Header

UZH-Logo

Maintenance Infos

Functional characterization of a novel SCN5A variant associated with long QT syndrome and sudden cardiac death


Neubauer, Jacqueline; Wang, Zizun; Rougier, Jean-Sébastien; Abriel, Hugues; Rieubland, Claudine; Bartholdi, Deborah; Haas, Cordula; Medeiros-Domingo, Argelia (2019). Functional characterization of a novel SCN5A variant associated with long QT syndrome and sudden cardiac death. International journal of legal medicine, 133(6):1733-1742.

Abstract

Sudden arrhythmic death syndrome (SADS) in young individuals is a devastating and tragic event often caused by an undiagnosed inherited cardiac disease. Although post-mortem genetic testing represents a promising tool to elucidate potential disease-causing mechanisms in such autopsy-negative death cases, a variant interpretation is still challenging, and functional consequences of identified sequence alterations often remain unclear. Recently, we have identified a novel heterozygous missense variant (N1774H) in the Nav1.5 channel-encoding gene SCN5A in a 19-year-old female SADS victim. The aim of this study was to perform a co-segregation analysis in family members of the index case and to evaluate the functional consequences of this SCN5A variant. Functional characterization of the SCN5A N1774H variant was performed using patch-clamp techniques in TsA-201 cell line transiently expressing either wild-type or variant Nav1.5 channels. Electrophysiological analyses revealed that variant Nav1.5 channels show a loss-of-function in the peak current densities, but an increased late current compared to the wild-type channels, which could lead to both, loss- and gain-of-function respectively. Furthermore, clinical assessment and genetic testing of the relatives of the index case showed that all N1774H mutation carriers have prolonged QT intervals. The identification of several genotype and phenotype positive family members and the functional implication of the SCN5A N1774H variant support the evidence of the in silico predicted pathogenicity of the here reported sequence alteration.

Abstract

Sudden arrhythmic death syndrome (SADS) in young individuals is a devastating and tragic event often caused by an undiagnosed inherited cardiac disease. Although post-mortem genetic testing represents a promising tool to elucidate potential disease-causing mechanisms in such autopsy-negative death cases, a variant interpretation is still challenging, and functional consequences of identified sequence alterations often remain unclear. Recently, we have identified a novel heterozygous missense variant (N1774H) in the Nav1.5 channel-encoding gene SCN5A in a 19-year-old female SADS victim. The aim of this study was to perform a co-segregation analysis in family members of the index case and to evaluate the functional consequences of this SCN5A variant. Functional characterization of the SCN5A N1774H variant was performed using patch-clamp techniques in TsA-201 cell line transiently expressing either wild-type or variant Nav1.5 channels. Electrophysiological analyses revealed that variant Nav1.5 channels show a loss-of-function in the peak current densities, but an increased late current compared to the wild-type channels, which could lead to both, loss- and gain-of-function respectively. Furthermore, clinical assessment and genetic testing of the relatives of the index case showed that all N1774H mutation carriers have prolonged QT intervals. The identification of several genotype and phenotype positive family members and the functional implication of the SCN5A N1774H variant support the evidence of the in silico predicted pathogenicity of the here reported sequence alteration.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Downloads

1 download since deposited on 16 Dec 2019
1 download since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Legal Medicine
Dewey Decimal Classification:340 Law
610 Medicine & health
510 Mathematics
Scopus Subject Areas:Health Sciences > Pathology and Forensic Medicine
Uncontrolled Keywords:Pathology and Forensic Medicine
Language:English
Date:1 November 2019
Deposited On:16 Dec 2019 11:14
Last Modified:22 Apr 2020 21:44
Publisher:Springer
ISSN:0937-9827
Additional Information:This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: https://doi.org/[insert DOI]
OA Status:Closed
Publisher DOI:https://doi.org/10.1007/s00414-019-02141-x
PubMed ID:31455979
Project Information:
  • : FunderSNSF
  • : Grant ID310030_165741
  • : Project TitleMultiple Nav1.5 Pools in Cardiac Cells: Molecular Determinants and Functional Roles
  • : FunderSNSF
  • : Grant ID320030_149456
  • : Project TitleGenetic determinants in sudden infant death syndrome (SIDS) and sudden unexplained death syndrome (SUDS)

Download

Closed Access: Download allowed only for UZH members