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Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density
  1. Cheng Shen1,2,
  2. Lei Xu1,
  3. Shasha Han1,
  4. Zhen Dong1,
  5. Xiaona Zhao3,
  6. Shaochun Wang4,
  7. Sanli Qian1,
  8. Bingyu Li1,
  9. Xin Ma1,5,
  10. Peng Wang1,
  11. Hong Zhu1,
  12. Yunzeng Zou1,5,
  13. Zheng Fan6,
  14. Junbo Ge1,5,
  15. Aijun Sun1,5
  1. 1 Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, China
  2. 2 Department of Cardiology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
  3. 3 Department of Cardiology, Huadong Hosptial, Fudan University, Shanghai, China
  4. 4 Department of Medical Ultrasound, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
  5. 5 Institute of Biomedical Science, Fudan University, Shanghai, China
  6. 6 Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
  1. Correspondence to Junbo Ge and Dr Aijun Sun, Shanghai Institute of Cardiovasular Disease, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China; jbge{at}, sun.aijun{at}


Background Variants of SCN5A, encoding cardiac sodium channel, have been linked to the development of dilated cardiomyopathy (DCM). We aimed to explore novel SCN5A variants in patients with idiopathic DCM (iDCM) and to identify the distribute characteristics and pathological mechanisms as well as clinical phenotypes associated with the variants in patients with iDCM.

Methods SCN5A exons sequencing was performed inpatients with iDCM (n=90) and two control cohorts (arrhythmias group, n=90, and healthy group, n=195). Clinical characteristics were compared between carriers and non-carriers. We then generated a novel heterozygous knock-in (KI) mouse by homologous recombination. Cardiac function, electrical parameters and histological characteristics were examined at basal or stimulating condition.

Results We found three novel non-synonymous SCN5A variants associated with iDCM, including c.674G>A, c.677C>T, and c.4340T>A. The newly defined iDCM-related variants mainly located in the S4 segment of domain I (DI-S4). Incidence of atrioventricular block was significantly higher in mutant patients with iDCM than in non-carriers. Structural injuries were absent at both basal and stress condition in KI mice carrying c.674G>A (R225Q); however, this variant significantly prolonged PR intervals at baseline without affecting other ECG parameters, which was linked to decreased peak sodium current density in KI cardiomyocytes. Histological analysis of the atrioventricular node did not show any evidences of cell damages.

Conclusion Our results suggest that the iDCM-related SCN5A variants in the DI-S4 could predispose electrical disorders by reducing peak sodium current density.

  • SCN5A
  • DI-S4 variants
  • dilated cardiomyopathy
  • arrhythmias

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  • Contributors AS, JG and ZF conceived and designed this study. CS, LX, SW and ZF collected and analyzed clinical data. CS, SQ and ZF generated and identified KI mice. CS, SH, ZD and XZ performed drug administration and electrocardiographic data acquisition. CS, BL, PW and XM contributed to the histological and immunofluorescent data acquisition. CS, ZF and AS contributed to the figures and statistical analysis. CS, LX and AS wrote the manuscript. YZ, JG and ZF contributed the revision of this manuscript.

  • Funding This work was supported by a grant to AS from the National Natural Science Foundation of China (81570224) and a grant of Innovative Research Groups from the National Natural Science Foundation of China (81521001).

  • Competing interests None declared.

  • Ethics approval The Ethics Committees of Zhongshan Hospital, Fudan University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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