Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies

Paola G. Meregalli, Hanno L. Tan, Vincent Probst, Tamara T. Koopmann, Michael W. Tanck, Zahurul A. Bhuiyan, Frederic Sacher, Florence Kyndt, Jean Jacques Schott, J. Albuisson, Philippe Mabo, Connie R. Bezzina, Herve Le Marec, Arthur A M Wilde

Research output: Contribution to journalArticle

Abstract

Background: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed. Objectives: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype. Methods: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with ≤90% (Mactive) or >90% (Minactive) peak INa reduction were analyzed separately. Results: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an Mactive mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak INa reduction (T and Minactive mutants) had a significantly longer PR interval, compared with Mactive mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and Minactive groups than in the Mactive group. Conclusion: In loss-of-function SCN5A channelopathies, patients carrying T and Minactive mutations develop a more severe phenotype than those with Mactive mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.

Original languageEnglish
Pages (from-to)341-348
Number of pages8
JournalHeart Rhythm
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 2009

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Channelopathies
Sodium
Mutation
Brugada Syndrome
Heart Diseases
Phenotype
Sex Distribution
Penetrance
Sudden Cardiac Death
Age Distribution
Syncope
Missense Mutation

Keywords

  • Arrhythmia
  • Brugada syndrome
  • Conduction disorders
  • Genetics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. / Meregalli, Paola G.; Tan, Hanno L.; Probst, Vincent; Koopmann, Tamara T.; Tanck, Michael W.; Bhuiyan, Zahurul A.; Sacher, Frederic; Kyndt, Florence; Schott, Jean Jacques; Albuisson, J.; Mabo, Philippe; Bezzina, Connie R.; Le Marec, Herve; Wilde, Arthur A M.

In: Heart Rhythm, Vol. 6, No. 3, 03.2009, p. 341-348.

Research output: Contribution to journalArticle

Meregalli, PG, Tan, HL, Probst, V, Koopmann, TT, Tanck, MW, Bhuiyan, ZA, Sacher, F, Kyndt, F, Schott, JJ, Albuisson, J, Mabo, P, Bezzina, CR, Le Marec, H & Wilde, AAM 2009, 'Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies', Heart Rhythm, vol. 6, no. 3, pp. 341-348. https://doi.org/10.1016/j.hrthm.2008.11.009
Meregalli, Paola G. ; Tan, Hanno L. ; Probst, Vincent ; Koopmann, Tamara T. ; Tanck, Michael W. ; Bhuiyan, Zahurul A. ; Sacher, Frederic ; Kyndt, Florence ; Schott, Jean Jacques ; Albuisson, J. ; Mabo, Philippe ; Bezzina, Connie R. ; Le Marec, Herve ; Wilde, Arthur A M. / Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. In: Heart Rhythm. 2009 ; Vol. 6, No. 3. pp. 341-348.
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abstract = "Background: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed. Objectives: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype. Methods: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with ≤90{\%} (Mactive) or >90{\%} (Minactive) peak INa reduction were analyzed separately. Results: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an Mactive mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak INa reduction (T and Minactive mutants) had a significantly longer PR interval, compared with Mactive mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and Minactive groups than in the Mactive group. Conclusion: In loss-of-function SCN5A channelopathies, patients carrying T and Minactive mutations develop a more severe phenotype than those with Mactive mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.",
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AU - Meregalli, Paola G.

AU - Tan, Hanno L.

AU - Probst, Vincent

AU - Koopmann, Tamara T.

AU - Tanck, Michael W.

AU - Bhuiyan, Zahurul A.

AU - Sacher, Frederic

AU - Kyndt, Florence

AU - Schott, Jean Jacques

AU - Albuisson, J.

AU - Mabo, Philippe

AU - Bezzina, Connie R.

AU - Le Marec, Herve

AU - Wilde, Arthur A M

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N2 - Background: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed. Objectives: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype. Methods: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with ≤90% (Mactive) or >90% (Minactive) peak INa reduction were analyzed separately. Results: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an Mactive mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak INa reduction (T and Minactive mutants) had a significantly longer PR interval, compared with Mactive mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and Minactive groups than in the Mactive group. Conclusion: In loss-of-function SCN5A channelopathies, patients carrying T and Minactive mutations develop a more severe phenotype than those with Mactive mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.

AB - Background: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed. Objectives: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype. Methods: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with ≤90% (Mactive) or >90% (Minactive) peak INa reduction were analyzed separately. Results: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an Mactive mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak INa reduction (T and Minactive mutants) had a significantly longer PR interval, compared with Mactive mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and Minactive groups than in the Mactive group. Conclusion: In loss-of-function SCN5A channelopathies, patients carrying T and Minactive mutations develop a more severe phenotype than those with Mactive mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.

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