SCN5A mutations and polymorphisms in patients with ventricular fibrillation during acute myocardial infarction

Abstract

Mutations in the SCN5A gene encoding the Nav1.5 channel α-subunit are known to be risk factors of arrhythmia, including Brugada Syndrome and Long QT syndrome subtype 3. The present study focused on the role of SCN5A variants in the development of ventricular fibrillation (VF) during acute myocardial infarction (AMI). Since VF during AMI is the major cause of sudden death in the Western world, SCN5A mutations represent genetic risk factors for sudden death. By exon re-sequencing, the entire coding region and flanking intron regions were sequenced in 46 AMI/VF+ patients. In total, nine single nucleotide variants were identified of which four represented common single nucleotide polymorphisms (SNPs; 87G>A, 1673A>G, IVS16‑6C>T and 5457T>A). Only five rare variants were identified, each in only one patient. Only two of the rare variants represented missense mutations (3578G>A and 4786T>A). The common SNPs and the missense mutations were also genotyped using polymerase chain reaction methods in 79 AMI/VF‑ patients and 480 healthy controls. The SNPs did not demonstrate significant differences in allele and genotype frequencies between the study groups. The 3578G>A mutation was identified in one out of the 480 controls, whereas the 4786T>A mutation was not present in AMI/VF- patients and controls. In conclusion, the majority of AMI/VF+ patients demonstrated a wild type sequence or common SNPs in SCN5A. Only two out of 46 (4.3%) AMI/VF+ patients revealed mutations that may be involved in Nav1.5 dysfunction and VF. However, this requires further functional validation.

Genotype–Phenotype Correlation in a Family with Brugada Syndrome Harboring the Novel p.Gln371* Nonsense Variant in the SCN5A Gene

“…It must be considered that a nonsense mutation can alter a channel protein more seriously than some other kinds of mutations. In fact, the Na V 1.5 protein displays some domains that are critical for protein function; one of these is the voltage sensor domain, which is localized close to exon 9, which maps the mutation described herein [37]. Taken together, all these data provide convincing evidence that a heterozygous state for the c.1111C>T variant in the SCN5A gene can predispose the carrier to BrS.…”

Ventricular Arrhythmias in First Acute Myocardial Infarction: Epidemiology, Mechanisms, and Interventions in Large Animal Models

“…A genome wide association study (GWAS) in the AGNES study cohort revealed a strong association between VF during AMI and a gene locus near the CXADR gene, that encodes for the coxsackie- and adenovirus receptor (20). Smaller studies point at genetic variations in the SCN5A gene, coding for the cardiac sodium channel Na v 1.5, as a predisposing factor for the development of VF upon AMI (21). Epidemiology and genetics of VF in AMI have been reviewed recently by Glinge et al (22).…”

Modifier genes for sudden cardiac death

“…Small studies tested the role of rare variants in arrhythmia-susceptibility genes and suggested a role for SCN5A rare variants. 59,60 Other studies evaluated the role of candidate SNPs. Specifically, NOS1AP variants were associated with higher risk for SCD in white adults 61 ; an association confirmed in the Rotterdam Study, which however did not exclusively include AMI.…”