Brugada syndrome: variability of clinical and genetic characteristics
Authors: Komissarova Svetlana M. , Chakova Natalia N. , Rineiska Nadiia M. , Niyazova Svetlana S. , Dolmatovich Tatyana V. , Barsukevich Veronika C. , Plashchinskaya Larisa I. 
Published: April 2024

AIM: To evaluate the clinical characteristics of patients with diverse genetic variants of Brugada syndrome.
MATERIALS AND METHODS: 24 patients (17 male and 7 female) aged 18 to 55 years (median age 32.5 [20; 42] years) with a pattern of Brugada syndrome on electrocardiogram were observed for 3 years. From their ECGs, a type 1 pattern was found in 9 (37.5%) of these patients, type 2 pattern in 14 (58.3%) and type 3 pattern only in 1 patient. The clinical and instrumental study included 12-lead electrocardiogram, 24-hour Holter electrocardiogram monitoring, provocative drug test with intravenous administration of sodium channel blockers (novocainamide), electrophysiologic study according to indications, genealogical history collection and family history of sudden cardiac death, transthoracic echocardiography and cardiac magnetic resonance imaging to detect structural myocardial changes. High-throughput sequencing was utilized to search for mutations in genes linked to the onset of channelopathies and other inherited rhythm disorders.
RESULTS: In 15 (62.5%) of the 24 probands included in the study, variants of the nucleotide sequence of pathogenicity classes III–V according to The American College of Medical Genetics and Genomics criteria (2015) were found in genes encoding sodium (SCN5A, SCN10A) and potassium (KCNE3, KCNJ2, KCNJ8, KCNA5) channels, as well as in HCN4 and SNTA1 genes linked with these channels. Moreover, 3 variants were identified in ANK2 gene associated with ankyrinopathies, and 3 variants in DSP and DES genes connected with arrhythmogenic right ventricular cardiomyopathy. Four genetic variants in SCN5A gene were of pathogenicity classes IV and V, the rest were variants of uncertain clinical significance (class III). Six (40.0%) of the 15 genotype-positive patients had several genetic variants. The most severe form of the disease, manifested by the development of ventricular fibrillation with successful resuscitation and subsequent cardioverter-defibrillator implantation, was observed in patients with mutations in SCN5A, SCN10A genes. Recurrent syncope, polymorphic ventricular tachycardia induced by programmed ventricular stimulation during electrophysiologic study, followed by cardioverter-defibrillator implantation were observed in patients with variants KCNJ8 and HCN4, DES and MYH11. In 2 patients with clinical manifestations, no mutations were identified. 13 (54.2%) patients were asymptomatic, while 3 of them had pathogenic and likely pathogenic mutations in SCN5A gene, as well as variants of uncertain clinical significance.
CONCLUSION: Thus, this study examined various genetic variants in patients with Brugada syndrome based on their clinical manifestation. The impact of the genotype on the Brugada syndrome phenotype is not unambiguous. The most severe form of the disease with the development of ventricular fibrillation and successful resuscitation with subsequent cardioverter-defibrillator implantation was observed mainly in patients with variants in several genes (SCN5A and JUP, KCNJ8 and HCN4, DES and MYH11). This substantiate the idea that Brugada syndrome, along with monogenic, may also have a polygenic nature of the disease, in which the clinical phenotype is determined by variants in respective genes linked to the onset of cardiovascular disorders.