Brugada Syndrome

A Guide for

Bru

gada

1 | Brugada Syndrome

Brugada Syndrome Introduction Brugada syndrome (BrS) is a potentially life-threatening cardiac disorder characterized by ST segment elevation in right precordial leads (V1 to V3) on an ECG, incomplete or complete right bundle branch block, and susceptibility to syncope, ventricular tachyarrhythmia and sudden cardiac death.1 Consensus conferences in 2002 and 2005 refined the diagnostic criteria for Brugada syndrome as detailed in Figure 2 and Side Box 2.2

Brugada syndrome occurs worldwide and is estimated to affect 5 per 10,000 individuals of all ethnicities, with some regional differences.3 BrS is a genetic cardiac channelopathy resulting from loss-of-function mutations causing changes in sodium and calcium ion flux. It is inherited as an autosomal dominant trait, occurring in males and females equally, although males are more likely to be symptomatic.4 Family history suggestive of BrS is an important diagnostic factor, as spontaneous mutation occurs rarely and most affected individuals are expected to have an affected parent.14

Figure 1: Illustration showing ST elevation in Brugada syndrome as compared to normal

Normal

ST elevation

SIde Box 1: Factors associated with BrS5

•Familyhistoryofsuddencardiacdeath•Personalhistoryofcardiacarrhythmiawithsleep,rest,and/orfever•Personalhistoryofsyncope

Clinician's Guide | 2

Clinical diagnosis

SIde Box 2: diagnostic criteria of BrS2

DiagnosisofBrScanbemadebaseduponthecharacteristicECGpatterninconjunctionwithotherelementsofthehistory.

A)ECGrepolarizationpatternintherightprecordialleadscharacterizedbyanST-segmentelevationofatleast2mmwitha"covedmorphology"(Type1ECG).Acoved-shapedECGpatternisassociatedwithrightbundlebranchblockfollowedbyanegativeTwave.RelatedECGpatterns(Types2and3)mayalsobeobservedandcanbeindicativeofBrS,butcannotbeusedforadefinitivediagnosis.SomepatientsexhibitingType2or3ECGsaregivenadrugchallengewithasodiumchannelblockingagentsuchasflecainideorprocainamide.IftheECGpatternconvertsfromType2or3toType1upondrugchallenge,thepatientcanbesaidtohaveBrS.

B)DiagnosisofBrSmustincludeaType1ECGpatterninatleastonerightprecordialleadinconjunctionwithoneormoreofthefollowing:• Documentedventricularfibrillation• Polymorphicventriculartachycardia• Familyhistoryofsuddencardiacdeathatage45oryounger• Type1ECGsinfamilymembers• InducibilityofVTwithprogrammedelectricstimulation• Syncope• Nocturnalagonalrespiration

Sensitivityofthesecriteriaisnotdefinitivelyknown,butforthosesymptomaticpatientscarryingamutationintheSCN5gene,thesensitivityis77%.6

Clinical presentation and differential diagnosis

BrShasvariableanddiverseclinicalmanifestations.Themostcommonclinicalsymptomsaresyncopeandcardiacarrestthatoccuratrestorduringsleep.SomepatientswithBrShavesupraventriculararrhythmias.MostindividualswithBrSareasymptomatic.ThediagnosticsignificanceofaBrugada-typeECGpatterninasymptomaticindividualsisuncertainandisanareaofongoingstudy.Mostsymptomaticindividualspresentbetweenages20and40,butsymptomshavebeenreportedfrominfancythroughlatelife.Malesare8to10timesmorelikelythanfemalestodevelopsymptomsofBrugadasyndrome,forunclearreasons.4

3 | Brugada Syndrome

ItisstronglyrecommendedthatstructuralabnormalitiesoftheheartbeexcludedbeforeaconclusivediagnosisofBrSismade.TheBrugadaECGpatterncanbeanearlysubclinicalmanifestationofarrhythmogenicrightventricularcardiomyopathy(ARVC).OtherfactorsthatcouldaccountforeithertheECGfindingsorsyncopeshouldalsobeexcluded.Theseincludeatypicalrightbundlebranchblock,leftventricularhypertrophy,earlyrepolarization,acutemyocardialinfarction,acutepericarditis,andtheECGchangessometimesseenintherightprecordialleadsinwell-trainedathletes.

Management

TheonlyproveneffectivetreatmentforBrSisanimplantablecardioverterdefibrillator(ICD).AnalgorithmhasbeendevelopedbytheHeartRhythmAssociationfortheuseofICDsinsymptomaticpatientswithBrS.9 Managementofasymptomaticpatientsislessclear.ProposedapproachesincludecloseobservationuntilsymptomsdevelopandimplantationofICDsinpatientswithafamilyhistoryofsuddencardiacdeath.Theclinicalmanifestationscanbetriggeredbyhighfever,largemeals,cocaine,excessivealcoholconsumption,andoverdoseoftricyclicantidepressants.10-13Research isongoingforpharmacologicandothermanagementstrategies.

Figure 2: Illustration showing Brugada ECG pattern, Types 1, 2, and 3.

TYPe 1

V1 V1 V1

V2 V2 V2

V3 V3 V3

TYPe 2 TYPe 3

Clinician's Guide | 4

Genetics of Brugada syndrome

BrSisageneticdisorderwithautosomaldominanttransmission.Mutationsinatleastsevengenes(seeTable1)influencingsodiumandcalciumcurrentsintheheartareassociatedwithBrSandaccountforatleast26%-41%ofcaseswithBrugadasyndrome.8,14Genetictestingtopredictthesyndromeinasymptomaticat-riskfamilymembersofapatientwithBrugadasyndromefirstrequiresidentificationofthedisease-causingmutationinthefamily.Ifadisease-causingmutationisfoundinanaffectedindividual,genetictestingofrelativesmaybeappropriate,allowingforevaluationandtreatmentofonlythefamilymembersatriskofarrhythmias.MostpatientswithBrugadasyndromehaveinheritedadisease-causingmutationfromaparent,asdenovomutationinBrSisrare.ChildrenofapatientdiagnosedwithBrShavea50%chanceofinheritingthemutationassociatedwiththesyndrome.AsindividualswithBrSmaybeasymptomatic,thelackofafamilyhistorydoesnotruleoutaheritabledisease.

Indications and utility of genetic testing

GenetictestinginapatientclinicallyaffectedwithBrScanbeusedtoconfirmthediagnosis.Genetictestingofat-riskfamilymemberscanthenbeusedtoidentifythosewhowillbenefitfromcardiacevaluationandintervention.Conversely,familymemberswhotestnegativeforaspecificfamilialmutationdonotneedserialcardiacevaluationsorintervention.

Genetic test results and what they mean

DiagnosticgenetictestingcanbeconsideredforpatientswhohavesymptomsandECGfindingscharacteristicofBrS,aswellasforasymptomaticpatientswithaknownfamilialmutationorpositivefamilyhistoryofBrS.

GeNe GeNe NAMe

SCN5A AlphasubunitofthevoltagegatedsodiumchanneltypeVGPd1L NAD-dependentglycerol-3-phosphatedehydrogenaseCACNA1C Alpha-1CsubunitoftheL-typevoltage-dependent

calciumchannelSCN1B Voltage-gatedsodiumchanneltype1betasubunitKCNe3 Beta-2subunitofthevoltage-dependentL-typecalciumchannelCACNB2 Potassiumvoltage-gatedchannel,Isk-relatedfamily,member3SCN3B Betasubunitofvoltage-gatedtypeIIIsodiumchannel

TABLe 1

5 | Brugada Syndrome

TestingshouldinitiallybeperformedonasymptomaticfamilymemberwithBrS.Preferably,themostseverelyaffectedfamilymembershouldbetestedfirst.Insomecases,genetictestingcanbeperformedonadeceasedindividualifthemedicalexaminerhasstoredbloodortissuethatcanbe usedforgenetictesting.Testingasymptomaticfamilymemberisdonetoidentifythefamilialmutation,ifonecanbeidentified.Thethreepossibleoutcomesofgenetictestingarepositive,negative,andvariantofunknownclinicalsignificance(VUS).Allpatientswhoundergogenetictestingshouldreceivepre-testandpost-testgeneticcounselingtounderstandtheimplicationsoftesting.Geneticcounselingservicesacrossthecountrycan befoundatwww.nsgc.org.

• A positive resultindicatesthatadisease-causingmutationwasidentifiedinthatindividual.ThisfindingconfirmsthediagnosisofBrSandprovidesvaluableinformationtothephysicianandfamilymembers.Allfirst-degreerelatives(children,siblings,parents)ofapatientwithapositivegenetictestresultcanthenbeofferedpredictivegenetictestingtoclarifytheriskforBrS.Ifafamilymemberisfoundtobepositiveforthefamilialmutation,thisindividualisconsideredtobeatriskforBrSandshouldbereferredforcardiacevaluationincludinganECG.Mutation-positivefamilymembersshouldhaveabaselineelectrocardiogramandannualECGscreening exams.CertainmedicationsshouldbeavoidedinpatientswithBrS (www.brugadadrugs.org),andantipyreticsshouldbeusedatthefirstsignoffever.Itisimportanttonotethatthereisvariabilityinsymptoms,evenwithinfamilies.

• A negative result inanaffectedindividualdoesnotnecessarilyruleoutBrS,andthepatientshouldbemanagedaccordingtohis/herclinicalsymptomsandECGfindings.Possiblereasonsforanegativeresultcouldbe(1)thepatientmayhaveamutationinagenenotcoveredinthetestingpanel,(2)thepatientmayhaveamutationinaBrS-associatedgenethatwasnotcoveredinthetest,or(3)thepatientdoesnothaveaheritableformofBrS.Predictive genetic testing of family members when the affected family member testing is negative will not be informative and is not warranted. FamilymembersofaclinicallyaffectedindividualwithnegativetestresultsmaystillbeatriskforBrSandthusshouldbeevaluatedbyacardiologist.

Ifanasymptomaticindividualisnegativeforamutationidentifiedinanaffectedfamilymember,thispersonisconsideredatruenegativeandisnotatincreasedgeneticriskforBrugadasyndrome.BrSclinicalmonitoringforthisindividualisnotnecessary,butthispatientcoulddevelopothertypesofcardiacdiseaseinthefuture.IftherearenosymptomaticmembersofaBrSfamilyavailablefortesting,anasymptomaticindividualmaypursuepredictivegenetictestingpriortoidentificationofthefamilialmutation.However,iftheasymptomaticfamilymemberisfoundtohaveanegativetestresult,thisresult

Clinician's Guide | 6

isconsideredanuninformativenegativeresult,andthisasymptomaticfamilymembershouldstillbeevaluatedregularlybyacardiologist.• A variant of unknown clinical significance (VUS)indicatesthatthepathogenicroleofthevariantcannotbeclearlyestablished.TheVUShasbeentestedinalargepanelofnormalindividualsandwasnotidentifiedinanyofthenormalindividuals.Tofurtherclarifytheclinicalsignificanceofthisvariant,testingoffamilymembersishelpful.Ifanaffectedrelativeisfoundtohavethesamevariant,itismorelikelythatitisadisease-causingvariant.ThegreaterthenumberofaffectedfamilymemberswhocarrytheVUS,thegreaterthelikelihoodthattheVUSispathogenic.WithconsistentlinkageoftheVUSwithsymptomaticfamilymembers,thevariantfoundwouldbereclassifiedasafamily-specificmutationandextendedfamilymemberscouldbeofferedpredictivegenetictesting.

References

1. BrugadaPandBrugadaJ.Rightbundlebranchblock,persistentSTsegmentelevation

andsuddencardiacdeath:adistinctclinicalandelectrocardiographicsyndrome—

amulticenterreport.JAmerCollCardiol1992;20:1391-1396.

2. AntzelevitchCetal.Brugadasyndrome:reportofthesecondconsensusconference.

HeartRhythm2005;4:429-440.

3. FowlerSJandPrioriSG.ClinicalspectrumofpatientswithaBrugadaECG.CurrOpin

Cardiol2008;24:74-81.

4. EkhardtL.GenderdifferencesinBrugadasyndrome.JCardiovascElectrophysiol2008;

18:422-424.

5. www.mayoclinic.com/health/brugada-syndrome/DS01142

6. NapolitanoCandPrioriSG.Brugadasyndrome.OrphanetJRareDis2006;14:1-35.

7. Hong,SGetal.Valueofelectrocardiographicparametersandajmalinetestinthediagnosis

ofBrugadasyndromecausedbySCN5Amutations.Circulation2004;110:3023-3027.

8. HedleyPetal.ThegeneticbasisofBrugadasyndrome:amutationupdate.HumMutation

2009;30:1-11.

9. BenitoB,BrugadaR,BrugadaJ,BrugadaP.Brugadasyndrome.ProgressinCardiovascular

Diseases2008;51(1):1-22.

10. TanHLandMeregalliPG.LethalECGchangeshiddenbytherapeutichypothermia.

Lancet2007;369:78.

11. FrustaciA,PrioriSG,PieroniM.Cardiachistologicsubstrateinpatientswithclinical

phenotypeofBrugadasyndrome.Circulation2005;112:3680-3687.

12. LittmanL,MonroeMH,SvensonRH.Brugada-typeelectrocardiographicpatterninduced

bycocaine.MayoClinicProc2000;75:845-849.

13. BebartaVS,PhillipsS,EberhardtA,etal.IncidenceofBrugadaECGpatternandoutcomes

afterintentionaltricyclicantidepressantingestion.AmJCardiol2007;100:656-660.

14. GeneReviews:Brugadasyndrome.BrugadaR,BrugadaP,BrugadaJ,andHongK.

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