High risk for bradyarrhythmic complications in patients with brugada syndrome caused by SCN5A gene mutations

• Published in: Journal of the American College of Cardiology 2005-12, Vol.46 (11), p.2100-2106
• Main Authors: MAKIYAMA, Takeru, AKAO, Masaharu, MAKITA, Naomasa, YANAGISAWA, Fumiko, HIGASHI, Yukei, TAKEYAMA, Youichi, KITA, Toru, HORIE, Minoru, TSUJI, Keiko, DOI, Takahiro, OHNO, Seiko, TAKENAKA, Kotoe, KOBORI, Atsushi, NINOMIYA, Tomonori, YOSHIDA, Hidetada, TAKANO, Makoto
• Format: Article
• Language: English
• Subjects: Adult; Aged; Asian Continental Ancestry Group - genetics; Biological and medical sciences; Bradycardia - complications; Bradycardia - genetics; Bundle-Branch Block - complications; Bundle-Branch Block - genetics; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Chromatography, High Pressure Liquid; Codon, Nonsense; DNA Mutational Analysis; Electrocardiography; Female; Frameshift Mutation; Heart; Heart attacks; Humans; Male; Medical sciences; Middle Aged; Mutagenesis, Site-Directed; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Sodium Channels - genetics; Syndrome
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2005.08.043

We carried out a complete screening of the SCN5A gene in 38 Japanese patients with Brugada syndrome to investigate the genotype-phenotype relationship. 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. 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. 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. Our findings suggest that loss-of-function SCN5A mutations resulting in Brugada syndrome are distinguished by profound bradyarrhythmias.