High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations.
OBJECTIVE
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.
Makiyama
Takeru
T
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Akao
Masaharu
M
Tsuji
Keiko
K
Doi
Takahiro
T
Ohno
Seiko
S
Takenaka
Kotoe
K
Kobori
Atsushi
A
Ninomiya
Tomonori
T
Yoshida
Hidetada
H
Takano
Makoto
M
Makita
Naomasa
N
Yanagisawa
Fumiko
F
Higashi
Yukei
Y
Takeyama
Youichi
Y
Kita
Toru
T
Horie
Minoru
M
D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D001919:Bradycardia / Q000150:complications* / Q000235:genetics*; D002037:Bundle-Branch Block / Q000150:complications* / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome
D018389:Codon, Nonsense; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels