A homozygous SCN5A mutation associated with atrial standstill and sudden death

Tan, Reina Bianca; Gando, Ivan; Bu, Lei; Cecchin, Frank; Coetzee, William A.

doi:10.1111/pace.13386

Cited by 17 publications

(7 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Homozygous mutation IIIS5 V 1340 L was found in two female patients with atrial standstill, while in three unaffected relatives the mutations was heterozygous. In a functional study, V 1340 L reduced the current density and impaired channel activation ( Tan et al, 2018 ). Another mutation, V 1340 I, did not alter biophysical characteristics at room temperature, but at 40°C it decreased the current density, caused hyperpolarizing shift of steady-state inactivation, and accelerated recovery from the fast inactivation ( Samani et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel

et al. 2021

View full text Add to dashboard Cite

Over 1,500 missense variants of sodium channel hNav1.5, which are reported in the ClinVar database, are associated with cardiac diseases. For most of the variants, the clinical significance is uncertain (VUS), not provided (NP), or has conflicting interpretations of pathogenicity (CIP). Reclassifying these variants as pathogenic/likely pathogenic (P/LP) variants is important for diagnosing genotyped patients. In our earlier work, several bioinformatics tools and paralogue annotation method consensually predicted that 74 VUS/NP/CIP variants of 54 wild type residues (set w54) are potentially damaging variants (PDVs). Atomic mechanisms underlying dysfunction of the PDVs are unknown. Here we employed a recent cryo-EM structure of the hNav1.5 channel with likely inactivated pore domain (PD) and activated voltage-sensing domains (VSDs), and ad hoc models of the closed and open PD and resting VSDs to explore intersegment contacts of w54 residues. We found that 44 residues from set w54 contact 84 residues with 118 disease missense variants. These include 104 VUS/NP/CIP variants, most of which are associated with the loss-of-function Brugada syndrome (BrS1) or gain-of-function long QT syndrome (LQT3). Matrix representation of the PDVs and their contact variants facilitated recognition of coupled mutations associated with the same disease. In particular, BrS1-associated coupled mutations, which disturb the P-loops region with the selectivity filter slow inactivation gate, would cause the channel dysfunction. Other likely causes of the channel dysfunction include coupled BrS1-associated variants within VSDs that would destabilize their activated states and coupled LQT3-associated variants, which would stabilize the open PD or activated VSDs. Our study proposes mechanisms of channel dysfunction for scores of BrS1- and LQT3-associated variants, confirms status for 82% of PDVs, and suggests damaging status for their contact variants, which are currently categorized as VUS/NP/CIP variants.

show abstract

Section: Resultsmentioning

confidence: 99%

Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel

et al. 2021

View full text Add to dashboard Cite

show abstract

“…SCN5A variants have been causatively associated with Brugada syndrome, long QT syndrome, cardiac conduction system dysfunction, dilated cardiomyopathy and so on 22. Some variants in SCN5A have been related to sudden death 16 23 24. Ala572Asp, Pro1090Leu, Pro2006Ala variants in SCN5A 7 and a missense mutation R523C12 were found in SUDEP cases previously.…”

Section: Discussionmentioning

confidence: 97%

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

Ding

Zhu

et al. 2019

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

ObjectiveSudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy-related mortality in young adults. It has been suggested that SUDEP may kill over 20 000 people with epilepsy in China yearly. The aetiology of SUDEP is unclear. Little is known about candidate genes for SUDEP in people of Chinese origin as most studies have ascertained this in Caucasians. No candidate genes for SUDEP in Chinese people have been identified.MethodsWe performed whole exome sequencing (WES) in DNA samples collected from five incident cases of SUDEP identified in a large epilepsy cohort in rural China. We filtered rare variants identified from these cases as well as screened for SUDEP, epilepsy, heart disease or respiratory disease-related genes from previous published reports and compared them with publicly available data, living epilepsy controls and ethnicity-match non-epilepsy controls, to identify potential candidate genes for SUDEP.ResultsAfter the filtering process, the five cases carried 168 qualified mutations in 167 genes. Among these genetic anomalies, we identified rare variants in SCN5A (1/5:20% in our cases), KIF6 (1/5:20% in our cases) and TBX18 (1/5:20% in our cases) which were absent in 330 living epilepsy control alleles from the same original cohort and 320 ethnicity-match non-epilepsy control alleles.ConclusionsThese three genes were previously related to heart disease, providing support to the hypothesis that underlying heart disorder may be a driver of SUDEP risk.

show abstract

“…31 There have been previous reports of SCN5A variants associated with atrial standstill. 32,33 Interestingly, a relatively close c.664C>G (p. Arg222Gly) was reported in a family with atrial standstill without cardiomyopathy or sudden death. 32 Further investigation using well-designed in vitro studies are needed to determine how disruption of the SCN5A protein in this region may contribute to atrial standstill as well as cardiomyopathic and arrhythmic phenotypes in this family.…”

Section: Discussionmentioning

confidence: 98%

Clinical characterisation of a novel SCN5A variant associated with progressive malignant arrhythmia and dilated cardiomyopathy

et al. 2019

View full text Add to dashboard Cite

Introduction:The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.Methods:A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.Results:All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination.Conclusions:There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.

show abstract

A homozygous SCN5A mutation associated with atrial standstill and sudden death

Abstract: A homozygous loss-of-function SCN5A mutation likely results in atrial standstill and sudden death due to suppression of initiation of action potential.

Cited by 17 publications

References 20 publications

Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel

Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

Clinical characterisation of a novel SCN5A variant associated with progressive malignant arrhythmia and dilated cardiomyopathy

Contact Info

Product

Resources

About