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

Baruteau, Alban-Elouen; Kyndt, Florence; Behr, Elijah R; Vink, Arja S; Lachaud, Matthias; Joong, Anna; Schott, Jean-Jacques; Horie, Minoru; Denjoy, Isabelle; Crotti, Lia; Shimizu, Wataru; Bos, Johan M; Stephenson, Elizabeth A; Wong, Leonie; Abrams, Dominic J; Davis, Andrew M; Winbo, Annika; Dubin, Anne M; Sanatani, Shubhayan; Liberman, Leonardo; ... (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. Oxford University Press 10.1093/eurheartj/ehy412

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Humangenetik
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Rieubland, Claudine

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0195-668X

Publisher:

Oxford University Press

Language:

English

Submitter:

André Schaller

Date Deposited:

20 Feb 2019 15:33

Last Modified:

04 Dec 2019 19:19

Publisher DOI:

10.1093/eurheartj/ehy412

PubMed ID:

30059973

BORIS DOI:

10.7892/boris.123120

URI:

https://boris.unibe.ch/id/eprint/123120

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