Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Epidemiology

Background:

• Mutations in SCN5A, encoding the cardiac sodium channel alpha subunit, are linked to inherited arrhythmias.
• The role of SCN5A promoter and regulatory variants in arrhythmia susceptibility remains unclear.

Purpose of the Study:

• To investigate whether variants in SCN5A promoter and regulatory regions contribute to arrhythmia risk.
• To identify and functionally characterize novel SCN5A variants associated with various cardiac arrhythmias.

Main Methods:

• Resequencing of SCN5A core promoter and regulatory regions in 1298 patients with diverse arrhythmia phenotypes.
• Identification of rare variants and analysis of their frequency compared to controls.
• Functional characterization of variants using luciferase reporter assays and alignment with ChIP-sequencing data.

Main Results:

• 26 novel rare variants were identified in the SCN5A promoter of 29 patients with arrhythmias.
• The frequency of rare SCN5A variants was higher in patients than in controls.
• Six functionally characterized variants demonstrated decreased promoter activity, and one regulatory variant also reduced promoter activity.

Conclusions:

• Variants in SCN5A promoter and regulatory regions are associated with multiple arrhythmia phenotypes.
• Altered SCN5A transcription levels due to these variants likely modulate susceptibility to cardiac arrhythmias.