br Other candidate genes br
Other candidate genes
The frequency of minor gene mutations in BrS As mentioned above, more than 10 genes have been reported to cause BrS. The proportions of BrS patients who are mutation carriers, however, are very small, except in the case of SCN5A. In a recent extensive mutation analysis of 129 BrS1 through BrS12 patients , 27 patients had a putative pathogenic mutation (21 patients with an SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a mutation in KCNJ8, KCND3, SCN1Bb, and HCN4) .
Other types of mutations in BrS patients Generally, mutation analysis is performed by PCR-based direct sequencing. However, the method has been known to fail in detecting large-scale rearrangements of genes. In a 14-year-old BrS patient, a everolimus of exon 9 and 10 in the SCN5A gene was identified using multiplex ligation-dependent probe amplification (MLPA) methods . In another cohort of 76 BrS patients screened for SCN5A mutations , no patient carried a large insertion/deletion abnormality. The frequency of large-scale gene rearrangements of SCN5A seems to be low; however, we have to keep in mind the limitations of direct sequencing methods, including next-generation sequencing methods, for detecting mutations.
Conclusion In the past 2 decades, an increasing number of mutations in over 10 genes have been reported in patients with BrS. With the exception of SCN5A-related BrS, the genotype–phenotype relations have not been completely characterized, likely due to the availability of a relatively small number of genotyped families. With regard to SCN5A-related BrS, although originally thought of as a separate disease entity, various arrhythmias are concurrently associated with SCN5A mutations (overlap syndromes). In the clinical setting, this particular finding may help in the diagnosis of SCN5A-related arrhythmia syndrome.
Conflict of interest
Acknowledgments This work was supported by research Grants from the Ministry of Education, Culture, Science and Technology of Japan; Health Science Research Grants from the Ministry of Health, Labor and Welfare of Japan for Clinical Research on Measures for Intractable Diseases; and the Translational Research Funds from the Japan Circulation Society.
Introduction Brugada syndrome (BrS) is a distinct form of idiopathic ventricular fibrillation (VF) characterized by a unique electrocardiography (ECG) pattern consisting of ST-segment elevation in right precordial leads with right bundle branch block-like morphology . BrS is estimated to be responsible for at least 4% of all sudden deaths and at least 20% of sudden deaths in patients with structurally normal hearts . VF usually occurs spontaneously at night, and the prevalence of BrS has been reported to be much higher in East/Southeast Asia [3,4]. “Pokkuri Death Syndrome” in Japan, “Lai Tai” in Thailand, “Bangungut” in the Philippines, “Dream Disease” in Hawaii, and “Sudden Unexplained Nocturnal Death Syndrome (SUNDS)” among south Asian immigrants in the United States of America (USA) are now thought to be the same disease as BrS.
Classification and diagnosis There are 3 types of ST-segment elevation in right precordial leads. A type 1 ECG pattern is diagnostic of BrS and shows pronounced elevation of the J point and coved-type ST-segment elevation ≥2mm (0.2mV) followed by an inverted T wave (Fig. 1). A type 2 ECG pattern consists of saddleback-type ST-segment elevation of ≥2mm (0.2mV) followed by either a positive or biphasic T wave. A type 3 ECG pattern shows either saddleback- or coved-type ST-segment elevation <1mm (0.1mV) . The diagnosis of BrS is confirmed by a type 1 ECG pattern in conjunction with one of the following: documented VF, self-terminating polymorphic ventricular tachycardia, a family history of sudden cardiac death, coved-type ECG in family members, VF inducibility during electrophysiological study, and syncope or nocturnal agonal respiration. Type 2 and type 3 ECG patterns are not diagnostic of BrS; however, the ST segment is usually highly dynamic in BrS, exhibiting profound day-to-day and beat-to-beat amplitude variation (Fig. 2) . Therefore, a pharmacological challenge test using a class Ia/Ic sodium channel blocker (ajmaline, flecainide, procainamide, or pilsicainide: the most widely used drugs in Japan at a dose of 1mg/kg over a 6-min period [7,8]) is sometimes required for the diagnosis of BrS in patients with a type 2 or 3 ECG pattern . Typical ST-segment elevation is often observed in the cranial position of V1 and V2 in the third or second intercostal space, as demonstrated by body surface mapping [9,10]. These observations strongly indicate that right ventricular outflow tract (RVOT) abnormalities are associated with the ECG signature in BrS .