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Brugada syndrome The role of genetic mutations
Venice Arrhythmia 2015
Arthur A.M. Wilde
Heart Centre
NO CONFLICT OF INTEREST TO
DECLARE
Heart Centre
Brugada syndrome
The diagnosis
Heart Centre
Heart Rhythm 2005;2:429-440
Type 1 Type 2 & 3
Circulation 2002;106:2514-9
Type 1 Type 2 & 3
Circulation 2002;106:2514-9
Heart Centre
Brugada syndrome should be considered:
♥ Type 1 ECG (± drugs) and ♥ documented VF or self terminating PMVT ♥ Family history of SCD < 45 y. ♥ Type 1 ECG in family members ♥ EPS inducibility, syncope ♥ Nocturnal agonal respiration
Heart Rhythm 2013, Europace 2013 Heart Centre
Brugada Syndrome
Expert Consensus Recommendations on Diagnosis
1. BrS is diagnosed in patients with ST segment elevation with type 1 morphology > 2 mm in > 1 lead among the right precordial leads V1,V2, positioned in the 2nd, 3rd or 4th intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of Class I antiarrhythmic drugs.
2. BrS is diagnosed in patients with type 2 or type 3 ST segment elevation in > 1
lead among the right precordial leads V1,V2 positioned in the 2nd, 3rd or 4th intercostal space when a provocative drug test with intravenous administration of Class I antiarrhythmic drugs induces a type 1 ECG morphology
Bottom line: one right precordial lead at any position
Heart Rhythm 2013, Europace 2013 Heart Centre
Heart Centre Veltmann et al, HR 2012;9:414-421
Heart Centre Veltmann et al, HR 2012;9:414-421
Miyamoto et al, AJC 2007;99:53-57 S = 4th ICS, H = higher (2nd and 3rd), Ic = drug induced
Heart Centre
Male 39 years (resuscitated)
Heart Centre
Brugada syndrome
Genetics
Heart Centre
♥ Genetically heterogeneous
________________________________________________Brugada syndrome, genetics
Heart Centre
SCN5A (3p21) mutations
: Brugada syndrome : LQTS
: (P)CCD
Heart Centre
28/130 (22%) : Priori et al., 2002 (mostly Italian)
23/77 (30%) : Smits et al., 2002 (NL, Fr, GER)
3/10 (30%) : Vatta et al., 2002 (Japan, Thailand)
4/39 (10%) : Makiyama ea., 2005 (Japan)
Brugada syndrome, genetics
0
20
40
60
80
100
BRS (N=213)*
Familial
Isolated
%
33/75
29/138
* Nrs of analyzed families (complete pedigree available) Hofman et al., Circulation 2013 Heart Centre
0
20
40
60
80
100
LQTS (N=256)*
BRS (N=213)*
Familial
Isolated
% 90/110
42/146
33/75
29/138
* Nrs of analyzed families (complete pedigree available) Hofman et al., Circulation 2013 Heart Centre
Brugada syndrome, geneticsLocus Ion channel Gene/Protein
BrS 1 3p21 INa SCN5A, Nav1.5
1
Brugada syndrome, geneticsLocus Ion channel Gene/Protein
BrS 1 3p21 INa SCN5A, Nav1.5 BrS 2 3p24 INa GPD1L BrS 3 12p13.3 ICa CACNA1C, Cav1.2 BrS 4 10p12.33 ICa CACNB2b, Cavb2b BrS 5 19q13.1 INa SCN1B, Navβ1 BrS 6 11q13-q14 Ito KCNE3, MiRP2 BrS 7 11q23.3 INa SCN3B, Navβ3
BrS 8 12p11.23 IK.ATP KCNJ8 BrS 9 7q21-q22 ICa CACNA2D1, Cavα2δBrS 10 1p13.3 Ito KCND3BrS 11 17p13.1 INa MOG1BrS 12 3p21.2-p14.3 INa SLMAPBrS 13 12p12.1 IK.ATP ABCC9, SUR2ABrS 14 11q23 INa SCN2B
1
Heart Centre
Brugada syndrome, geneticsLocus Ion channel Gene/Protein
BrS 15 12p11 INa PKP2 BrS 16 3q28 INa FGF12 BrS 17 3q22.2 INa SCN10A BrS 18 7p12.1 ITO SEMA3A
2
Heart Centre
Brugada syndrome, geneticsLocus Ion channel Gene/Protein
BrS modifying 15q24-25 IF HCN4 BrS modifying 7q35 IKr KCNH2 BrS modifying Xq22.3 Ito KCNE5 BrS modifying 6q22 INa HEY2
Courtesy: M. AckermanCourtesy: M. Ackerman
Heart Centre
Circ Cardiovasc Genet. 2009;2:552-557
Total number of genotyped BrS probands
SCN5A positive SCN5A negative
Large families (> 4 family members)
n=444
n= 13 probands, 263 family members
n = 118
Total number of genotyped BrS probands
SCN5A positive SCN5A negative
Large families (> 4 family members)
n=444
n= 13 probands, 263 family members
n = 118
n=115 Mutation carriers n=148 Mutation-negative subjects
PR=193+/-37 ms; QRS=113+/-20 ms PR=162+/-29 ms; QRS=95+/-16 ms
Total number of genotyped BrS probands
SCN5A positive SCN5A negative
Large families (> 4 family members)
n=444
n= 13 probands, 263 family members
n = 118
n=115 Mutation carriers n=148 Mutation-negative subjects
PR=193+/-37 ms; QRS=113+/-20 ms PR=162+/-29 ms; QRS=95+/-16 ms
BrS-ECG + N=54
BrS-ECG – N=61
BrS-ECG + N=7
BrS-ECG – N=141
PR=194+/-37 ms; QRS= 113+/-18 ms
PR=193+/-37 ms; QRS=113+/-21 ms
PR=170+/-14 ms; QRS= 99+/-14 ms
PR=162+/-30 ms; QRS= 94+/-14 ms
i1 d2 f1
V1
V2
a2 d1 a1 m1
Heart Centre
Heart Centre
Does SCN5a play a role?: ♥ there are no linkage data for SCN5a! ♥ loss-of-function mutation not mandatory! ♥ could it be an important modifier? ♥ if this would have been the first family then…
BrS, genetics
167 BrS patients, 167 ‘controls’ (>65 year old without cardiac history)
Heart Centre
Which genes do play a role?: ♥ SCN5a probably yes, but……. ♥ All the other genes doubtful
♥ Modifying role for all? ♥ some stronger than others?
BrS, genetics
Heart Centre
Gene$cs'of'Brugada'Syndrome:'new'strategy'
Case7control'
Genome'Wide'Associa$on'Study'
N=1115'General'popula$on'
600 000 SNPs (Axiom chip)
N=312'Type7I'BrS'index'cases
Bezzina et al., Nature Genetics 2013
Heart Centre
Brugada Syndrome patients ascertained at 13 clinical centers in Europe, U.S., Japan
Identification of 2 loci associated with BrS
Chr3
6.8 x 10-26 8.9 x 10-10
Chr6
ControlsBrS cases
Cumula$ve'effect'of'alleles'at'the'three'loci'on'suscep$bility'to'BrS'
Cumula$ve'effect'of'alleles'at'the'three'loci'on'suscep$bility'to'BrS'
ControlsBrS cases
Heart Centre
Conclusions: ♥ Genetically heterogeneous ♥ SCN5a 15-30% of patients ♥ likely oligogenetic
Brugada syndrome, genetics
Heart Centre
0"10"20"30"40"50"60"70"80"90"
100"
Pa.ent"1" Pa.ent"2" Pa.ent"3" Pa.ent"4" Pa.ent"5" Pa.ent"6"
MUTATION" "SNP"1" SNP"2" SNP"3"
Mag
nitu
de o
f ST
elev
atio
n
ST elevation V1-2
Heart Centre
0"10"20"30"40"50"60"70"80"90"
100"
Pa.ent"1" Pa.ent"2" Pa.ent"3" Pa.ent"4" Pa.ent"5" Pa.ent"6"
MUTATION" "SNP"1" SNP"2" SNP"3"
Mag
nitu
de o
f ST
elev
atio
n
ST elevation V1-2
Heart Centre
0"10"20"30"40"50"60"70"80"90"
100"
Pa.ent"1" Pa.ent"2" Pa.ent"3" Pa.ent"4" Pa.ent"5" Pa.ent"6"
MUTATION" "SNP"1" SNP"2" SNP"3"
Mag
nitu
de o
f ST
elev
atio
n
ST elevation V1-2
Heart Centre
0"10"20"30"40"50"60"70"80"90"
100"
Pa.ent"1" Pa.ent"2" Pa.ent"3" Pa.ent"4" Pa.ent"5" Pa.ent"6"
MUTATION" "SNP"1" SNP"2" SNP"3"
Heart Failure Research Centre
Mag
nitu
de o
f ST
elev
atio
n
ST elevation V1-2
Heart Centre
0"10"20"30"40"50"60"70"80"90"
100"
Pa.ent"1" Pa.ent"2" Pa.ent"3" Pa.ent"4" Pa.ent"5" Pa.ent"6"
MUTATION" "SNP"1" SNP"2" SNP"3"
Mag
nitu
de o
f ST
elev
atio
n
ST elevation V1-2
Heart Centre
0"10"20"30"40"50"60"70"80"90"
100"
Pa.ent"1" Pa.ent"2" Pa.ent"3" Pa.ent"4" Pa.ent"5" Pa.ent"6"
MUTATION" "SNP"1" SNP"2" SNP"3"
Mag
nitu
de o
f ST
elev
atio
n
ST elevation V1-2
Heart Centre
whether this impacts on prognosis remains to be proven
Brugada syndrome, genetics
Heart Centre *: Meregalli et al. Heart Rhythm 6, 341-348 , 2009
Brugada syndrome Genotype-phenotype relation
Heart Centre
With more severe Na-channel ♥ there are more symptoms ♥ wider PR-interval ♥ Wider PR and QRS after class 1a
Brugada syndrome Genotype-phenotype relation
*: Meregalli et al. Heart Rhythm 6, 341-348 , 2009
For information and registration see www.20yrsCG.nl
Organising committee:Karin Y. van Spaendonck
J. Peter van TintelenArthur Wilde
20years
cardiogeneticsin the Netherlands
Amsterdam, the NetherlandsDecember 4th 2015
Heart Centre
Thank you
Heart Centre
Conclusions: ♥ still much to learn! ♥ expanding genetics (pathophysiol.), role SCN5a ♥ symptomatic patients are at risk, ICD treatment ♥ asymptomatic patients, risk ill defined. ♥ plea for large registries!!!!