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Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia

Molecular Genetics and Genomics volume 294, pages 1059–1071 (2019)Cite this article

Abstract

Ventricular tachycardia (VT) causes sudden cardiac death, however, the majority of risk genes for VT remain unknown. SCN4B encodes a β-subunit, Navβ4, for the voltage-gated cardiac sodium channel complex involved in generation and conduction of the cardiac action potential. We hypothesized that genomic variants in SCN4B increase the risk of VT. We used high-resolution melt analysis followed by Sanger sequencing to screen 199 VT patients to identify nonsynonymous variants in SCN4B. Two nonsynonymous heterozygous variants in SCN4B were identified in VT patients, including p.Gly8Ser in four VT patients and p.Ala145Ser in one VT patient. Case–control association studies were used to assess the association between variant p.Gly8Ser and VT in two independent populations for VT (299 VT cases vs. 981 controls in population 1 and 270 VT patients vs. 639 controls in population 2). Significant association was identified between p.Gly8Ser and VT in population 1 (P = 1.21 × 10−4, odds ratio or OR = 11.04), and the finding was confirmed in population 2 (P = 0.03, OR = 3.62). The association remained highly significant in the combined population (P = 3.09 × 10−5, OR = 6.17). Significant association was also identified between p.Gly8Ser and idiopathic VT (P = 1.89 × 10−5, OR = 7.27). Functional analysis with Western blotting showed that both p.Gly8Ser and p.Ala145Ser variants significantly reduced the expression level of Navβ4. Based on 2015 ACMG Standards and Guidelines, p.Gly8Ser and p.Ala145Ser can be classified as the pathogenic and likely pathogenic variant, respectively. Our data suggest that SCN4B is a susceptibility gene for common VT and idiopathic VT and link rare SCN4B variants with large effects (OR = 6.17–7.27) to common VT.

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Abbreviations

VT:

Ventricular tachycardia

SNP:

Single nucleotide polymorphism

LQTS:

Long QT syndrome

BrS:

Brugada syndrome

GWAS:

Genome-wide association studies

MI:

Myocardial infarction

VF:

Ventricular fibrillation

ECG:

Electrocardiogram

AF:

Atrial fibrillation

CT:

Computed tomography

PCR:

Polymerase chain reaction

HRM:

High resolution melt analysis

OR:

Odds ratio

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Acknowledgements

We thank the study participants for their invaluable support of this study, and other members of the GeneID team members for assistance. This work was supported by the National Natural Science Foundation of China Grants (81630002, 31430047 and 81600263) (C.X. and P.W.), Hubei Province’s Innovative Team Grant (2017CFA014) (X.C.), and NIH/NHLBI grant R01 HL126729 (Q.K.W.).

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Author notes

  1. Qin Yang, Hongbo Xiong, Chengqi Xu, Yuan Huang, and Xin Tu contributed equally to this work.

Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China

    Qin Yang

  2. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, 430074, People’s Republic of China

    Qin Yang, Hongbo Xiong, Chengqi Xu, Yuan Huang, Xin Tu, Fenfen Fu, Zhijie Wang, Longfei Wang, Yuanyuan Zhao, Sisi Li, Yufeng Huang, Dan Wang, Yufeng Yao, Fan Wang, Yongbo Wang, Yu Xue, Pengyun Wang & Qing K. Wang

  3. Renmin Hospital, Wuhan University, Wuhan, People’s Republic of China

    Gang Wu

  4. School of Life Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, People’s Republic of China

    Chuchu Wang

  5. Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Qiuyun Chen & Qing K. Wang

  6. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA

    Qiuyun Chen & Qing K. Wang

  7. Department of Cardiology, East Hospital, Tongji University, Shanghai, Beijing, 100037, People’s Republic of China

    Jielin Pu

  8. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Qing K. Wang

  9. Tongji University Affiliated East Hospital, Beijing, 100037, People’s Republic of China

    Jielin Pu

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  1. Qin Yang
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  2. Hongbo Xiong
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  6. Gang Wu
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  20. Qiuyun Chen
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  22. Qing K. Wang
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Correspondence to Qiuyun Chen, Jielin Pu or Qing K. Wang.

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Yang, Q., Xiong, H., Xu, C. et al. Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia. Mol Genet Genomics 294, 1059–1071 (2019). https://doi.org/10.1007/s00438-019-01567-7

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Keywords

  • Single nucleotide polymorphism (SNP)
  • Ventricular tachycardia (VT)
  • Cardiac sodium channel β4 subunit (SCN4B, Navβ4)
  • SCN5A/Nav1.5
  • Genetics