Case Report: A Novel Variant c.2262+3A>T of the Gene Results in Intron Retention Associated With Incessant Ventricular Tachycardias.

Voltage-gated sodium channel Na1.5 encoded by the gene plays crucial roles in cardiac electrophysiology. Previous genetic studies have shown that mutations in are associated with multiple inherited cardiac arrhythmias. Here, we investigated the molecular defect in a Chinese boy with clinical manifestations of arrhythmias. Gene variations were screened using whole-exome sequencing and validated by direct Sanger sequencing. A minigene assay and reverse transcription PCR (RT-PCR) were performed to confirm the effects of splice variants . Western blot analysis was carried out to determine whether the c.2262+3A>T variant produced a truncated protein. By genetic analysis, we identified a novel splice variant c.2262+3A>T in gene in a Chinese boy with incessant ventricular tachycardias (VT). This variant was predicted to activate a new cryptic splice donor site and was identified by analysis. The variant retained 79 bp at the 5' end of intron 14 in the mature mRNA. Furthermore, the mutant transcript that created a premature stop codon at 818 amino acids [p.(R818)] could be produced as a truncated protein. We verified the pathogenic effect of splicing variant c.2262+3A>T, which disturbed the normal mRNA splicing and caused a truncated protein, suggesting that splice variants play an important role in the molecular basis of early onset incessant ventricular tachycardias, and careful molecular profiling of these patients will be essential for future effective personalized treatment options.