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

Alban Elouen Baruteau, Florence Kyndt, Elijah R. Behr, Arja S. Vink, Matthias Lachaud, Anna Joong, Jean Jacques Schott, Minoru Horie, Isabelle Denjoy, Lia Crotti, Wataru Shimizu, Johan M. Bos, Elizabeth A. Stephenson, Leonie Wong, Dominic J. Abrams, Andrew M. Davis, Annika Winbo, Anne M. Dubin, Shubhayan Sanatani, Leonardo LibermanJuan Pablo Kaski, Boris Rudic, Sit Yee Kwok, Claudine Rieubland, Jacob Tfelt-Hansen, George F. Van Hare, Béatrice Guyomarc'h-Delasalle, Nico A. Blom, Yanushi D. Wijeyeratne, Jean Baptiste Gourraud, Hervé Le Marec, Junichi Ozawa, Véronique Fressart, Jean Marc Lupoglazoff, Federica Dagradi, Carla Spazzolini, Takeshi Aiba, David J. Tester, Laura A. Zahavich, Virginie Beauséjour-Ladouceur, Mangesh Jadhav, Jonathan R. Skinner, Sonia Franciosi, Andrew D. Krahn, Mena Abdelsayed, Peter C. Ruben, Tak Cheung Yung, Michael John Ackerman, Arthur A. Wilde, Peter J. Schwartz, Vincent Probst

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2879-2887
Number of pages9
JournalEuropean Heart Journal
Volume39
Issue number31
DOIs
StatePublished - Aug 1 2018

Fingerprint

Genetic Association Studies
Newborn Infant
Mutation
Phenotype
Genotype
Brugada Syndrome
Tertiary Care Centers
Electrocardiography
Cohort Studies
Retrospective Studies
Pediatrics

Keywords

  • Brugada syndrome
  • Genotype-phenotype correlation
  • Long QT syndrome
  • Progressive cardiac conduction disorders
  • SCN5A
  • Sodium channelopathy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Baruteau, A. E., Kyndt, F., Behr, E. R., Vink, A. S., Lachaud, M., Joong, A., ... Probst, V. (2018). SCN5A mutations in 442 neonates and children: Genotype-phenotype correlation and identification of higher-risk subgroups. European Heart Journal, 39(31), 2879-2887. https://doi.org/10.1093/eurheartj/ehy412

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; 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; Marec, Hervé Le; 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 John; Wilde, Arthur A.; Schwartz, Peter J.; Probst, Vincent.

In: European Heart Journal, Vol. 39, No. 31, 01.08.2018, p. 2879-2887.

Research output: Contribution to journalArticle

Baruteau, AE, Kyndt, F, Behr, ER, Vink, AS, Lachaud, M, Joong, A, Schott, JJ, Horie, M, Denjoy, I, Crotti, L, Shimizu, W, Bos, JM, Stephenson, EA, Wong, L, Abrams, DJ, Davis, AM, Winbo, A, Dubin, AM, Sanatani, S, Liberman, L, Kaski, JP, Rudic, B, Kwok, SY, Rieubland, C, Tfelt-Hansen, J, Van Hare, GF, Guyomarc'h-Delasalle, B, Blom, NA, Wijeyeratne, YD, Gourraud, JB, Marec, HL, Ozawa, J, Fressart, V, Lupoglazoff, JM, Dagradi, F, Spazzolini, C, Aiba, T, Tester, DJ, Zahavich, LA, Beauséjour-Ladouceur, V, Jadhav, M, Skinner, JR, Franciosi, S, Krahn, AD, Abdelsayed, M, Ruben, PC, Yung, TC, Ackerman, MJ, Wilde, AA, Schwartz, PJ & Probst, V 2018, 'SCN5A mutations in 442 neonates and children: Genotype-phenotype correlation and identification of higher-risk subgroups', European Heart Journal, vol. 39, no. 31, pp. 2879-2887. https://doi.org/10.1093/eurheartj/ehy412
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 ; Marec, Hervé Le ; 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 John ; Wilde, Arthur A. ; Schwartz, Peter J. ; Probst, Vincent. / SCN5A mutations in 442 neonates and children : Genotype-phenotype correlation and identification of higher-risk subgroups. In: European Heart Journal. 2018 ; Vol. 39, No. 31. pp. 2879-2887.
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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.",
keywords = "Brugada syndrome, Genotype-phenotype correlation, Long QT syndrome, Progressive cardiac conduction disorders, SCN5A, Sodium channelopathy",
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TY - JOUR

T1 - SCN5A mutations in 442 neonates and children

T2 - Genotype-phenotype correlation and identification of higher-risk subgroups

AU - Baruteau, Alban Elouen

AU - Kyndt, Florence

AU - Behr, Elijah R.

AU - Vink, Arja S.

AU - Lachaud, Matthias

AU - Joong, Anna

AU - Schott, Jean Jacques

AU - Horie, Minoru

AU - Denjoy, Isabelle

AU - Crotti, Lia

AU - Shimizu, Wataru

AU - Bos, Johan M.

AU - Stephenson, Elizabeth A.

AU - Wong, Leonie

AU - Abrams, Dominic J.

AU - Davis, Andrew M.

AU - Winbo, Annika

AU - Dubin, Anne M.

AU - Sanatani, Shubhayan

AU - Liberman, Leonardo

AU - Kaski, Juan Pablo

AU - Rudic, Boris

AU - Kwok, Sit Yee

AU - Rieubland, Claudine

AU - Tfelt-Hansen, Jacob

AU - Van Hare, George F.

AU - Guyomarc'h-Delasalle, Béatrice

AU - Blom, Nico A.

AU - Wijeyeratne, Yanushi D.

AU - Gourraud, Jean Baptiste

AU - Marec, Hervé Le

AU - Ozawa, Junichi

AU - Fressart, Véronique

AU - Lupoglazoff, Jean Marc

AU - Dagradi, Federica

AU - Spazzolini, Carla

AU - Aiba, Takeshi

AU - Tester, David J.

AU - Zahavich, Laura A.

AU - Beauséjour-Ladouceur, Virginie

AU - Jadhav, Mangesh

AU - Skinner, Jonathan R.

AU - Franciosi, Sonia

AU - Krahn, Andrew D.

AU - Abdelsayed, Mena

AU - Ruben, Peter C.

AU - Yung, Tak Cheung

AU - Ackerman, Michael John

AU - Wilde, Arthur A.

AU - Schwartz, Peter J.

AU - Probst, Vincent

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - Brugada syndrome

KW - Genotype-phenotype correlation

KW - Long QT syndrome

KW - Progressive cardiac conduction disorders

KW - SCN5A

KW - Sodium channelopathy

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