Referenced in: none

Automatically associated channels: Nav1.5

Title: High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations.

Authors: Takeru Makiyama, Masaharu Akao, Keiko Tsuji, Takahiro Doi, Seiko Ohno, Kotoe Takenaka, Atsushi Kobori, Tomonori Ninomiya, Hidetada Yoshida, Makoto Takano, Naomasa Makita, Fumiko Yanagisawa, Yukei Higashi, Youichi Takeyama, Toru Kita, Minoru Horie

Journal, date & volume: J. Am. Coll. Cardiol., 2005 Dec 6 , 46, 2100-6

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16325048

Abstract
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.