Overlapping genetic
syndromes
Ramon Brugada
Director, Centre de Genètica Cardiovascular IDIBGI
Cardiologist, Hospital Josep Trueta
Dean, School of Medicine, University of Girona
Girona, Catalonia
20 years of research
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 ___
Genetic defects in familial channelopathies
AF
kcnq1
kcna5
kcne2
Kcnj2
kcnh2
scn1b
scn3b
scn2b
gpd1l kcnj8
kcnd3
mog1
kcne3
kcne5
hcn4
scn5a
cacnb2
BrS
cacna1c
ryr2
kcnj2
casq2
CPVT
snta1
scn4b
ank2
cav3
akap9
kcne1
kcnq1
kcnj2
kcnh2
kcne2
LQTS
SQTS
Brugada syndrome associated with SCN5A
* Long QT3 Syndrome
* Brugada Syndrome
Reduced INA
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
- Prolonged PR
- RBBB
- ST segment 
- Negative T waves
Brugada P et al, JACC1992
Brugada syndrome:
Genotype-Phenotype correlations
Smits et al, JACC 2002
Meregalli et al., Heart Rhythm 2009
Promoter Haplotype associated with worse phenotype
Bezzina, C. R. et al. Circulation 2006
Trafficking restoration by SCN5A polymorphism
Clinically H558 associated with higher J point, wider QRS and more symptoms
Poelzing, S. et al. Circulation 2006
Lizotte, E et al. JCE 2009
Brugada syndrome, SSS and conduction disease
Smits J. P. et al. JMCC 2005
Brugada syndrome:
the worse case scenario?
Cordeiro, J. M. et al. Circulation 2006
A mutation in SCN5A responsible for Brugada and long
QT syndromes
Bezzina C et al. Circ Research 1999
Mutations in SCN5A responsible for Dilated
Cardiomyopathy
McNAir et al Circulation 2004
Mutations in SCN5A responsible for Dilated
Cardiomyopathy
Olson T et al. JAMA 2005
Mutation in SCN5A responsible for Conduction disease
and atrial arrhythmias
Laitinen et al JCE 2006
Mutations in SCN5A responsible for Atrial Fibrillation
Darbar et al Circulation 2008
Brugada syndrome and Atrial Fibrillation
Amin A et al. Europace 2011
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
GPD1L responsible for Brugada Syndrome and SIDS
London B et al. Circ 2007
Van Norstrand DW. Circ 2007
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
SCN1B responsible for Brugada Syndrome
Also associated with atrial fibrillation
Watanabe et al, JCI 2008
SCN2B responsible for Brugada Syndrome
Also associated with atrial fibrillation
Riuró et al Human Mut 2013
CACNA1C and CACNB2b responsible for
Brugada Syndrome and shorter QT intervals
CACNA1C associated with long QT syndrome and IVF
CACNB2b associated with IVF
Antzelevitch, C. et al. Circ 2007
KCNJ8 responsible for Brugada Syndrome
Also associated with ERS
Genetic defects in familial channelopathies
AF
kcnq1
kcna5
kcne2
Kcnj2
kcnh2
scn1b
scn3b
scn2b
gpd1l kcnj8
kcnd3
mog1
kcne3
kcne5
hcn4
scn5a
cacnb2
BrS
cacna1c
ryr2
kcnj2
casq2
CPVT
snta1
scn4b
ank2
cav3
akap9
kcne1
kcnq1
kcnj2
kcnh2
kcne2
LQTS
SQTS
Thank you