SCN5A mutations in 442 neonates and children: genotype–phenotype correlation and identification of higher-risk subgroups. (27th July 2018)

• Record Type: Journal Article
• Authors: 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; Kaski, Juan Pablo; Rudic, Boris; Kwok, Sit Yee; Rieubland, Claudine; Tfelt-Hansen, Jacob; Van Hare, George F; Guyomarc'h-Delasalle, Béatrice; Blom, Nico A; Wijeyeratne, Yanushi D; Gourraud, Jean-Baptiste; Le Marec, Hervé; Ozawa, Junichi; Fressart, Véronique; Lupoglazoff, Jean-Marc; Dagradi, Federica; Spazzolini, Carla; Aiba, Takeshi; Tester, David J; Zahavich, Laura A; Beauséjour-Ladouceur, Virginie; Jadhav, Mangesh; Skinner, Jonathan R; Franciosi, Sonia; Krahn, Andrew D; Abdelsayed, Mena; Ruben, Peter C; Yung, Tak-Cheung; Ackerman, Michael J; Wilde, Arthur A; Schwartz, Peter J; Probst, Vincent;
• Is Part Of: European heart journal. Volume 39:Number 31(2018)
• Page Start: 2879
• Page End: 2887
• Publication Date: 2018-07-27
• Subjects: Brugada syndrome -- Genotype–phenotype correlation -- Long QT syndrome -- Progressive cardiac conduction disorders -- SCN5A -- Sodium channelopathy; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehy412
• Languages: English
• ISSNs: 0195-668X

Abstract

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.