben Abdellah-Fes, Multidisciplinary Faculty of Taza, Taza, Morocco;Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

关键词: Brugada syndrome;    inherited channelopathy;    KCNH2;    Nav1.5;    SCN5A;   

DOI  :  10.14814/phy2.12256

来源: Wiley

【 摘 要 】

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 Na_v1.5, 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 Na_v1.5 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 Na_v1.5 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.

【 授权许可】

CC BY   
© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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