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SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups

Baruteau, A-E; Kyndt, F; Behr, ER; Vink, AS; Lachaud, M; Joong, A; Schott, J-J; ... Probst, V; + view all (2018) SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups. European Heart Journal , 39 (31) pp. 2879-2887. 10.1093/eurheartj/ehy412. Green open access

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Abstract

AIMS: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. METHODS AND RESULTS: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. CONCLUSION: In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Type: Article
Title: SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/eurheartj/ehy412
Publisher version: http://dx.doi.org/10.1093/eurheartj/ehy412
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Brugada syndrome, Genotype–phenotype correlation, Long QT syndrome, Progressive cardiac conduction disorders, SCN5A, Sodium channelopathy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
URI: https://discovery.ucl.ac.uk/id/eprint/10055497
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