Open AccessComplex genetic background in a large family with Brugada syndrome
Author(s) -
Saber Siamak,
Amarouch MohamedYassine,
Fazelifar AmirFarjam,
Haghjoo Majid,
Emkanjoo Zahra,
Alizadeh Abolfath,
Houshmand Massoud,
Gavrilenko Alexander V.,
Abriel Hugues,
Zaklyazminskaya Elena V.
Publication year - 2015
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12256
Subject(s) - brugada syndrome , sodium channel , nav1.5 , mutation , medicine , mutant , gene , genetics , sudden cardiac death , biology , chemistry , organic chemistry , sodium
The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST ‐segment elevation in V 1 –V 3 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 SCN 5A , the gene coding for the cardiac sodium channel Na v 1.5, 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 SCN 5A . By performing whole‐cell patch‐clamp experiments using HEK 293 cells expressing wild‐type ( WT ) or p.P1506S Na v 1.5 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 v 1.5 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 KCNH 2 gene in SCN 5A ‐negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN 5A genetic variant.