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

  • Qin Yang
  • Hongbo Xiong
  • Chengqi Xu
  • Yuan Huang
  • Xin Tu
  • Gang Wu
  • Fenfen Fu
  • Zhijie Wang
  • Longfei Wang
  • Yuanyuan Zhao
  • Sisi Li
  • Yufeng Huang
  • Chuchu Wang
  • Dan Wang
  • Yufeng Yao
  • Fan Wang
  • Yongbo Wang
  • Yu Xue
  • Pengyun Wang
  • Qiuyun ChenEmail author
  • Jielin PuEmail author
  • Qing K. WangEmail author
Original Article
  • 85 Downloads

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.

Keywords

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

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

Notes

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.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the ethics committee on human subject research at Huazhong University of Science and Technology and local hospitals.

Informed consent

Informed consent was obtained from all participants for whom identifying information is included in this article.

Supplementary material

438_2019_1567_MOESM1_ESM.docx (464 kb)
Supplementary material 1 (DOCX 464 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Qin Yang
    • 1
    • 2
  • Hongbo Xiong
    • 2
  • Chengqi Xu
    • 2
  • Yuan Huang
    • 2
  • Xin Tu
    • 2
  • Gang Wu
    • 3
  • Fenfen Fu
    • 2
  • Zhijie Wang
    • 2
  • Longfei Wang
    • 2
  • Yuanyuan Zhao
    • 2
  • Sisi Li
    • 2
  • Yufeng Huang
    • 2
  • Chuchu Wang
    • 4
  • Dan Wang
    • 2
  • Yufeng Yao
    • 2
  • Fan Wang
    • 2
  • Yongbo Wang
    • 2
  • Yu Xue
    • 2
  • Pengyun Wang
    • 2
  • Qiuyun Chen
    • 5
    • 6
    Email author
  • Jielin Pu
    • 7
    • 9
    Email author
  • Qing K. Wang
    • 2
    • 5
    • 6
    • 8
    Email author
  1. 1.State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople’s Republic of China
  2. 2.Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome ResearchHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  3. 3.Renmin Hospital, Wuhan UniversityWuhanPeople’s Republic of China
  4. 4.School of Life SciencesZhengzhou UniversityZhengzhouPeople’s Republic of China
  5. 5.Department of Cardiovascular and Metabolic SciencesLerner Research Institute, Cleveland ClinicClevelandUSA
  6. 6.Department of Molecular MedicineCleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityClevelandUSA
  7. 7.Department of CardiologyEast Hospital, Tongji UniversityBeijingPeople’s Republic of China
  8. 8.Department of Genetics and Genome SciencesCase Western Reserve University School of MedicineClevelandUSA
  9. 9.Tongji University Affiliated East HospitalBeijingPeople’s Republic of China

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