TY - JOUR

T1 - Genotype-Phenotype Correlation of SCN5A Genotype in Patients With Brugada Syndrome and Arrhythmic Events

T2 - Insights From the SABRUS in 392 Probands

AU - Milman, Anat

AU - Behr, Elijah R

AU - Gray, Belinda

AU - Johnson, David C

AU - Andorin, Antoine

AU - Hochstadt, Aviram

AU - Gourraud, Jean-Baptiste

AU - Maeda, Shingo

AU - Takahashi, Yoshihide

AU - Jm Juang, Jimmy

AU - Kim, Sung-Hwan

AU - Kamakura, Tsukasa

AU - Aiba, Takeshi

AU - Postema, Pieter G

AU - Mizusawa, Yuka

AU - Denjoy, Isabelle

AU - Giustetto, Carla

AU - Conte, Giulio

AU - Huang, Zhengrong

AU - Sarquella-Brugada, Georgia

AU - Mazzanti, Andrea

AU - Jespersen, Camilla H.

AU - Arbelo, Elena

AU - Brugada, Ramon

AU - Calo, Leonardo

AU - Corrado, Domenico

AU - Casado-Arroyo, Ruben

AU - Allocca, Giuseppe

AU - Takagi, Masahiko

AU - Delise, Pietro

AU - Brugada, Josep

AU - Tfelt-Hansen, Jacob

AU - Priori, Silvia G

AU - Veltmann, Christian

AU - Yan, Gan-Xin

AU - Brugada, Pedro

AU - Gaita, Fiorenzo

AU - Leenhardt, Antoine

AU - Wilde, Arthur A M

AU - Kusano, Kengo F

AU - Nam, Gi-Byoung

AU - Hirao, Kenzo

AU - Probst, Vincent

AU - Belhassen, Bernard

PY - 2021

Y1 - 2021

N2 - BACKGROUND: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event.METHODS: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed.RESULTS: The study group comprised 392 probands: 92 (23.5%) SCN5A+(44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P=0.023). The proportion of females was higher among patients with P/LP compared with SCN5A- (18.2% versus 6.3%, P=0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A- (41.9% versus 16.8%, P<0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P<0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P<0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P=0.009) were independent variables associated with P/LP genotype following logistic regression.CONCLUSIONS: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A-. In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

AB - BACKGROUND: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event.METHODS: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed.RESULTS: The study group comprised 392 probands: 92 (23.5%) SCN5A+(44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P=0.023). The proportion of females was higher among patients with P/LP compared with SCN5A- (18.2% versus 6.3%, P=0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A- (41.9% versus 16.8%, P<0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P<0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P<0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P=0.009) were independent variables associated with P/LP genotype following logistic regression.CONCLUSIONS: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A-. In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

U2 - 10.1161/CIRCGEN.120.003222

DO - 10.1161/CIRCGEN.120.003222

M3 - Journal article

C2 - 34461752

VL - 14

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 2574-8300

IS - 5

M1 - e003222

ER -