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Published on: October 9, 2014
Brugada syndrome and abnormal splicing of SCN5A in myotonic dystrophy type 1
Karim Wahbi1, Vincent Algalarrondo, Henri Marc Bécane
1Service de cardiologie, université Paris-Descartes, hôpital Cochin, AP-HP, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France; Institut de myologie, université Pierre et Marie-Curie, hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France.
Insights
Brugada syndrome may contribute to sudden cardiac death in myotonic dystrophy type 1 (DM1). Abnormal SCN5A gene splicing, not mutations, appears linked to this risk in DM1 patients.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Sudden cardiac death (SCD) affects up to one-third of myotonic dystrophy type 1 (DM1) patients.
- The precise mechanisms driving SCD in DM1 remain poorly understood.
Purpose of the Study:
- Investigate the potential role of Brugada syndrome in ventricular arrhythmias and SCD within the DM1 population.
- Explore the genetic and molecular underpinnings of cardiac events in DM1.
Main Methods:
- Screened 914 DM1 patients for Brugada pattern on ECG.
- Conducted SCN5A gene sequencing in patients with Brugada pattern.
- Analyzed SCN5A splicing in myocardial tissue from a DM1 patient and controls.
Main Results:
- 0.8% of DM1 patients exhibited a type 1 Brugada pattern; five met Brugada syndrome criteria.
- SCN5A sequencing revealed no pathogenic mutations.
- DM1 myocardial tissue showed abnormal SCN5A exon 6 splicing, with exon 6A over-expression.
Conclusions:
- Brugada syndrome is implicated in SCD in DM1, potentially due to SCN5A missplicing.
- This study offers novel insights into the cardiac pathophysiology of DM1.
- Abnormal SCN5A splicing, not mutations, may be a key factor in DM1-related cardiac events.
Background:
In patients with myotonic dystrophy type 1 (DM1), the mechanisms underlying sudden cardiac death, which occurs in up to 1/3 of patients, are unclear.
Aims:
To study the potential role of Brugada syndrome in ventricular tachyarrhythmias and sudden death in DM1 patients.
Methods:
We screened 914 adult patients included in the DM1 Heart Registry during 2000-2009 for the presence of type 1 Brugada pattern on electrocardiogram (ECG). We also performed direct sequencing of SCN5A in patients with Brugada pattern. Further, we analysed SCN5A splicing on ventricular myocardial specimens harvested during cardiac transplantation in a 45-year-old patient with DM1 and three controls with inherited dilated cardiomyopathy.
Results:
A type 1 Brugada pattern was present on the ECG of seven of 914 patients (0.8%), including five with a history of sustained ventricular tachyarrhythmia or sudden death, who fulfilled the criteria for Brugada syndrome. SCN5A sequencing was normal in all patients. Ventricular myocardial specimen analysis displayed abnormal splicing of SCN5A exon 6, characterized by over-expression of the 'neonatal' isoform, called exon 6A, in the patient with DM1, but not from the controls.
Conclusion:
Our findings suggest a potential implication of Brugada syndrome in sudden death in DM1, which may be related to missplicing of SCN5A. Our findings provide a new insight into the pathophysiology of heart disease in DM1.
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