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), pp. 1733-1742. Springer 10.1007/s00414-019-02141-x

[img] Text
Neubauer2019_Article_FunctionalCharacterizationOfAN.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Wang, Zizun; Rougier, Jean-Sébastien; Abriel, Hugues and Medeiros Domingo, Argelia


600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology








Kevin Marc Rupp

Date Deposited:

17 Sep 2019 08:13

Last Modified:

26 Oct 2019 01:32

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Co-segregation analysis Exome sequencing Long QT syndrome Patch-clamp analysis SCN5A Sudden arrhythmic death syndrome




Actions (login required)

Edit item Edit item
Provide Feedback