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 Liberman; Juan 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 J Ackerman; Arthur A Wilde; Peter J Schwartz; Vincent Probst

doi:10.1093/eurheartj/ehy412

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 J Ackerman, Arthur A Wilde, Peter J Schwartz, Vincent Probst

14 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 language	English
Journal	European Heart Journal
Volume	39
Issue number	31
Pages (from-to)	2879-2887
ISSN	0195-668X
DOIs	https://doi.org/10.1093/eurheartj/ehy412
Publication status	Published - 14 Aug 2018

Keywords

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

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Baruteau, A.-E., Kyndt, F., Behr, E. R., Vink, A. S., Lachaud, M., Joong, A., Schott, J.-J., Horie, M., Denjoy, I., Crotti, L., Shimizu, W., Bos, J. M., Stephenson, E. A., Wong, L., Abrams, D. J., Davis, A. M., Winbo, A., Dubin, A. M., Sanatani, S., ... 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

Baruteau, A-E, Kyndt, F, Behr, ER, Vink, AS, Lachaud, M, Joong, A, Schott, J-J, 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, J-B, Le Marec, H, Ozawa, J, Fressart, V, Lupoglazoff, J-M, 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, T-C, 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

@article{823b32fce8254158acf97859bd020d3a,

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

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",

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

year = "2018",

month = aug,

day = "14",

doi = "10.1093/eurheartj/ehy412",

language = "English",

volume = "39",

pages = "2879--2887",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "31",

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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 - Le Marec, Hervé

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 J

AU - Wilde, Arthur A

AU - Schwartz, Peter J

AU - Probst, Vincent

PY - 2018/8/14

Y1 - 2018/8/14

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

U2 - 10.1093/eurheartj/ehy412

DO - 10.1093/eurheartj/ehy412

M3 - Journal article

C2 - 30059973

SN - 0195-668X

VL - 39

SP - 2879

EP - 2887

JO - European Heart Journal

JF - European Heart Journal

IS - 31

ER -

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

Abstract

Keywords

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