A1180V of Cardiac Sodium Channel Gene (SCN5A): Is It a Risk Factor for Dilated Cardiomyopathy or Just a Common Variant in Han Chinese?

Abstract

Our previous study of a Chinese family with dilated cardiomyopathy (DCM) suggested that A1180V of the cardiac sodium channel gene (SCN5A) was associated with the disease within this family. According to data deposited in dbSNP, however, A1180V has been found in some small samples of the Asian population. In this study, we followed up the affected pedigree and expanded the investigation of the prevalence of A1180V in 460 unrelated healthy Han Chinese. Besides, we searched and analyzed it in other database as well. During the follow-up period, 1 A1180V carrier's condition deteriorated alot, and another 4 carriers progressed to DCM or atrioventricular block (AVB). We also found that the A1180V was absent among the 460 individuals (0%, 0/460), and the carrier frequency of A1180V among Chinese was about 0.51% obtained from the 1000 genome project. In conclusion, our finding suggests that A1180V is a potential risk factor for DCM, and it is extremely rare among Healthy Han Chinese.

Dilated Cardiomyopathy and Nav1.5

“…Recently published results of extended testing of a DCM proband carrying the SCN5A-p.A1180V mutation is an example of the possible complex genetic backgrounds of DCM in SCN5A-positive patients. 30 The patient had rare genetic variants in several DCMrelated genes: p.G1117S, p.P1119R, p.Y498H in LAMA4 gene, p.W768S in RBM20 gene, and p.P398S in VCL gene. 30 The search for mutations in all known genes is a low diagnostic yield because DCM is genetically heterogeneous.…”

“…30 The patient had rare genetic variants in several DCMrelated genes: p.G1117S, p.P1119R, p.Y498H in LAMA4 gene, p.W768S in RBM20 gene, and p.P398S in VCL gene. 30 The search for mutations in all known genes is a low diagnostic yield because DCM is genetically heterogeneous. The introduction of new-generation sequencing technologies might enable more in-depth investigations, resulting in more accurate genotype-phenotype correlations.…”

Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels

“…The majority of studies that link the SCN5A gene to the occurrence of DCM demonstrate that this phenotype is usually associated with alterations in cardiac excitability (McNair et al, 2004 ; Ge et al, 2008 ; Nguyen et al, 2008 ; Gosselin-Badaroudine et al, 2012 ; Laurent et al, 2012 ; Mann et al, 2012 ; Shen et al, 2013 ; Beckermann et al, 2014 ). This observation raises several questions about the real origin of the observed structural defects.…”

“…These observations suggest that the association between Na v 1.5 mutations and DCM is multifactorial. Some of the known involved factors are the existence of long-standing arrhythmias, the alteration of sodium channel function, the genetic background of the patient, and the presence of structural abnormalities (McNair et al, 2004 ; Ge et al, 2008 ; Nguyen et al, 2008 ; Cheng et al, 2010 ; Gosselin-Badaroudine et al, 2012 ; Laurent et al, 2012 ; Mann et al, 2012 ; Shen et al, 2013 ; Beckermann et al, 2014 ).…”

SCN5A Variants: Association With Cardiac Disorders

“…However, sodium channel remodeling manifested with alterations in Na v 1.5 clustering was also discovered within distinct cardiomyocyte microdomains in some pathophysiological procedures such as heart failure (Rivaud et al, 2017 ). We previously found that the SCN5A variant A1180V could directly lead to cardiac structural impairment without involvement of long-time arrhythmias (Shen et al, 2013 ). Similarly, the environmental and genetic factors may also play additional roles in pathogenesis of disorders linked to SCN5A variants.…”