Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia
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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.
KeywordsSingle nucleotide polymorphism (SNP) Ventricular tachycardia (VT) Cardiac sodium channel β4 subunit (SCN4B, Navβ4) SCN5A/Nav1.5 Genetics
Single nucleotide polymorphism
Long QT syndrome
Genome-wide association studies
Polymerase chain reaction
High resolution melt analysis
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.
This study was approved by the ethics committee on human subject research at Huazhong University of Science and Technology and local hospitals.
Informed consent was obtained from all participants for whom identifying information is included in this article.
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