Genetic testing in children with Brugada syndrome: results from a large prospective registry

Luigi Pannone; Antonio Bisignani; Randy Osei; Anaïs Gauthey; Antonio Sorgente; Pasquale Vergara; Cinzia Monaco; Domenico Giovanni Della Rocca; Alvise Del Monte; Antanas Strazdas; Joerelle Mojica; Maysam Al Housari; Vincenzo Miraglia; Sahar Mouram; Gaetano Paparella; Robbert Ramak; Ingrid Overeinder; Gezim Bala; Alexandre Almorad; Erwin Ströker; Gudrun Pappaert; Juan Sieira; Thomy de Ravel; Mark La Meir; Pedro Brugada; Gian Battista Chierchia; Sonia Van Dooren; Carlo de Asmundis

doi:10.1093/europace/euad079

Genetic testing in children with Brugada syndrome: results from a large prospective registry

Luigi Pannone, Antonio Bisignani, Randy Osei, Anaïs Gauthey, Antonio Sorgente, Pasquale Vergara, Cinzia Monaco, Domenico Giovanni Della Rocca, Alvise Del Monte, Antanas Strazdas, Joerelle Mojica, Maysam Al Housari, Vincenzo Miraglia, Sahar Mouram, Gaetano Paparella, Robbert Ramak, Ingrid Overeinder, Gezim Bala, Alexandre Almorad, Erwin StrökerGudrun Pappaert, Juan Sieira, Thomy de Ravel, Mark La Meir, Pedro Brugada, Gian Battista Chierchia, Sonia Van Dooren, Carlo de Asmundis

Research output: Contribution to journal › Article › peer-review

Abstract

AIMS: A pathogenic/likely pathogenic (P/LP) variant in SCN5A is found in 20-25% of patients with Brugada syndrome (BrS). However, the diagnostic yield and prognosis of gene panel testing in paediatric BrS is unclear. The aim of this study is to define the diagnostic yield and outcomes of SCN5A gene testing with ACMG variant classification in paediatric BrS patients compared with adults.

METHODS AND RESULTS: All consecutive patients diagnosed with BrS, between 1992 and 2022, were prospectively enrolled in the UZ Brussel BrS registry. Inclusion criteria were: (i) BrS diagnosis; (ii) genetic analysis performed with a large gene panel; and (iii) classification of gene variants following ACMG guidelines. Paediatric patients were defined as ≤16 years of age. The primary endpoint was ventricular arrhythmias (VAs). A total of 500 BrS patients were included, with 63 paediatric patients and 437 adult patients. Among children with BrS, 29 patients (46%) had a P/LP variant (P+) in SCN5A and no variants were found in 34 (54%) patients (P-). After a mean follow-up of 125.9 months, 8 children (12.7%) experienced a VA, treated with implanted cardioverter defibrillator shock. At survival analysis, P- paediatric patients had higher VA-free survival during the follow-up, compared with P+ paediatric patients. P+ status was an independent predictor of VA. There was no difference in VA-free survival between paediatric and adult BrS patients for both P- and P+.

CONCLUSION: In a large BrS cohort, the diagnostic yield for P/LP variants in the paediatric population is 46%. P+ children with BrS have a worse arrhythmic prognosis.

Original language	English
Number of pages	10
Journal	Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology
Volume	25
Issue number	5
Early online date	16 Apr 2023
DOIs	https://doi.org/10.1093/europace/euad079
Publication status	Published - 2023

Keywords

Brugada syndrome
Genetics
SCN5A
Sudden cardiac death
Ventricular arrhythmias

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Pannone, L., Bisignani, A., Osei, R., Gauthey, A., Sorgente, A., Vergara, P., Monaco, C., Della Rocca, D. G., Del Monte, A., Strazdas, A., Mojica, J., Al Housari, M., Miraglia, V., Mouram, S., Paparella, G., Ramak, R., Overeinder, I., Bala, G., Almorad, A., ... de Asmundis, C. (2023). Genetic testing in children with Brugada syndrome: results from a large prospective registry. Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology, 25(5). https://doi.org/10.1093/europace/euad079

Pannone, Luigi ; Bisignani, Antonio ; Osei, Randy ; Gauthey, Anaïs ; Sorgente, Antonio ; Vergara, Pasquale ; Monaco, Cinzia ; Della Rocca, Domenico Giovanni ; Del Monte, Alvise ; Strazdas, Antanas ; Mojica, Joerelle ; Al Housari, Maysam ; Miraglia, Vincenzo ; Mouram, Sahar ; Paparella, Gaetano ; Ramak, Robbert ; Overeinder, Ingrid ; Bala, Gezim ; Almorad, Alexandre ; Ströker, Erwin ; Pappaert, Gudrun ; Sieira, Juan ; de Ravel, Thomy ; La Meir, Mark ; Brugada, Pedro ; Chierchia, Gian Battista ; Van Dooren, Sonia ; de Asmundis, Carlo. / Genetic testing in children with Brugada syndrome : results from a large prospective registry. In: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2023 ; Vol. 25, No. 5.

@article{0d168fc8cd5e446a82ffcf6d8e916ca6,

title = "Genetic testing in children with Brugada syndrome: results from a large prospective registry",

abstract = "AIMS: A pathogenic/likely pathogenic (P/LP) variant in SCN5A is found in 20-25% of patients with Brugada syndrome (BrS). However, the diagnostic yield and prognosis of gene panel testing in paediatric BrS is unclear. The aim of this study is to define the diagnostic yield and outcomes of SCN5A gene testing with ACMG variant classification in paediatric BrS patients compared with adults.METHODS AND RESULTS: All consecutive patients diagnosed with BrS, between 1992 and 2022, were prospectively enrolled in the UZ Brussel BrS registry. Inclusion criteria were: (i) BrS diagnosis; (ii) genetic analysis performed with a large gene panel; and (iii) classification of gene variants following ACMG guidelines. Paediatric patients were defined as ≤16 years of age. The primary endpoint was ventricular arrhythmias (VAs). A total of 500 BrS patients were included, with 63 paediatric patients and 437 adult patients. Among children with BrS, 29 patients (46%) had a P/LP variant (P+) in SCN5A and no variants were found in 34 (54%) patients (P-). After a mean follow-up of 125.9 months, 8 children (12.7%) experienced a VA, treated with implanted cardioverter defibrillator shock. At survival analysis, P- paediatric patients had higher VA-free survival during the follow-up, compared with P+ paediatric patients. P+ status was an independent predictor of VA. There was no difference in VA-free survival between paediatric and adult BrS patients for both P- and P+.CONCLUSION: In a large BrS cohort, the diagnostic yield for P/LP variants in the paediatric population is 46%. P+ children with BrS have a worse arrhythmic prognosis.",

keywords = "Brugada syndrome, Genetics, SCN5A, Sudden cardiac death, Ventricular arrhythmias",

author = "Luigi Pannone and Antonio Bisignani and Randy Osei and Ana{\"i}s Gauthey and Antonio Sorgente and Pasquale Vergara and Cinzia Monaco and {Della Rocca}, {Domenico Giovanni} and {Del Monte}, Alvise and Antanas Strazdas and Joerelle Mojica and {Al Housari}, Maysam and Vincenzo Miraglia and Sahar Mouram and Gaetano Paparella and Robbert Ramak and Ingrid Overeinder and Gezim Bala and Alexandre Almorad and Erwin Str{\"o}ker and Gudrun Pappaert and Juan Sieira and {de Ravel}, Thomy and {La Meir}, Mark and Pedro Brugada and Chierchia, {Gian Battista} and {Van Dooren}, Sonia and {de Asmundis}, Carlo",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2023",

doi = "10.1093/europace/euad079",

language = "English",

volume = "25",

journal = "Europace",

issn = "1099-5129",

publisher = "Oxford University Press",

number = "5",

}

Genetic testing in children with Brugada syndrome : results from a large prospective registry. / Pannone, Luigi; Bisignani, Antonio; Osei, Randy; Gauthey, Anaïs; Sorgente, Antonio ; Vergara, Pasquale ; Monaco, Cinzia ; Della Rocca, Domenico Giovanni ; Del Monte, Alvise ; Strazdas, Antanas; Mojica, Joerelle; Al Housari, Maysam; Miraglia, Vincenzo; Mouram, Sahar ; Paparella, Gaetano; Ramak, Robbert; Overeinder, Ingrid ; Bala, Gezim ; Almorad, Alexandre ; Ströker, Erwin ; Pappaert, Gudrun; Sieira, Juan; de Ravel, Thomy ; La Meir, Mark ; Brugada, Pedro ; Chierchia, Gian Battista ; Van Dooren, Sonia ; de Asmundis, Carlo.

In: Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology, Vol. 25, No. 5, 2023.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genetic testing in children with Brugada syndrome

T2 - results from a large prospective registry

AU - Pannone, Luigi

AU - Bisignani, Antonio

AU - Osei, Randy

AU - Gauthey, Anaïs

AU - Sorgente, Antonio

AU - Vergara, Pasquale

AU - Monaco, Cinzia

AU - Della Rocca, Domenico Giovanni

AU - Del Monte, Alvise

AU - Strazdas, Antanas

AU - Mojica, Joerelle

AU - Al Housari, Maysam

AU - Miraglia, Vincenzo

AU - Mouram, Sahar

AU - Paparella, Gaetano

AU - Ramak, Robbert

AU - Overeinder, Ingrid

AU - Bala, Gezim

AU - Almorad, Alexandre

AU - Ströker, Erwin

AU - Pappaert, Gudrun

AU - Sieira, Juan

AU - de Ravel, Thomy

AU - La Meir, Mark

AU - Brugada, Pedro

AU - Chierchia, Gian Battista

AU - Van Dooren, Sonia

AU - de Asmundis, Carlo

PY - 2023

Y1 - 2023

N2 - AIMS: A pathogenic/likely pathogenic (P/LP) variant in SCN5A is found in 20-25% of patients with Brugada syndrome (BrS). However, the diagnostic yield and prognosis of gene panel testing in paediatric BrS is unclear. The aim of this study is to define the diagnostic yield and outcomes of SCN5A gene testing with ACMG variant classification in paediatric BrS patients compared with adults.METHODS AND RESULTS: All consecutive patients diagnosed with BrS, between 1992 and 2022, were prospectively enrolled in the UZ Brussel BrS registry. Inclusion criteria were: (i) BrS diagnosis; (ii) genetic analysis performed with a large gene panel; and (iii) classification of gene variants following ACMG guidelines. Paediatric patients were defined as ≤16 years of age. The primary endpoint was ventricular arrhythmias (VAs). A total of 500 BrS patients were included, with 63 paediatric patients and 437 adult patients. Among children with BrS, 29 patients (46%) had a P/LP variant (P+) in SCN5A and no variants were found in 34 (54%) patients (P-). After a mean follow-up of 125.9 months, 8 children (12.7%) experienced a VA, treated with implanted cardioverter defibrillator shock. At survival analysis, P- paediatric patients had higher VA-free survival during the follow-up, compared with P+ paediatric patients. P+ status was an independent predictor of VA. There was no difference in VA-free survival between paediatric and adult BrS patients for both P- and P+.CONCLUSION: In a large BrS cohort, the diagnostic yield for P/LP variants in the paediatric population is 46%. P+ children with BrS have a worse arrhythmic prognosis.

AB - AIMS: A pathogenic/likely pathogenic (P/LP) variant in SCN5A is found in 20-25% of patients with Brugada syndrome (BrS). However, the diagnostic yield and prognosis of gene panel testing in paediatric BrS is unclear. The aim of this study is to define the diagnostic yield and outcomes of SCN5A gene testing with ACMG variant classification in paediatric BrS patients compared with adults.METHODS AND RESULTS: All consecutive patients diagnosed with BrS, between 1992 and 2022, were prospectively enrolled in the UZ Brussel BrS registry. Inclusion criteria were: (i) BrS diagnosis; (ii) genetic analysis performed with a large gene panel; and (iii) classification of gene variants following ACMG guidelines. Paediatric patients were defined as ≤16 years of age. The primary endpoint was ventricular arrhythmias (VAs). A total of 500 BrS patients were included, with 63 paediatric patients and 437 adult patients. Among children with BrS, 29 patients (46%) had a P/LP variant (P+) in SCN5A and no variants were found in 34 (54%) patients (P-). After a mean follow-up of 125.9 months, 8 children (12.7%) experienced a VA, treated with implanted cardioverter defibrillator shock. At survival analysis, P- paediatric patients had higher VA-free survival during the follow-up, compared with P+ paediatric patients. P+ status was an independent predictor of VA. There was no difference in VA-free survival between paediatric and adult BrS patients for both P- and P+.CONCLUSION: In a large BrS cohort, the diagnostic yield for P/LP variants in the paediatric population is 46%. P+ children with BrS have a worse arrhythmic prognosis.

KW - Brugada syndrome

KW - Genetics

KW - SCN5A

KW - Sudden cardiac death

KW - Ventricular arrhythmias

UR - http://www.scopus.com/inward/record.url?scp=85160871510&partnerID=8YFLogxK

U2 - 10.1093/europace/euad079

DO - 10.1093/europace/euad079

M3 - Article

C2 - 37061847

VL - 25

JO - Europace

JF - Europace

SN - 1099-5129

IS - 5

ER -

Pannone L, Bisignani A, Osei R, Gauthey A, Sorgente A , Vergara P et al. Genetic testing in children with Brugada syndrome: results from a large prospective registry. Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2023;25(5). https://doi.org/10.1093/europace/euad079

Genetic testing in children with Brugada syndrome: results from a large prospective registry

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