Brugada syndrome The role of genetic mutations

Venice Arrhythmia 2015

Arthur A.M. Wilde

Heart Centre

NO CONFLICT OF INTEREST TO

DECLARE

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Brugada syndrome

The diagnosis

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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

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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

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Male 39 years (resuscitated)

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Brugada syndrome

Genetics

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♥  Genetically heterogeneous

________________________________________________Brugada syndrome, genetics

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SCN5A (3p21) mutations

: Brugada syndrome : LQTS

: (P)CCD

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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

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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

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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Thank you

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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!!!!