1. Overlapping genetic syndromes Ramon Brugada Director, Centre de Genètica Cardiovascular IDIBGI Cardiologist, Hospital Josep Trueta Dean, School of Medicine, University of Girona Girona, Catalonia

2. 20 years of research

3. 1990 ___ ___ Hypertrophic Cardiomyopathy (HCM) ___ ___ Long QT Syndrome (LQTS) ___ 1995 ___ Dilated Cardiomyopathy (DCM) ___ ___ Atrial Fibrillation (AF) ___ Brugada Syndrome (BrS) ___ Arrhythmogenic Cardiomyopathy (ARVC) 2000 ___ ___ Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) ___ ___ Sudden Unexpected Death Syndrome (SUDS) ___ Short QT Syndrome (SQTS) 2005 ___ ___ Atrial Fibrillation & Short QT Syndrome ___ ___ SCD associated with Acute Myocardial Infarction ___ Early Repolarization Syndrome 2010 ___

4. gpd1l kcne3 scn1b scn3b scn2b kcnj8 kcnd3 mog1 hcn4 kcne5 kcne1 kcne2 akap9 scn4b cav3 snta1 ank2 cacnb2 scn5a cacna1c kcnq1 kcnj2 kcnh2 LQTS SQTS BrS CPVT ryr2 kcnj2 casq2 Genetic defects in familial channelopathies AF kcnq1 kcna5 kcne2 Kcnj2 kcnh2

5. Brugada syndrome associated with SCN5A * Long QT3 Syndrome * Brugada Syndrome Reduced I NA Failure of the channel to express Accelerated inactivation Entry of the channel into an intermediate inactivation state from which it recovers more slowly. Chen Q et al, Nature 1998

6. - Prolonged PR - RBBB - ST segment  - Negative T waves Brugada P et al, JACC1992

7. Brugada syndrome: Genotype-Phenotype correlations Smits et al, JACC 2002 Meregalli et al., Heart Rhythm 2009

8. Promoter Haplotype associated with worse phenotype Bezzina, C. R. et al. Circulation 2006

9. Poelzing, S. et al. Circulation 2006 Lizotte, E et al. JCE 2009 Trafficking restoration by SCN5A polymorphism Clinically H558 associated with higher J point, wider QRS and more symptoms

10. Brugada syndrome, SSS and conduction disease Smits J. P. et al. JMCC 2005

11. Brugada syndrome: the worse case scenario? Cordeiro, J. M. et al. Circulation 2006

12. A mutation in SCN5A responsible for Brugada and long QT syndromes Bezzina C et al. Circ Research 1999

13. Mutations in SCN5A responsible for Dilated Cardiomyopathy McNAir et al Circulation 2004

14. Mutations in SCN5A responsible for Dilated Cardiomyopathy Olson T et al. JAMA 2005

15. Mutation in SCN5A responsible for Conduction disease and atrial arrhythmias Laitinen et al JCE 2006

16. Mutations in SCN5A responsible for Atrial Fibrillation Darbar et al Circulation 2008

17. Brugada syndrome and Atrial Fibrillation Amin A et al. Europace 2011

18. Genetic diseases associated with SCN5A * Long QT3 Syndrome * Brugada Syndrome * SSS (recessive forms) * PCCD/Lenegre/Lev Syndrome * SUDS / SIDS / IVF * Atrial Fibrillation * DCM Chen Q et al, Nature 1998

19. GPD1L responsible for Brugada Syndrome and SIDS London B et al. Circ 2007 Van Norstrand DW. Circ 2007

20. SCN3B responsible for Brugada Syndrome Valdivia C R et al. Cardiovasc Res 2010 Hu, D. et al. Circ Cardiovasc Genet 2009 Also associated with atrial fibrillation and IVF

21. SCN1B responsible for Brugada Syndrome Watanabe et al, JCI 2008 Also associated with atrial fibrillation

22. Riuró et al Human Mut 2013 SCN2B responsible for Brugada Syndrome Also associated with atrial fibrillation

23. CACNA1C and CACNB2b responsible for Brugada Syndrome and shorter QT intervals Antzelevitch, C. et al. Circ 2007 CACNA1C associated with long QT syndrome and IVF CACNB2b associated with IVF

24. KCNJ8 responsible for Brugada Syndrome Also associated with ERS

25. gpd1l kcne3 scn1b scn3b scn2b kcnj8 kcnd3 mog1 hcn4 kcne5 kcne1 kcne2 akap9 scn4b cav3 snta1 ank2 cacnb2 scn5a cacna1c kcnq1 kcnj2 kcnh2 LQTS SQTS BrS CPVT ryr2 kcnj2 casq2 Genetic defects in familial channelopathies AF kcnq1 kcna5 kcne2 Kcnj2 kcnh2

26. Thank you