In Children and Adolescents From Brugada Syndrome–Families, Only <i>SCN5A</i> Mutation Carriers Develop a Type-1 ECG Pattern Induced By Fever

Abstract

pediatrics retrospective studies B rugada syndrome (BrS) is a rare inherited condition in which ventricular arrhythmias may cause syncope, aborted cardiac arrest, or sudden cardiac death.Although BrS is associated with mutations in the SCN5A gene, most adult patients are SCN5A-mutation negative. 1Fever can unmask the diagnostic Brugada type-1 pattern on the ECG 2 and precede arrhythmic symptoms, especially in children. 3 All children considered at risk for BrS, based on a family history of BrS or a BrS genotype are currently advised to record an ECG during fever (38.5C/101.3Fahrenheit) for diagnosis and risk stratification.This is stressful and time consuming for both patients and parents.We hypothesized that a type-1 fever-ECG and symptoms only occur in children with a familial SCN5A mutation.One hundred eleven pediatric patients aged <19 years were eligible because they had 1 fever-ECG recorded and were at-risk for BrS, by having a BrS genotype, a first-degree family member with BrS, or a first-degree family member with a BrS genotype.After exclusion of probands, carriers of overlap syndrome mutations or multiple SCN5A variants, and those with structural cardiac abnormalities, 97 children were included.Fever-ECGs and nonfever-ECGs recorded during outpatient visits closest to the date of the fever-ECGs were analyzed for a type-1 pattern by a blinded expert (A.A.M.W.) and patient characteristics were collected.Patients with 1 type-1 fever-ECG during follow-up were compared with those without.Categorical variables were compared using a 2 test or Fisher exact test, and Bonferroni correction for multiple comparisons was applied where appropriate.Continuous variables were compared using a Wilcoxon rank-sum test for not-normal distributions.The study was approved by the Institutional Review Board.Informed consent was waived because the study used retrospective data from regular care.A total of 309 ECGs from 97 patients were analyzed (193 fever-ECGs and 116 nonfever-ECGs).A type-1 pattern was seen on 22 (11.4%)fever-ECGs from 14 different patients and on none of the nonfever-ECGs.The median age at first episode of a fever-induced type-1 was 7.1 (2.8-10.6)years.In 7 patients the type-1 pattern was not apparent on the first recorded fever-ECG, but on a subsequent fever-ECG recorded after a median of 0.7 (0.1-4.9) years.A positive family history for sudden cardiac death, sex, first-degree family member with phenotypic BrS, median age at first presentation, and follow-up duration were similar in the 2 groups (Table ).All patients with 1 type-1 fever-ECG were carriers of a (likely) pathogenic SCN5A variant (13 [92.9%]) or had a 50% likelihood of being a carrier (1 [7.1%]).This genetic background differed significantly from the group without type-1 fever-ECG (P<0.001),where 31 patients (37.3%) were carriers of a (likely) pathogenic SCN5A variant and 38 (45.8%) were from a genotype-elusive family (Table ).In the child with 1 type-1 fever-ECG and a 50% likelihood of being a carrier, no genetic diagnostic testing had been performed.His father was diagnosed with BrS after

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