Identification of Six Novel SCN5A Mutations in Japanese Patients With Brugada Syndrome

Abstract

SummaryMutations in SCN5A are linked to Brugada syndrome in approximately 20% of all cases (BrS1). Several dozen distinct SCN5A mutations in BrS1 have been associated with the increased risk of cardiac arrhythmias. However, the genotype-phenotype relationship remains elusive. The current study analyzed the SCN5A gene to elucidate the potential variability of clinical features in Japanese BrS1 subjects. Subjects of the present study included 30 probands (25 male subjects, 45 ± 15 years of age) with Brugada-pattern ECG. Seven patients had been resuscitated from cardiopulmonary arrest (CPA group). Another 10 patients had a history of syncope (Sy group), and 13 more remain asymptomatic (Asy group). We identified 8 different SCN5A mutations, including 6 novel mutations (CPA group: 1/7, Sy group: 3/10, Asy group: 4/13). An A735E mutation (located at segment (S)1 in domain (D)2) was identified in the CPA group. A novel splice acceptor site mutation (c.393-1c>t), which may produce a prematurely truncated protein, was identified in the Sy group. An E1784K mutation (C-terminus) and a novel mutation V1951M (C-terminus) were also identified in the Sy group. Four novel missense mutations, A586T (D1-D2 linker), R689H (D1-D2 linker), S1553R (S1-S2 in D4), and Q1706H (S5-Pore in D4) were identified in the Asy group. These data may help us understand the genetic heterogeneity of BrS1, which is more prevalent in Japanese than in whites and other ethnic groups. (Int Heart J 2011; 52: 27-31) Key words: Brugada syndrome, SCN5A, Mutation T he Brugada syndrome (BrS), characterized by ST-segment elevations in the right precordial ECG leads without structural heart disease, is a hereditable disease associated with an increased risk of sudden death due to polymorphic ventricular tachycardia or ventricular fibrillation (VF).1) Genetic analyses of BrS revealed that BrS is genetically heterogeneous, and is linked to at least 7 different genes. [2][3][4][5][6][7][8] Mutations in SCN5A, which encodes the pore-forming subunit of the cardiac voltage-gated sodium channel, have been associated with the major form of BrS (BrS1) in approximately 20% of cases. [9][10][11] The clinical severity of BrS may vary with the responsible genes and/or mutation sites, although the genotypephenotype relationship remains poorly characterized. The presence of SCN5A mutations is not related to the severity of the disease.9,10,12) However, Meregalli, et al have recently reported that the type of SCN5A mutation in BrS1 in European countries may determine the clinical severity.13) Because the clinical features of BrS vary among different ethnicities, 14,15) it is of great value to investigate the genotype-phenotype relationship of BrS in Asians in whom the ratio of BrS patients is relatively high compared to subjects from different ethnic backgrounds.In the present study, we analyzed the SCN5A gene to elucidate the potential variability of clinical features of BrS1 subjects recruited from Gunma University Hospital. Consequently, we identified 8 SCN5A mutations, incl...

Compound and Digenic Heterozygosity in Desmosome Genes as a Cause of Arrhythmogenic Right Ventricular Cardiomyopathy in Japanese Patients

“…All coding exons of desmosome genes (JUP, DSP, PKP2, DSG2, and DSC2) and their splice sites were amplified by polymerase chain reaction (PCR) using primers flanking the intronic sequences as reported previously. 15 The PCR products were purified and directly sequenced using an ABI PRISM 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). The rare variants were analyzed at least twice by independent PCR amplification and sequencing.…”

The global distribution of the p.R1193Q polymorphism in the SCN5A gene

“…The p.R1193Q substitution was previously shown to accelerate inactivation of the sodium channel current [5]. This substitution has been identified in patients with Brugada syndrome [5,6] and long QT syndrome [4,7]. The p.R1193Q substitution has been characterized functionally as either a "loss-of-function" variant consistent with Brugada syndrome [5], or as a "gain-of-function" variant consistent with previously defined long QT syndrome type 3 [4].…”

An autopsy case of sudden unexpected nocturnal death syndrome with R1193Q polymorphism in the SCN5A gene

“…It was reported that the R1193Q substitution accelerates the inactivation of the sodium channel current [4]. The R1193Q substitution was identified in patients with Brugada syndrome [4,9] and long QT syndrome [8,10]. The R1193Q substitution has been characterized functionally as either a ''loss of function'' variant consistent with Brugada syndrome [4], or a ''gain of function'' variant consistent with previously defined long QT syndrome type 3-causing substitution [8].…”