The puzzle of genetics in Brugada syndrome: a disease with a high risk of sudden cardiac death in young people.

Ann Palliat Med 2020;9(6):4394-4397 | http://dx.doi. org/10.21037/apm-20-1510 Brugada syndrome (BrS) is an arrhythmia syndrome that carries a high risk of death for sufferers. First reported by Brugada et al. in 1992, BrS is as an inherited cardiac disorder characterized by a distinct electrocardiogram (ECG) pattern. BrS mainly affects young people, with the average age at diagnosis being 40±22 years, and males (1-3), although some old and female BrS patients have also been reported (4-6). Since 1 diagnostic criteria of BrS was published in 2002, the diagnostic criteria for BrS have changed over time (7-11). BrS is currently diagnosed when ST-segment elevation showing type 1 morphology ≥2 mm in ≥1 lead among the leads V1 or V2 positioned in the 2, 3, or 4 intercostal space in 12-lead electrocardiogram, appears spontaneously or after a provocative drug test with administration of class I antiarrhythmic drugs and an assessment of the patient’s clinical presentations and genetic mutations (10). Many clinical conditions, including neuromuscular diseases, electrolyte imbalance or alcohol intoxication, may elicit the ECG patterns of BrS; such cases are referred to as acquired BrS or Brugada phenocopy (12-14). Provocative pharmacological testing with class I sodium channel blockers can be used to differentiate congenital BrS from acquired BrS. Because genetic testing is recommended only for congenital BrS, acquired BrS must be ruled out before a diagnosis of true congenital BrS is made. Although some studies have reported that BrS is an inherited disorder that is mostly autosomal dominant and displays incomplete penetrance, many sporadic BrS cases have been recorded. Priori et al. reported that the overall disease penetrance in 4 small BrS families with mutations in the SCN5A gene was 16%(range, 12.5% to 50%) (15). The gene SCN5A encodes α subunits of the human major cardiac sodium channel (Nav1.5), and it was reported as the first BrS-causal gene in 1998. Defects in the genes encoding for calcium channels and potassium channels have also been linked with BrS phenotype. After two decades, variants in several susceptibility genes have been identified in Sodium Voltage-Gated Channel Alpha Subunit 5 (SCN5A), calcium voltage-gated channel subunit alpha1 C (CACNA1C), calcium channel, voltage-dependent, beta 2 (CACNB2), calcium voltage-gated channel auxiliary subunit alpha2delta 1(CACNA2D1), glycerol-3-phosphate dehydrogenase 1 like (GPD1L), sodium channel beta-1 subunit (SCN1B), sodium voltage-gated channel beta subunit 2 (SCN2B), sodium voltage-gated channel beta subunit 3 (SCN3B), potassium voltage-gated channel subfamily D member 3 (KCND3), potassium voltage-gated channel subfamily E member 3 (KCNE3), potassium voltage-gated channel subfamily D member 5 (KCNE5), potassium voltage-gated channel subfamily J member 8 (KCNJ8), Sodium VoltageGated Channel Alpha Subunit 10 (SCN10A), RAN Guanine Nucleotide Release Factor (RANGRF), plakophilin-2 (PKP2), potassium voltage-gated channel subfamily B member 2 (KCNB2), and Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2), accounting for less than 30% of BrS cases (3,16,17). However, in approximately 70% of BrS patients, the genes that caused their disease are unknown. Large geographic differences have been reported, not Editorial Commentary