OBJECTIVES: We carried out a complete screening of the SCN5A gene in 38 Japanese 
patients with Brugada syndrome to investigate the genotype-phenotype 
relationship.
BACKGROUND: The gene SCN5A encodes the pore-forming alpha-subunit of 
voltage-gated cardiac sodium (Na) channel, which plays an important role in 
heart excitation/contraction. Mutations of SCN5A have been identified in 15% of 
patients with Brugada syndrome.
METHODS: In 38 unrelated patients with clinically diagnosed Brugada syndrome, we 
screened for SCN5A gene mutations using denaturing high-performance liquid 
chromatography and direct sequencing, and conducted a functional assay for 
identified mutations using whole-cell patch-clamp in heterologous expression 
system.
RESULTS: Four heterozygous mutations were identified (T187I, D356N, K1578fs/52, 
and R1623X) in 4 of the 38 patients. All of them had bradyarrhythmic 
complications: three with sick sinus syndrome (SSS) and the other (D356N) with 
paroxysmal complete atrioventricular block. SCN5A-linked Brugada patients were 
associated with a higher incidence of bradyarrhythmia (4 of 4) than 
non-SCN5A-linked Brugada patients (2 of 34). Families with T187I and K1578fs/52 
had widespread penetrance of SSS. Notably, the patient with K1578fs/52, who had 
been diagnosed as having familial SSS without any clinical signs of Brugada 
syndrome, showed a Brugada-type ST-segment elevation after intravenous 
administration of pilsicainide and programmed electrical stimulation-induced 
ventricular tachycardia. All of the mutations encoded non-functional Na 
channels, and thus were suggested to cause impulse propagation defect underlying 
bradyarrhythmias.
CONCLUSIONS: Our findings suggest that loss-of-function SCN5A mutations 
resulting in Brugada syndrome are distinguished by profound bradyarrhythmias.