Rare Variants in the SCN5A Promoter and Conserved Noncoding Sequence Associated with Various Arrhythmias

Abstract

Mutations in the coding sequence of SCN5A have been associated with various arrhythmias. However, it is unknown whether variants in the promoter and transcription regulatory regions of SCN5A modulate the risk of arrhythmias. We resequenced the promoter region of SCN5A in 1288 patients with various arrhythmia syndromes. We also resequenced the conserved noncoding sequences（CNS）in intron 1. We identified novel 26 variants in 29 patients. We performed luciferase-reporter assay to elucidate the functional change caused by the rare variants. Six variants revealed decreased promoter activity compared with wild-type sequence. ChIP-Seq analyses revealed that the majority of the promoter variants are located at the regions bound by the transcription factors or active histone marks. We also identified a rare variant in CNS28 in patients with atrial fibrillation. CNS28 includes 3 binding sites for TEF1, a muscle-specific transcription factor, and the variant was predicted to disrupt one of these binding sites. This variant was associated with decreased promoter activity. Variants in the promoter and the transcription regulatory region of SCN5A were identified in the patients with various arrhythmias, which supported the hypothesis that altered SCN5A transcription levels modulate susceptibility to arrhythmias.