Skip to main content
Springer Nature Link
Log in

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

  • Original Article
  • Published:
International Journal of Legal Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP, Heart Rhythm S, European Heart Rhythm A (2011) HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace 13(8):1077–1109. https://doi.org/10.1093/europace/eur245

    Article  PubMed  Google Scholar 

  2. Basso C, Aguilera B, Banner J, Cohle S, d'Amati G, de Gouveia RH, di Gioia C, Fabre A, Gallagher PJ, Leone O, Lucena J, Mitrofanova L, Molina P, Parsons S, Rizzo S, Sheppard MN, Mier MPS, Kim Suvarna S, Thiene G, van der Wal A, Vink A, Michaud K, Association for European Cardiovascular P (2017) Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology. Virchows Arch 471(6):691–705. https://doi.org/10.1007/s00428-017-2221-0

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cerrone M, Priori SG (2011) Genetics of sudden death: focus on inherited channelopathies. Eur Heart J 32(17):2109–2118. https://doi.org/10.1093/eurheartj/ehr082

    Article  PubMed  Google Scholar 

  4. Narula N, Tester DJ, Paulmichl A, Maleszewski JJ, Ackerman MJ (2014) Post-mortem whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series. Pediatr Cardiol 36(4):768–778. https://doi.org/10.1007/s00246-014-1082-4

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hertz CL, Christiansen SL, Ferrero-Miliani L, Fordyce SL, Dahl M, Holst AG, Ottesen GL, Frank-Hansen R, Bundgaard H, Morling N (2015) Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases. Int J Legal Med 129(4):793–800. https://doi.org/10.1007/s00414-014-1105-y

    Article  CAS  PubMed  Google Scholar 

  6. Anderson JH, Tester DJ, Melissa L, Ackerman MJ (2016) Whole-exome molecular autopsy after exertion-related sudden unexplained death in the young. Circ Cardiovasc Genet 9(3):260–265. https://doi.org/10.1161/CIRCGENETICS.115.001370

    Article  Google Scholar 

  7. Bagnall RD, Weintraub RG, Ingles J, Duflou J, Yeates L, Lam L, Davis AM, Thompson T, Connell V, Wallace J, Naylor C, Crawford J, Love DR, Hallam L, White J, Lawrence C, Lynch M, Morgan N, James P, du Sart D, Puranik R, Langlois N, Vohra J, Winship I, Atherton J, McGaughran J, Skinner JR, Semsarian C (2016) A prospective study of sudden cardiac death among children and young adults. N Engl J Med 374(25):2441–2452. https://doi.org/10.1056/NEJMoa1510687

    Article  PubMed  Google Scholar 

  8. Christiansen SL, Hertz CL, Ferrero-Miliani L, Dahl M, Weeke PE, Camp L, Ottesen GL, Frank-Hansen R, Bundgaard H, Morling N (2016) Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting. Eur J Hum Genet 24(12):1797–1802. https://doi.org/10.1038/ejhg.2016.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lahrouchi N, Raju H, Lodder EM, Papatheodorou E, Ware JS, Papadakis M, Tadros R, Cole D, Skinner JR, Crawford J, Love DR, Pua CJ, Soh BY, Bhalshankar JD, Govind R, Tfelt-Hansen J, Winkel BG, van der Werf C, Wijeyeratne YD, Mellor G, Till J, Cohen MC, Tome-Esteban M, Sharma S, Wilde AAM, Cook SA, Bezzina CR, Sheppard MN, Behr ER (2017) Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome. J Am Coll Cardiol 69(17):2134–2145. https://doi.org/10.1016/j.jacc.2017.02.046

    Article  PubMed  PubMed Central  Google Scholar 

  10. Neubauer J, Lecca MR, Russo G, Bartsch C, Medeiros-Domingo A, Berger W, Haas C (2018) Exome analysis in 34 sudden unexplained death (SUD) victims mainly identified variants in channelopathy-associated genes. Int J Legal Med 132(4):1057–1065. https://doi.org/10.1007/s00414-018-1775-y

    Article  PubMed  Google Scholar 

  11. Shanks GW, Tester DJ, Ackerman JP, Simpson MA, Behr ER, White SM, Ackerman MJ (2018) Importance of variant interpretation in whole-exome molecular autopsy: population-based case series. Circulation 137(25):2705–2715. https://doi.org/10.1161/CIRCULATIONAHA.117.031053

    Article  PubMed  Google Scholar 

  12. Ackerman JP, Bartos DC, Kapplinger JD, Tester DJ, Delisle BP, Ackerman MJ (2016) The promise and peril of precision medicine: phenotyping still matters most. Mayo Clin Proc. https://doi.org/10.1016/j.mayocp.2016.08.008

    Article  Google Scholar 

  13. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  14. Neubauer J, Haas C, Bartsch C, Medeiros-Domingo A, Berger W (2016) Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases. Int J Legal Med 130(4):1011–1021. https://doi.org/10.1007/s00414-016-1317-4

    Article  PubMed  Google Scholar 

  15. Gui J, Wang T, Trump D, Zimmer T, Lei M (2010) Mutation-specific effects of polymorphism H558R in SCN5A-related sick sinus syndrome. J Cardiovasc Electrophysiol 21(5):564–573. https://doi.org/10.1111/j.1540-8167.2010.01762.x

    Article  PubMed  Google Scholar 

  16. Zareba W, Sattari MN, Rosero S, Couderc JP, Moss AJ (2001) Altered atrial, atrioventricular, and ventricular conduction in patients with the long QT syndrome caused by the ΔKPQ SCN5A sodium channel gene mutation. Am J Cardiol 88

  17. Clancy CE, Tateyama M, Liu H, Wehrens XH, Kass RS (2003) Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia. Circulation 107(17):2233–2237. https://doi.org/10.1161/01.CIR.0000069273.51375.BD

    Article  CAS  PubMed  Google Scholar 

  18. Remme CA, Verkerk AO, Nuyens D, van Ginneken AC, van Brunschot S, Belterman CN, Wilders R, van Roon MA, Tan HL, Wilde AA, Carmeliet P, de Bakker JM, Veldkamp MW, Bezzina CR (2006) Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD. Circulation 114(24):2584–2594. https://doi.org/10.1161/CIRCULATIONAHA.106.653949

    Article  CAS  PubMed  Google Scholar 

  19. Makita N (2009) Phenotypic overlap of cardiac sodium channelopathies: indiviudal-specific or mutation-specific? Circ J 73:810–817

    Article  PubMed  Google Scholar 

  20. Remme CA, Wilde AA, Bezzina CR (2008) Cardiac sodium channel overlap syndromes: different faces of SCN5A mutations. Trends Cardiovasc Med 18(3):78–87. https://doi.org/10.1016/j.tcm.2008.01.002

    Article  CAS  PubMed  Google Scholar 

  21. Veltmann C, Barajas-Martinez H, Wolpert C, Borggrefe M, Schimpf R, Pfeiffer R, Caceres G, Burashnikov E, Antzelevitch C, Hu D (2016) Further insights in the most common SCN5A mutation causing overlapping phenotype of long QT syndrome, Brugada syndrome, and conduction defect. J Am Heart Assoc 5(7). https://doi.org/10.1161/JAHA.116.003379

  22. Makita N, Behr E, Shimizu W, Horie M, Sunami A, Crotti L, Schulze-Bahr E, Fukuhara S, Mochizuki N, Makiyama T, Itoh H, Christiansen M, McKeown P, Miyamoto K, Kamakura S, Tsutsui H, Schwartz PJ, George AL Jr, Roden DM (2008) The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J Clin Invest 118(6):2219–2229. https://doi.org/10.1172/JCI34057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kato K, Makiyama T, Wu J, Ding WG, Kimura H, Naiki N, Ohno S, Itoh H, Nakanishi T, Matsuura H, Horie M (2014) Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench. J Cardiovasc Electrophysiol 25(1):66–73. https://doi.org/10.1111/jce.12270

    Article  PubMed  Google Scholar 

  24. Horigome H, Nagashima M, Sumitomo N, Yoshinaga M, Ushinohama H, Iwamoto M, Shiono J, Ichihashi K, Hasegawa S, Yoshikawa T, Matsunaga T, Goto H, Waki K, Arima M, Takasugi H, Tanaka Y, Tauchi N, Ikoma M, Inamura N, Takahashi H, Shimizu W, Horie M (2010) Clinical characteristics and genetic background of congenital long-QT syndrome diagnosed in fetal, neonatal, and infantile life: a nationwide questionnaire survey in Japan. Circ Arrhythm Electrophysiol 3(1):10–17. https://doi.org/10.1161/CIRCEP.109.882159

    Article  PubMed  Google Scholar 

  25. Postema PG, Van den Berg MP, Van Tintelen JP, Van den Heuvel B, Grundeken M, Hofman N, Van der Roest WP, Nannenberg EA, Krapels IPC, Bezzina CR, Wilde AAM (2009) Founder mutations in the Netherlands: SCN5A 1795insD, the first described arrhythmia overlap syndrome and one of the largest and best characterised families worldwide. Neth Hear J 17(11):422–428

    Article  CAS  Google Scholar 

  26. Beaufort-Krol GC, van den Berg MP, Wilde AA, van Tintelen JP, Viersma JW, Bezzina CR, Bink-Boelkens MT (2005) Developmental aspects of long QT syndrome type 3 and Brugada syndrome on the basis of a single SCN5A mutation in childhood. J Am Coll Cardiol 46(2):331–337. https://doi.org/10.1016/j.jacc.2005.03.066

    Article  PubMed  Google Scholar 

  27. Mazzanti A, Maragna R, Faragli A, Monteforte N, Bloise R, Memmi M, Novelli V, Baiardi V, Baiardi P, Etheridge SP, Napolitano C, Priori SG (2016) Gene-specific therapy with mexiletine reduces arrhythmic events in patients with long QT syndrome type 3. J Am Coll Cardiol 67(9):1053–1058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nakaya H (2014) SCN5A mutations associated with overlap phenotype of long QT syndrome type 3 and Brugada syndrome. Circ J 78(5):1061–1062. https://doi.org/10.1253/circj.CJ-14-0319

    Article  CAS  PubMed  Google Scholar 

  29. Andreasen C, Nielsen JB, Refsgaard L, Holst AG, Christensen AH, Andreasen L, Sajadieh A, Haunso S, Svendsen JH, Olesen MS (2013) New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet 21(9):918–928. https://doi.org/10.1038/ejhg.2012.283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hübner CA, Jentsch TJ (2002) Ion channel diseases. Hum Mol Genet 11:2435–2445

    Article  PubMed  Google Scholar 

  31. Moreno JD, Clancy CE (2012) Pathophysiology of the cardiac late Na current and its potential as a drug target. J Mol Cell Cardiol 52(3):608–619. https://doi.org/10.1016/j.yjmcc.2011.12.003

    Article  CAS  PubMed  Google Scholar 

  32. Gardill BR, Rivera-Acevedo RE, Tung CC, Okon M, McIntosh LP, Van Petegem F (2018) The voltage-gated sodium channel EF-hands form an interaction with the III-IV linker that is disturbed by disease-causing mutations. Sci Rep 8(1):4483. https://doi.org/10.1038/s41598-018-22713-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wilders R (2018) Cellular mechanisms of sinus node dysfunction in carriers of the SCN5A-E161K mutation and role of the H558R polymorphism. Front Physiol 9:1795. https://doi.org/10.3389/fphys.2018.01795

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Swiss Heart Foundation and the Swiss National Science Foundation SNF (project nos. 310030_165741 and 320030_149456).

Author information

Author notes

  1. Jacqueline Neubauer and Zizun Wang contributed equally to this work.

Authors and Affiliations

  1. Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland

    Jacqueline Neubauer & Cordula Haas

  2. Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland

    Zizun Wang, Jean-Sébastien Rougier & Hugues Abriel

  3. Department of Pediatrics, Division of Human Genetics, Inselspital, University of Bern, Bern, Switzerland

    Claudine Rieubland & Deborah Bartholdi

  4. Department of Cardiology, Inselspital, University Hospital Bern, Bern, Switzerland

    Argelia Medeiros-Domingo

  5. Swiss DNAlysis, Dübendorf, Switzerland

    Argelia Medeiros-Domingo

Authors
  1. Jacqueline Neubauer
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Zizun Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Jean-Sébastien Rougier
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Hugues Abriel
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Claudine Rieubland
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Deborah Bartholdi
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Cordula Haas
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Argelia Medeiros-Domingo
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Jacqueline Neubauer.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.

Statement of informed consent

All available family members signed an informed consent form for co-segregation analysis and gave approval for publication of this case report (Cantonal Ethics Committee Bern (KEK-BE-Nr. 2016-01602)).

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 63 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neubauer, J., Wang, Z., Rougier, JS. et al. Functional characterization of a novel SCN5A variant associated with long QT syndrome and sudden cardiac death. Int J Legal Med 133, 1733–1742 (2019). https://doi.org/10.1007/s00414-019-02141-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00414-019-02141-x

Keywords

Profiles

  1. Cordula Haas View author profile