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Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia
- Source :
- Molecular Genetics and Genomics. 294:1059-1071
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Ventricular tachycardia (VT) causes sudden cardiac death, however, the majority of risk genes for VT remain unknown. SCN4B encodes a β-subunit, Na(v)β4, 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 Na(v)β4. 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.
- Subjects :
- Adult
Male
0106 biological sciences
0301 basic medicine
Nonsynonymous substitution
medicine.medical_specialty
Population
Down-Regulation
Biology
Ventricular tachycardia
01 natural sciences
Article
Sudden cardiac death
03 medical and health sciences
symbols.namesake
Internal medicine
Genetics
medicine
Humans
Genetic Predisposition to Disease
education
Molecular Biology
Genetic Association Studies
Aged
Genetic association
Sanger sequencing
education.field_of_study
Voltage-Gated Sodium Channel beta-4 Subunit
Sequence Analysis, DNA
General Medicine
Odds ratio
Middle Aged
medicine.disease
HEK293 Cells
030104 developmental biology
Amino Acid Substitution
Case-Control Studies
Sodium channel complex
Tachycardia, Ventricular
Cardiology
symbols
Female
010606 plant biology & botany
Subjects
Details
- ISSN :
- 16174623 and 16174615
- Volume :
- 294
- Database :
- OpenAIRE
- Journal :
- Molecular Genetics and Genomics
- Accession number :
- edsair.doi.dedup.....ff272998f13337cea7cdacfa89a26b8c