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

• Published in: International journal of legal medicine 2019-11, Vol.133 (6), p.1733-1742
• Main Authors: Neubauer, Jacqueline, Wang, Zizun, Rougier, Jean-Sébastien, Abriel, Hugues, Rieubland, Claudine, Bartholdi, Deborah, Haas, Cordula, Medeiros-Domingo, Argelia
• Format: Article
• Language: English
• Subjects: Autopsies; Cardiovascular disease; Death; Death & dying; Death, Sudden, Cardiac - etiology; Female; Forensic Medicine; Genetic testing; Genotype; Heterozygote; Humans; Infant; Long QT Syndrome - genetics; Male; Medical Law; Medicine; Medicine & Public Health; Mutation; Mutation, Missense; NAV1.5 Voltage-Gated Sodium Channel - genetics; Original Article; Pedigree; Phenotype; Teenagers; Whole Exome Sequencing; Young Adult; Young adults
• ISSN: 0937-9827; 1437-1596
• DOI: 10.1007/s00414-019-02141-x

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 Na v 1.5 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 Na v 1.5 channels. Electrophysiological analyses revealed that variant Na v 1.5 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.