2:CardiovascularGenetics

Overview
UnderstandingthegeneticunderpinningsofCVdiseasehasassumedgreaterimportanceinpatientcare.Thischapterreviews prototypicalMendelianCVdisorderssuchasMarfansyndrome,hypertrophiccardiomyopathy,andlongQTsyndromes.Thereis additionaldiscussionofcoagulationdisordersandcomplexCVdiseasegenetics,suchasthosepertainingtocoronaryartery disease.

Authors
PatrickT.O'Gara,MD,FACC EditorinChief ThomasM.Bashore,MD,FACC AssociateEditor JamesC.Fang,MD,FACC AssociateEditor GlennA.Hirsch,MD,MHS,FACC AssociateEditor JuliaH.Indik,MD,PhD,FACC AssociateEditor DonnaM.Polk,MD,MPH,FACC AssociateEditor SunilV.Rao,MD,FACC AssociateEditor

2.1:CardiovascularGenetics
Author(s): SvatiH.Shah,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. RecognizetheclinicalpresentationofMendeliancardiovascular(CV)disorderstoidentifypatientsforreferraltogenetic clinics,facilitategeneticcounselingandtesting,andinitiateappropriatetherapies,andtherebypreventadverseevents. 2. DifferentiatebetweenMendelianandcommoncomplexCVdiseases(CVDs)toprioritizepatientswhoshouldbereferred forpossiblegenetictestingfordiagnosis,screening,andriskprediction. 3. Recognizetheroleofgenetictestinginidentifyinghighriskpatientswithafamilyhistoryofcoronaryarterydisease(CAD) forprimarypreventionofCVDevents.

Introduction
SincetheadventoftheHumanGenomeProject(http://www.genome.gov/12011238),alargenumberofstudieshave focusedonseekingtounderstandthegeneticbasisunderlyingmanyCVDsandrelatedriskfactors.Whileclinicians involvedintheroutineclinicalcareofpatientswithCVDmaynotneedextensiveknowledgeofthevastliterature,itis importanttounderstandbasicgeneticconceptsandthekeyfindingsinCVgeneticsresearchasitappliestopatientcare. Thischapterwillprovideabriefoverviewofimportantgeneticconcepts,andwilldetailclinicallyrelevantandapplicable findingsinCVgeneticsresearch.

Overview
TheHumanGenomeProjectdocumentedtheentirenucleotidesequence(threebillionbasepairs)ofthehuman genomethroughsequencinginasmallnumberofindividuals.TheHapMapProject(http://www.hapmap.org) subsequentlydeterminedthecommonvariationthatexistsinthissequenceinalargernumberofindividuals,and importantly,evaluateddiversityofthisvariationbyrace/ethnicity.Theseprojectssetthefoundationforalargenumberof studiesthathaverelatedthisgeneticvariationtodiseaserisk. MendelianVersusCommon,ComplexDiseases PriortotheHumanGenomeProject,humangeneticsresearchprimarilyfocusedonMendeliandiseases.Theserare diseasesarecharacterizedbycleargeneticmodelsofrisktransmission(i.e.,autosomaldominant,autosomal recessive,orXlinked).Theyarecausedbymutationsinoneorafewgenes,whichusuallyproducegrossperturbationin theproteinproductofthegeneandshowalargerelativeriskofdisease. ExamplesofMendelianCVDsincludehypertrophiccardiomyopathy(HCM),longQTsyndrome(LQTS),andMarfan syndrome.However,itisalsowelldocumentedthatcommonatheroscleroticCVDhasaheritablecomponent,withfamily historybeingastrongriskfactortheriskincreasesintherelativewhenthereisanearlieronsetofthedisease.1 IncontrasttoMendelianCVDs,atheroscleroticCVDismoreappropriatelytermeda"common,complex"diseasewith regardtoitsgeneticcomponent.Suchdiseasesarecharacterizedby:1)multiplegenesconferringrisk,withonlymodest effects2)variablepenetrance(i.e.,iftheindividualhasageneticmutation,thatdoesnotnecessarilymeanheorshewill developthedisease)3)noclearmodelofrisktransmissionand4)oftenhavingmultiplegenegeneandgene environmentinteractions.Itisimportantforclinicianstounderstandthesedistinctions,asitcaninfluenceclinical decisionsrelatedtotheutilityofgenetictesting,diseasescreening,andcounseling. GeneticNomenclatureandTechnologies Afullreviewisbeyondthescopeofthischapter.However,afewkeyconceptsaregermanetounderstandingCVD genetics.While99%ofthehumangenomeisthesameinallhumans,itcontainssinglenucleotidechangesthatare commoninthepopulation(i.e.,>1%frequency),socalled"singlenucleotidepolymorphisms"(SNPs). Thereare>3millionSNPsthroughoutthehumangenome,inproteincodingregionsofgenes(exons),nonprotein codingregionsingenes(introns),andinintergenicregionsbetweengenes.MostMendelianCVDsareduetomorerare geneticchanges(i.e.,<1%frequencyinthepopulation),socalled"mutations,"whichcanbesinglenucleotidechanges orbiggerdisturbancesintheDNAsequencesuchasduplicationsordeletions. Incontrast,forcommon,complexgeneticdiseases,studieshavefocusedonrelatingrelativelycommonSNPsto diseaserisk,evenintheabsenceofgrossperturbationsintheproteinproductofagene.Forexample,SNPsinthe NOS1APgenehavebeenshowntobeassociatedwithvariationintheQTintervalonanelectrocardiogram(ECG),even inpopulationbasedstudies,andthesesameSNPsincreaseanindividual'sriskofsuddencardiacdeath.2 GeneticTesting Adetailedlistingofclinicallyavailablegenetictestsandtestingcentersisavailable (http://www.ncbi.nlm.nih.gov/sites/GeneTests/).ClinicalgenetictestingisofferedformostMendelianCVgenetic diseases,butfew(ifany)clinicalgenetictestsareavailableforcommon,complexCVDs. GuidelinesforgeneticevaluationofpatientswitharrhythmiasandcardiomyopathiesfromtheHeartRhythmSociety (HRS)andtheEuropeanHeartRhythmAssociation(EHRA)arenowavailable(HRS/EHRAExpertConsensusStatement ontheStateofGeneticTestingfortheChannelopathiesandCardiomyopathies: http://www.hrsonline.org/ClinicalGuidance/upload/2011_HRSEHRA_GeneticTesting.pdf).Theseguidelinesemphasize theimportanceofgeneticcounselingforallpatientsandrelativeswithfamilialheartdiseases,includingdiscussionof risks,benefits,andoptionsforgenetictesting,andsuggestreferralofsuchpatientstocentersexperiencedinthegenetic evaluationandfamilybasedmanagementoftheMendelianCVDs,detailedlater. WhenconsideringgenetictestinginmostMendelianCVdisorders,themostcosteffectiveandhighyieldmethod involvesidentificationofthediseasecausingmutationbyafullscreenofallavailablemutations(ordirectsequencingof allthenucleotides)withingene(s)implicatedinthatdiseaseintheindexcase(proband).Ifageneticmutationis identified,thengenetictestingofthatsinglemutationisofferedtoatriskfamilymembers.Theprobabilityofidentifyinga mutationintheprobanddependsonthedisease,withalowyieldforBrugadasyndrome(2530%)andmuchhigher yieldsintheLQTS(upto75%).Thecostofgenetictestingvarieswidelyingeneral,thecostoftestingintheprobandis uptoseveralthousanddollars(withvaryingcoveragebyinsurance),butonlyafewhundreddollarsformutationspecific testinginfamilymembers.

MendelianCardiovascularGeneticDiseases (1of3)
ThereareseveralgeneticCVDsthatdemonstrateMendelianinheritance.Although thesediseasesarerelativelyrare,CVclinicianswillnodoubtencounterindividuals eitherwithdiagnosedorundiagnoseddisease,aswellasindividualsatriskof diseaseduetoafamilyhistory,whorequirecarefulscreeningfordisease.Thus,itis importanttorecognizethekeyclinicalfeaturesofthesediseases,theunderlying geneticmodels,andguidelinesforscreeningoffamilymembers.Thisknowledge willfacilitatepromptidentificationofatriskindividualsfordiagnostictestingand referraltospecialtycareforgeneticcounselingandpotentialgenetictesting. MarfanSyndrome MarfansyndromeisaconnectivetissuedisordercharacterizedbyCV(aortic dilatationanddissection,mitralandtricuspidvalveprolapse,andpulmonaryartery dilatation)andnoncardiac(ocularlensdisplacement,retinaldetachment,early cataracts,jointlaxity,longboneovergrowth,scoliosis,pectusexcavatumor carinatum)manifestations.MarfansyndromeisoneofthemostcommonMendelian disorders,withaprevalenceof1in3,0005,000individuals.3 Thediagnosisof Marfansyndromeismadeclinically,incorporatingfamilyhistoryandpresenceof clinicalmanifestationsofdiseaseinmultipleorgansystems.Figure1displaysa patientwiththetypicalphenotypicmanifestationsofMarfansyndrome.Clinical diagnosticcriteria,includingtheGhentcriteria,havebeenpublished.4,5 Marfansyndromeisinheritedinanautosomaldominantfashionandiscausedby mutationsinthefibrillin1extracellularmatrixproteingene(FBN1),althoughupto 30%ofcasesdonothaveaffectedparentsandthuspresumablyrepresentdenovo mutations.3 Genetictestingisavailableandthelikelihoodoffindingacausative mutationis95%.Marfansyndromeneedstobeclinicallydistinguishedfromother similargeneticdisordersincludingfamilialectopialentis,MASSphenotype(mitral valveprolapse,aorticrootdiameteratupperlimitsofnormal,stretchmarks,and skeletalconditions),andfamilialaorticaneurysm,allofwhichmayalsohave mutationsinFBN1,3 aswellasmorerare,butrelatedgeneticdisorderscausedby othergenessuchasLoeysDietzsyndromeandEhlersDanlossyndrome(EDS), vasculartype. AswithmanyMendeliandisorders,genetictestingisindicatednotforconfirming diagnosisintheindexcase(whichismadeclinically),buttofocusgenetictestingin otherfamilymembers.Theseresultscanhelpdeterminewhethertheyneedtohave longitudinalclinicalmonitoringorwhethertheycanbereassuredthattheyhavenot inheritedthepathologicmutation.3 ThereareseveralMendelianCVgeneticdisorderswithmanifestationsthatcan presentsimilarlytoMarfansyndrome.Forexample,thevasculartypeofEDS(EDS typeIV)isanautosomaldominantdisordercharacterizedbyjointlaxity,translucent skin,easybruising,wideanddystrophicscars,visceralorganrupture,anda predilectiontowardsaneurysmand/ordissectionofmediumtolargearteries, withoutpredilectionforinvolvementofaorticroot.4 EDS,vasculartype,iscausedby mutationsinthecollagenCOL3A1gene. Amuchmoreraredisorder,LoeysDietzsyndrome,istransmittedinanautosomal dominantfashionandsharesmanyfeatureswithMarfansyndrome(craniofacial abnormalities,pectusdeformity,arachnodactyly,jointlaxity,duralectasia,andaortic rootaneurysmwithdissection).4 UniquefeaturesofLoeysDietzinclude hypertelorism,broadorbifiduvula,cleftpalate,ChiariImalformation,bluesclerae, translucentskin,easybruising,andthesyndromeisparticularlynotablefora propensityfordiffuseandaggressivevasculardiseaseincludingarterialtortuosity andaneurysmswithdissections.LoeysDietziscausedbymutationsinthe TGFBR1orTGFBR2genes.4 FamilialDilatedCardiomyopathy

Figure1

Table1

Figure2

Familialdilatedcardiomyopathy(DCM),alsooftencalledhereditaryoridiopathic DCM,manifestsclinicallyasleftventricular(LV)systolicdysfunctionanddilatationin theabsenceofothercausesofcardiomyopathy,andpredisposespatientsto congestiveheartfailure,arrhythmias,andsuddencardiacdeath.Itaccountsforupto 50%ofcasesofDCM.FamilialDCMoftendisplaysanagedependentpenetrance, withpatientsmanifestingdiseaseintheirfourthtosixthdecades.6 Thediagnosisis usuallymadewhentwoormorecloselyrelatedfamilymembersmeetadiagnosis foridiopathicDCM.5 TheprevalenceoffamilialDCMhasbeenestimatedat ~1:2,700,butthisislikelyunderestimated.Pathologicevaluationrevealsmyocyte deathandmyocardialfibrosis.7 FamilialDCMisoverallaveryheterogeneousgeneticdisease,characterizedby variablepresentationandageofonset,reducedpenetrance,anddifferentmodesof inheritance,dependingonthegene/mutationinvolved.Autosomaldominantisthe mostcommonlyseenpatternofinheritance.7Mutationsin33genesencodinga widevarietyofcomponentsofthemyocyte,includingtwoXlinkedgenes,havebeen implicatedinfamilialDCM(Table1Figure2).Intotal,theyonlyaccountfor3035% ofgeneticcausesofthedisease.6 Itisimportanttonotethatclassificationbasedon theunderlyinggeneticmutationshouldnotoverridediagnosisbasedonclinical findings,sincedifferentmutationsindifferentgenescancausedifferentCV disorders.Forexample,mutationsinthemyosinheavychaincauseeither hypertrophiccardiomyopathyorfamilialDCM.7 TheroleofgenetictestinginfamilialDCMisunclear,sincethediagnosticyieldin identifyingacausativemutationisrelativelylowandthisknowledgedoesnot changemanagementfortheaffectedpatient.However,thisknowledgecouldhelp withcounselingatriskfamilymembersandcouldhelpdeterminetheneedand frequencyofclinicalevaluations.Inaddition,inpatientswithconcomitantsignificant conductiondisease,familialDCMduetomutationsintheLMNAgeneshouldbe considered,andifconfirmedbygenetictesting,useofanimplantablecardioverter defibrillator(ICD)shouldbeconsidered.7 ClinicalscreeningoffirstdegreerelativesofpatientswithfamilialDCMshouldbe pursued,withhistory,physicalexam,ECG,andechocardiogram.However,giventhe variableageofonset,abaselinenormalECGandechodoesnotruleoutfamilial DCM,andlongitudinalfollowupshouldbeperformed.Withanewdiagnosisof DCM,clinicalscreeningoffirstdegreefamilymemberswillrevealDCMin2035%of familymembers.6

TypicalPhenotypicManifestationsofMarfanSyndrome Figure1 TypicalphenotypicmanifestationsofMarfansyndromeincluding(a)pectuscarinatum,(b)pectusexcavatum,(candd)jointhypermobility,(e) protrusioacetabulae(medialdisplacementofthefemoralheadintothepelviccavity),and(f)stretchmarks. ReproducedwithpermissionfromCanadasV,VilacostaI,BrunaI,FusterV.Marfansyndrome.Part1:pathophysiologyanddiagnosis.NatRev Cardiol20107:25665.

GenesImplicatedinFamilialDilatedCardiomyopathy Table1 DCM=dilatedcardiomyopathyN/A=notapplicableN=noY=yes. AdaptedwithpermissionfromHershbergerRE,SiegfriedJD.Update2011:clinicalandgeneticissuesinfamilialdilatedcardiomyopathy.JAmColl Cardiol201157:16419.

DiagramofaCardiacMyocyteWithAnnotationofGenesCausingDilatedand/orHypertrophicCardiomyopathy Figure2 Displayedarekeystructuresofthecardiacmyocyte(extracellularmatrix,sarcolemma,sarcomere,mitochondrion,sarcoplasmicreticulum,and nucleus)andtheirkeyindividualcomponents.Withintheextracellularmatrix(topofdiagraminmediumblue)arefoundcomponentsofintegrins (whichbindthemyocytetotheextracellularmatrixandbasementmembrane),thesarcoglycancomplex,andionchannels(allofwhichspanthe sarcolemmamembrane). Intracellularly(inlightblue),residesthesarcomere(thefundamentalcontractileunitofthemyocyte)itiscomposedofthinfilaments(actin)and thickfilaments(myosin),alongwithotherfundamentalproteinsofthecontractileapparatusincludingmyosin,tropomyosin,andthetroponin complex.Thesarcoplasmicreticulum(indarkblue)isanintracellularmembranenetworkthathandlesregulationofcytosoliccalcium.Genesthat havebeenshowntocausedilatedand/orhypertrophiccardiomyopathythatencodethesecardiacmyocytecomponentsareannotatedinitalics.

MendelianCardiovascularGeneticDiseases (2of3)
FamilialHypertrophicCardiomyopathy HCMisageneticdisordercharacterizedbyLVhypertrophy(LVH)withoutLVdilation, particularlyoftheinterventricularseptum,intheabsenceofotherpredisposing conditionssuchashypertensionorvalvulardisease.Itisarelativelycommon geneticdisease,witha1in500prevalencebyechocardiographyinthegeneral population.8 Theclinicaldiagnosisistypicallymadewithechocardiography.Twentyfivepercent ofpatientswithHCMhaveadetectableobstructivegradient,andevenmorehavea gradientwithprovocation.9 ThepresenceanddegreeofLVHcanbeagerelated thus,theimportanceofseriallongitudinalfollowupinatriskindividuals.HCMcan causediastolicdysfunctionandLVoutflowtractobstruction,andapredispositionto increasedriskofheartfailureandsuddencardiacdeath.Infact,HCMisthemost commoncauseofsuddendeathinyoungindividuals.8 Pathologicevaluationoftenrevealsdisarrayofcardiacmyocyteswithfibrosis. Treatmentcaninvolvebetablockersorcalciumchannelblockers,antiarrhythmics, alcoholseptalablation,orsurgicalmyomectomy.AnICDshouldbeconsideredin individualswithpriorcardiacarrestorthosedeemedatincreasedrisk(i.e.,family historyofsuddencardiacdeath,ventricularectopyonHoltermonitoring,unexplained syncope,extremeLVH[>3cm],oradropinbloodpressurewithexercise). FamilialHCMisaMendeliangeneticdisorderwithautosomaldominantinheritance causedbyoneof>900identifiedmutationsinoneof14genesthatencode componentsofthesarcomere(Figure2).MutationsinMYH7(myosinheavychain) andMYBPC3(encodingcardiacmyosinbindingproteinC)arethemostcommon, witheachattributableto40%ofHCMcases.7 Theremainingsevengenesaccount for<15%ofcases(Table2). Genetictestingisclinicallyavailableformostoftheknownmutations (http://www.ncbi.nlm.nih.gov/sites/GeneTests/).Panelsareavailablethatcoverallof theidentifiedHCMsarcomericgenes,andalsoincludemutationsingenescausing metaboliccardiomyopathiesthatcanpresentsimilarlytoHCM(describedlater).10A mutationisidentifiablein5075%offamilialcasesofHCM,asopposedtoonly30 35%infamilialDCM.6 FamilialHCMneedstobedifferentiatedfromLVHresultingfromothergenetic disorderssuchasinbornerrorsofmetabolism(Fabrydisease,causedby mutationsinthegenegalactosidase[GLA]cardiacamyloidosisDanondisease, causedbymutationsinLAMP2othermetaboliccardiomyopathies,i.e.,cardiac hypertrophycausedbymutationsinPRKAG2andneuromusculardisorders) especiallyinyoungerindividuals. Thepresenceofpreexcitationandconductiondiseaseinthecontextofunexplained cardiachypertrophyshouldraiseconcernforPRKAG2cardiomyopathy,the concurrentpresenceofaskeletalmyopathy,neurologicinvolvement,and/orpre excitationshouldraiseconcernforDanondisease.10Identificationofthese disordershassignificantimplicationsforclinicalmanagement.Forexample,ifFabry diseaseispresent,enzymereplacementtherapyisavitalpartoftherapeutic management.GenetictestinginHCMmaybeusefulformanyreasons.For example,itcanbeusedtohelpconfirmadiagnosisinthepresenceofunexplained LVHthepresenceofaknownHCMgeneticmutationconfirmsthediagnosisof HCM.10 Genetictestingcanalsohelpguidetreatment,prognosis,andscreeninginatrisk familymembers.Thereisalsosomesuggestionthatdifferentmutationsmaybe associatedwithdifferentmanifestationsofthegene(althoughnotwellestablished enoughtoenabletheseclinicalpresentationstoguidewhichgenestogenotype). Regardless,familyhistoryisofgreatimportinmanagement.Individualswitha
Figure2

Table2

Table3

Figure3

strongfamilyhistoryofHCMshouldbescreened,andevenmildLVHthatdoesnot meetdiagnosticcriteria(i.e.,septalwallthickness>15mm)shouldbefurther evaluated.11 Guidelinesforthescreeningofclinicallyunaffected,atriskfamilymembershave beenproposed,12includingrepeatevaluationwithphysicalexam,andECG,every 1218monthsforfamilymembersages1218years,andevery35yearsforages >1821years(orinresponsetoanychangeinsymptoms). Screeninginchildren<12yearsofageisoptional,butrecommendedifhighrisk featuresinthefamilyarepresent,thechildisacompetitiveathlete,orthechildhas symptomsorotherclinicalfindingsthatsuggestearlyLVhypertrophy.12Asingle negativeevaluationdoesnotexcludedevelopmentofHCMlongitudinal,serial followupsareoftennecessary. LongQTSyndrome AnindepthdiscussionofthegeneticsoftheLQTSisbeyondthescopeofthis chapter,butexcellentreviewshavebeenpublished.13,14Inaddition,asdescribed earlierinthesectiononGeneticTesting,theHRSandEHRAwroteanExpert ConsensusStatementontheStateofGeneticTestingfortheChannelopathiesand Cardiomyopathies,availableat: http://www.hrsonline.org/ClinicalGuidance/upload/2011_HRS EHRA_GeneticTesting.pdf. ThereareseveraltypesofLQTS,eachcharacterizedbyuniqueclinical manifestationsandunderlyinggeneticmutations(Table3).LQTSisdividedinto typesbasedontheunderlyinggeneticmutationand,thus,theindividualclinical syndromescanbetheresultofoneofseveralmutations.Asagroup,these disordersarecharacterizedbydelayedventricularrepolarization,whichmanifestsas prolongationoftheQTintervalonECG(Figure3).14,15,16LQTShasaprevalenceof approximately1:3,0001:5,000.14PatientsaffectedwithLQTShaveanincreasedrisk ofarrhythmias,includingpolymorphicventriculartachycardia(VT)(i.e.,torsadede pointes)andsuddencardiacdeath. PatientswithsuspectedLQTSusuallypresentforevaluationafterexperiencingan arrhythmia,abortedcardiacarrest,orsuddendeathinarelative.Thedifferential diagnosisinthesepatientsincludesLQTS,HCM(mostcommon),arrhythmogenic rightventricularcardiomyopathy/dysplasia(ARVC/D),Brugadasyndrome,andother moreraredisordersmentionedlater.14,15Thepatient'shistorycanhelpnarrowthe diagnosisforexample,arrhythmic/syncopaleventsoccurmorefrequentlyduring exerciseinpatientswithHCM,LQTS1(swimminginparticular),and catecholaminergicpolymorphictachycardia,whereasarrhythmiceventsoccurmore frequentlyatrestinpatientswithLQTS2,LQTS3,Brugadasyndrome,and ARVC/D.14,15 ExerciseECG,ambulatoryECGtesting,and/orintravenouspharmacologic provocationtestingmaybeusefulforsomeindividualswhohaveanuncertainQT intervalonrestingECG.SerialQTintervalmeasurementsareimportantandare betterindefiningthesubsequentriskofcardiaceventsthanasingleQT measurement.14TreatmentofLQTSincludesbetablockersforprophylaxisof arrhythmias,andshouldbegiventoallintermediateorhighriskpatientswith LQTS,andshouldbeconsideredforsomelowriskpatients.Patientsremaining symptomaticdespitebetablockertherapy,andveryhighriskpatientsshouldbe consideredforimplantationofanICDforprimarypreventionofsuddencardiac death.14ICDimplantationshouldalsobepursuedforsecondarypreventionin patientswithLQTSalreadyhavingsufferedacardiacevent. LQTSisahereditarydiseasecausedbymutationsingenesencodingthemyocyte ionchannels,typicallyshowinganautosomaldominantmodeofinheritance,but withvariablepenetrance.LQTSissubdividedbasedontheunderlyinggenetic mutation(Table3).GenetictestingwillidentifyaknownLQTSmutationin approximately75%ofpatientswithLQTS.GenetictestingforLQTScanhelpwiththe diagnosis(particularlyinpatientswithlessclearmanifestationsofLQTS,i.e.,a correctedQTintervalof<500ms),andtherearestudiessuggestingthatclinical

courseisinfluencedbygenotype.14,15Aswell,genetictestingintheindexindividual ishelpfulforguidinggenetictestingandclinicalscreeninginatriskfamily members. RomanoWardsyndrome(RWS)isthemostcommonformofinheritedLQTS,witha prevalenceof1:3,000to1:7,000.16RWSincludesLQT1,LQT2,LQT3,LQT5,and LQT6,andmanifestsasacardiacdisorderwithoutothersystemicmanifestations. Symptomsofsyncopeusuallyoccurduringexercise(LQTS1andLQTS2),timesof highstress(LQTS),orduringsleep(LQTS2andLQTS3),andusuallyoccurduring theadolescentyearsthroughtheseconddecadeoflife.RWSisinheritedinan autosomaldominantfashion,withapproximately70%offamiliesidentifiableas havingoneoftheknowndiseasecausingmutations. FivegenesareknowntocauseRWS,andclinicalgenetictestingisavailableforall ofthem:KCNQ1(LQT1,58%ofRWSisattributabletomutationsinthisgene), KCNH2(LQT2,35%),SCN5A(LQT3,5%),KCNE1(LQT5,1%),andKCNE2(LQT6, 1%).16Thereisacorrelationbetweenthetypeofgeneticmutationandclinical presentationandtherapy.LQTS1andLQTS2areusuallytreatedwithbetablockers ifsymptomaticandcanbeconsideredforsomeasymptomaticindividuals prophylacticICDcanbeconsideredforthosewhohaveresistantsymptomsand/or historyofcardiacarrest.AnICDshouldbeconsideredforsymptomaticLQT3 individuals.PatientswithRWSshouldbecounseledtoavoidintensephysical activity,emotionalstress,anddrugsthatcouldfurtherprolongtheQTinterval.Other geneshavebeenimplicatedinLQTS:ANK2(LQTS4),KCNJ2(LQT7),andmutations inCAV3(LQT9)havebeenassociatedwithLQTS,16andthus,areproposedas additionalgenesforRWS. SeveraldisordersaregeneticallyrelatedtoRWS.JervellandLangeNielsen syndromepresentswithcongenitalbilateralsensorineuralhearinglossand prolongedQTinterval,whichisassociatedwithanincreasedriskofventricular arrhythmiasandsuddencardiacdeath.JervellandLangeNielsonsyndromeis inheritedinanautosomalrecessivepatternandiscausedbymutationsinthe KCNQ1(LQT1)orKCNE1(LQT5)genes.Brugadasyndrome(describedlater),is causedbymutationsinSCN5A(LQT3)andisassociatedwithpolymorphic VT/ventricularfibrillationandsuddendeath.AcquiredLQTSischaracterizedby prolongationoftheQTintervalinthecontextoftreatmentwithanoffendingdrug someindividualswithacquiredLQTShaveageneticpredispositioncausedbya mutationinoneoftheknownRWSgenes. AndersenTawilsyndromemanifestsasatriadofperiodicparalysis,highfrequency bidirectionalVT,andprolongedQTinterval,andalsoshowsothernoncardiac features.ItiscausedbyonemutationinKCNJ2,withapproximately70%of individualswithAndersenTawilhavingthismutation,andhasbeenproposedas LQT7,butthereisuncertaintyaboutwherethereistrueQTprolongationinthis syndromeorwhetherthelargeUwavesareprecludingaccuratemeasurement.16 Timothysyndrome(LQT8)canpresentwithcardiacdefects(prolongedQTandother congenitalcardiacdefects),syndactylyandfacialandneurodevelopmentalchanges, andiscausedbyamutationintheCav1.2calciumchannelgeneCACNA1C.16 LQT4isveryrareandiscausedbymutationsintheankyrin(ANK2)gene.LQT4 showsvariablepenetrancewithonlyaminorityofindividualswithamutation showingQTprolongation,andatrialarrhythmiasbeingaprominentmanifestation, includingsinusbradycardiaandatrialfibrillation.16

DiagramofaCardiacMyocyteWithAnnotationofGenesCausingDilatedand/orHypertrophicCardiomyopathy Figure2 Displayedarekeystructuresofthecardiacmyocyte(extracellularmatrix,sarcolemma,sarcomere,mitochondrion,sarcoplasmicreticulum,and nucleus)andtheirkeyindividualcomponents.Withintheextracellularmatrix(topofdiagraminmediumblue)arefoundcomponentsofintegrins (whichbindthemyocytetotheextracellularmatrixandbasementmembrane),thesarcoglycancomplex,andionchannels(allofwhichspanthe sarcolemmamembrane). Intracellularly(inlightblue),residesthesarcomere(thefundamentalcontractileunitofthemyocyte)itiscomposedofthinfilaments(actin)and thickfilaments(myosin),alongwithotherfundamentalproteinsofthecontractileapparatusincludingmyosin,tropomyosin,andthetroponin complex.Thesarcoplasmicreticulum(indarkblue)isanintracellularmembranenetworkthathandlesregulationofcytosoliccalcium.Genesthat havebeenshowntocausedilatedand/orhypertrophiccardiomyopathythatencodethesecardiacmyocytecomponentsareannotatedinitalics.

GenesImplicatedinHypertrophicCardiomyopathy Table2 HCM=hypertrophiccardiomyopathyN=noY=yes. AdaptedwithpermissionfromHershbergerRE,SiegfriedJD.Update2011:clinicalandgeneticissuesinfamilialdilatedcardiomyopathy.JAmColl Cardiol201157:16419.

ClinicalCharacteristicsandGeneticMutationsAssociatedWithLongQTSyndrome Table3 JLNS=JervellandLangeNielsensyndromeRWS=RomanoWardsyndrome. ModifiedwithpermissionfromVincentGM.RomanoWardsyndrome.In:PagonRA,BirdTD,DolanCR,StephensK,eds.GeneReviews.Seattle: UniversityofWashington,Seattle1993,andGoldenbergI,ZarebaW,MossAJ.LongQTSyndrome.CurrProblCardiol200833:62994.

TypicalElectrocardiograminLongQTSyndrome Figure3 ReproducedwithpermissionfromBrugadaR.Suddendeath:managingthefamily,theroleofgenetics.Heart201197:67681.

MendelianCardiovascularGeneticDiseases (3of3)
BrugadaSyndrome BrugadasyndromeischaracterizedbyRVconductionabnormalitiesandcovedtype STsegmentelevationintheanteriorrightprecordialleads(V1 V3 )onECG(Figure 4),andleadstoventricularfibrillationandsuddencardiacdeathatanearlyage.17 Brugadasyndromeisrelativelyrare,affectinganestimated3in10,000people.It displaysanautosomaldominantinheritancepatternwithvariablepenetranceand expressivity,rangingfromasymptomaticindividualstosuddencardiacdeathduring thefirstyearoflife.18 MostmutationscausingBrugadasyndromeoccuringeneswithinorrelatedtothe sodiumchannel(SCN5A),whichcause2025%ofBrugadasyndrome,although otherionchannelshavebeenimplicated.17Inaddition,severalgenesencoding auxiliaryproteinsofthecardiacsodiumchannelhavebeenlinkedtoBrugada syndrome,includingSCN5A,1subunitofthecardiacsodiumchannel(SCN1B), 3subunitofthecardiacsodiumchannel(SCN3B),andglycerol3phosphate dehydrogenase1like(GPDL1),17aswellasmutationsinvolvingtheLtypecalcium channelsubunit(CACNA1C)andsubunit(CACNB2B)implicatedinalmost10% ofBrugadasyndromecases.18 Clinicalgenetictestingisavailableformanyofthesemutations (http://www.ncbi.nlm.nih.gov/sites/GeneTests/)however,thediagnosticyieldislow, withupto65%ofpatientsnothavinganidentifiablemutationongenetictesting.18 GenetictestinginBrugadasyndromecanhelpwithriskstratificationintheproband, assomemutationsdemonstrateamoredeleteriousmoleculardeficitand,thus,a moreseverephenotypicpresentation,althoughtheprimaryutilityisfordiagnostic confirmationintheprobandandtestinginfirstdegreefamilymemberstohelpguide screening.18 ArrhythmogenicRightVentricularDysplasia/Cardiomyopathy ARVD/Cisageneticdisordercharacterizedbycardiomyopathypredominantly affectingtherightventriclethatpathologicallyconsistsoffibrofattyreplacementof cardiomyocytes,19resultinginanincreasedriskofsuddencardiacdeathdueto ventriculararrhythmiasatayoungage.Theclinicaldiagnosisismadebasedonthe presenceoftwomajorcriteria,oronemajorandtwominorcriteria,orfourminor criteria. Majorcriteriainclude:1)severeRVdilatationorlocalizedRVaneurysm2)fibrofatty infiltrationoftheRVmyocardiumonbiopsy3)Epsilonwavesorlocalized prolongationoftheQRScomplexinV1 V3 or4)familyhistoryofARVD/Cconfirmed onautopsyorsurgery.Minorcriteriainclude:1)mildglobalRVdilationorregional RVhypokinesia2)latepotentialsonsignalaveragedECG3)invertedTwavesin leadsV1 V3 (intheabsenceofrightbundlebranchblock)4)leftbundlebranch blocktypeVTorfrequentprematureventricularcontractionor5)familyhistoryof ARVD/Cbasedonclinicaldiagnosisorfamilyhistoryofprematuresuddendeath duetosuspectedARVD/C.19 Tworelateddiseasesinclude:1)Naxosdisease,characterizedbyARVD/Cwith woollyhairandpalmoplantarkeratoderma,and2)theCarvajalsyndrome, characterizedbyasimilardermatologicpresentationasNaxosdisease,butwith predominantlyLVinvolvement.7 ARVD/Cisahereditarydisease,withanautosomaldominantmodeof transmission,butthegeneticpenetranceislowandthereishighvariabilityinthe clinicalpresentation.Mutationsingenesencodingproteinsofthecardiac desmosome,importantformechanicalcelltocelladhesion,areresponsiblefor ARVD/C,Naxosdisease,andCarvajalsyndrome.
Figure4

Mutationsinthedesmosomalproteinplakophilin2(PKP2)arepresentinupto43% ofcases.Othergenesinvolvedincludedesmocollin2(DSC2),desmoplakin(DSP), desmoglein2(DSG2),andplakoglobin(JUP).19Twonondesmosomalgeneshave alsobeenimplicatedinARVD/C:transforminggrowthfactor3(TGF3)and transmembraneprotein43(TMEM43).6 Clinicaltestingisavailableforallofthe desmosomalgenemutationshowever,givenlowyields,highbackgroundnoise, andunclearclinicalimplicationsfortheproband,theroleofgenetictestingin ARVD/Cisnotwellestablished.18 Itisimportanttonotethatmutationshavebeenidentifiedinonly50%ofcases. Thus,a"negative"genetictestforARVDdoesnotruleoutthepresenceofthe disease.GenetictestingforARVD/Cisoftenforidentificationoffamilymembersat riskforthedisease.GenetictestinginARVD/C,ingeneral,shouldnotbeusedto confirmthediagnosis,asclinicalimagingandotherclinicalevaluationshave greaterdiagnosticutility.19 CatecholaminergicPolymorphicVentricularTachycardia CatecholaminergicpolymorphicVT(CPVT)ischaracterizedbyanormalresting ECG,sometimeswithbradycardiaandUwaves,whichpresentswithsignificant ventricularectopyincludingbidirectionalVTwithtreadmillorcatecholaminestress testing,andlikeLQT1,isassociatedwithswimmingprecipitatinganarrhythmia.18 PatientswithCPVTgenerallyhaveastructurallynormalheart,buthaveaverystrong riskforsuddencardiacdeath. CPVTisaheritabledisordercausedbymutationsingenesencodingcomponents oftheintracellularcalciumreleasechannelcomplexwithinthesarcoplasmic reticulumofthecardiacmyocyte,withmutationsinthecardiacryanodinereceptor 2/calciumreleasechannelgene(RYR2)causing5060%ofcases.18Clinical genetictestingisavailable(http://www.ncbi.nlm.nih.gov/sites/GeneTests/)however, thereiscurrentlynoconsensusabouttheutilityofacomprehensivescreenofall 105RYR2exons,orwhethermoretargetedgenetictestingwouldbesufficient. Interestingly,almost30%ofpossibleoratypicalLQTScases(correctedQTinterval <480ms)withexertionalsyncopehavebeenfoundtoharboramutationinRYR2.18 Genetictestinghasbeensuggestedforpatientswithexerciseinducedsyncopeor cardiacarrestorneardrowningwhohaveacorrectedQTinterval<460ms,aswell asallimmediatefamilymembersofaknownCPVTproband.18 AtrialFibrillation Althoughatrialfibrillationdoesappeartohaveahereditarycomponent,20familial formsofatrialfibrillationarerare.GenescausingmonogenicMendelianatrial fibrillationincludemutationsinthepotassiumchannelsubunitsKCNQ1,KCNJ2, KCNA5thecardiacsodiumchannelSCN5AandsubunitsSCN1BandSCN2Band theconnexin40gene.20However,theseraremutationsdonotappeartobeacause ofcommon,nonMendelianatrialfibrillation,whichisbestcharacterizedasa common,complexgeneticdisease. Severalgeneshavebeenshowntobeassociatedwithincreasedriskofatrial fibrillationdevelopment,includingcommonvariationingenesencodingthecardiac potassiumandsodiumchannelsandsubunits,andcommonvariantsnearthe PITX2gene,whichencodesatranscriptionfactor,aswellasmanycommon variantsidentifiedthroughgenomewideassociationstudies(GWAS),whichtakean "unbiased"wholegenomeapproachtoidentifyinggenesassociatedwithdisease. Evenincombination,however,thesevariantsonlyexplainasmallproportionofthe riskofatrialfibrillation.21Therefore,althoughatrialfibrillationisaheritabledisease, muchworkremainstobedonebeforegenetictestingisindicated.

TypicalElectrocardiogramFindingsinBrugadaSyndrome Figure4

GeneticsofCoagulationandBleeding
Coagulationandhemostasisarethedelicatebalanceofacomplexinterrelationshipofcoagulationfactors,platelets,and fibrinolyticproteins.Geneticvariantsassociatedwithchangesinthesefactorsmaycausederangementofthis coordinatedsystem,resultinginabnormalcoagulationorfibrinolysisandincreasedriskofthrombosis.Untiltheearly 1990s,onlythreesinglegenedisordershadbeenidentifiedthatresultedinincreasedriskofthromboembolism: antithrombinandproteinCandproteinSdeficiencies,whichtogetheroccurinonly15%offamilieswithfamilialvenous thromboembolism(VTE).Forarterialthrombosis,fewgeneticvariantshadbeenreproduciblyassociatedwithincreased risk. Onemustkeepinmindthatthepathophysiologyofmostthrombosisisfundamentallylinkedtoacquirednongenetic factorsthatinteractwithabackgroundofinheritedgeneticrisktoproducedisease.Thefollowingisabriefreviewofthe currentlyavailableknowledgeofthegeneticsofhumanthrombosis,butthereremainsalargeamountofunexplained variationinthegenetic,molecular,andclinicalmanifestationsofthisdisease. FactorVLeiden(ActivatedProteinCResistance) ActivatedproteinC(APC)resistancepredisposestoVTE,andapproximately90%ofcasesofVTEduetoAPCresistance arecausedbyaSNPinthefactorVgeneknownasfactorVLeiden.FactorVLeidenisthemostcommongeneticcause ofVTE,responsibleforupto50%ofcases,withaprevalenceofupto6%inCaucasiansandafrequencyofhomozygosity of1:5,000.FactorVLeidenshowsvariablepenetranceandexpressivityandistransmittedinanautosomaldominant fashion,althoughindividualshomozygousforthemutationhaveamuchgreaterthromboticriskthanheterozygoteswho haveaslightlyincreasedrisk.22TheriskforVTEvariesfromathreefoldincreasedriskinindividualscarryingonecopy, increasingtoa10foldincreasedriskinindividualscarryingtwocopies(i.e.,homozygotes),andupto18foldincreased riskforhomozygotesfromthrombophilicfamilies.22 FactorVLeidendoesnotappeartobeconsistentlyassociatedwithriskofarterialthrombosis,althoughtherearedatato suggestthatitmaycontributetomyocardialinfarction(MI)inyoungerpatientsandpatientswithotherCVDriskfactors.22 ThepresenceoffactorVLeideninconjunctionwithanotherthromboticdefectcanresultinincreasingthethromboticrisk uptothreefoldincomparisonwithriskofasingledefect. InpatientswithfactorVLeidenwhosufferafirstthromboembolicevent,inadditiontostandardguidelinesfortreatment, longtermoralanticoagulationshouldbeconsideredinpatientswith:1)recurrentVTE,2)multiplethrombophilic disorders,3)concomitantriskfactors,or4)homozygousstatusforfactorVLeiden.22Inheterozygousindividuals, prophylacticanticoagulationisnotroutinelyrecommended,althoughashortcoursecouldbeconsideredwhenotherrisk factorsarepresent.22WomenwhocarrythefactorVLeidenpolymorphismshouldbecounseledtoavoidoral contraceptivesandsmoking. FactorVLeidenisdiagnosedbyeitheracoagulationscreeningtest(APCresistanceassay)orbyDNAanalysisofthe factorVgene(F5).22Genetictestingshouldbeconsideredinindividualswith:1)afirstunprovokedVTEatanyage, especiallyatyoungerages2)historyofrecurrentVTE3)VTEatunusualsitesor4)VTEduringpregnancyorassociated withtheuseofhormonereplacementtherapyororalcontraceptives.22Genetictestingmayalsobeconsideredin individualswithunexplainedfetalloss,femalesmokers<50yearsoldwithanMIorstroke,individuals>50yearsoldwith afirstVTEintheabsenceofmalignancyorintravasculardevice,asymptomaticadultfamilymembersofindividualswitha factorVLeidenmutation(especiallythosewhoarepregnantorconsideringpregnancyororalcontraceptiveuse),and childrenwithnoncatheterrelatedunexplainedVTEorstroke.22 AntithrombinIII,ProteinC,andProteinSDeficiencies AlthoughantithrombinIII,proteinC,andproteinSdeficienciesarestrongriskfactorsforVTE(strongerthanfactorV Leiden),theyarerelativelyraredisorders,accountingindividuallyfor<5%ofcausesofVTE.Greaterthan100genetic mutationshavebeenidentifiedintheantithrombingenewhichleadtoantithrombinIIIdeficiency,anautosomaldominant disorder,withdifferentmutationsresultinginmolecularandclinicalheterogeneity. Antithrombindeficiencyhasanestimatedprevalenceofupto1:500inthegeneralpopulationandisrelativelyrare, accountingfor<1%ofpatientspresentingwithafirstthromboticevent.Diagnosisisusuallybasedonanantithrombin functionalassaythatmeasurestheabilityofheparintobindantithrombin,andifabnormal,anantithrombinantigenlevel todifferentiatebetweentypesofantithrombindeficiencies.Thefunctionalassayshouldbeperformedwhenthepatientis notreceivingheparinandideally,atleast2weeksafteroralanticoagulanttherapy.23 ProteinSdeficiencyisinheritedasanautosomaldominanttrait,causedbyoneofseveralmutationsintheproteinS gene,andpredisposestorecurrentVTEinheterozygousindividuals.However,only5060%ofpatientswithproteinS deficiencyhaveidentifiedgeneticmutations.TheclinicaldiagnosisofproteinSdeficiencyusesafunctionaland immunoassay,aswithantithrombinIIIdeficiency.ProteinCdeficiencyisalsoinheritedinanautosomaldominant

mannerandiscausedbyoneof>100geneticmutationsintheproteinCgene.TheprevalenceofheterozygousproteinC deficienciesisupto1:200inthegeneralpopulationandupto5%inpatientswithVTE.ProteinCdeficiencyisdiagnosed byavarietyofimmunologicandfunctionalassays.HomozygousproteinSorproteinCdeficiencyisrare,andusually associatedwithneonatalorfetaldeath.24Genetictestingisnotindicatedforanyofthesedeficiencies. Prothrombin20210A Thisgeneticvariantintheprothrombin(factorII)genehasbeenassociatedwithuptoathreefoldincreasedriskofVTE andisthesecondmostfrequentprothromboticpolymorphism.Thetransmissionisautosomaldominant,witha prevalenceof2%inthegeneralpopulation,6%inpatientspresentingwithafirstdeepvenousthrombosis,andpresent inupto18%ofindividualswhohavealreadyhadathromboticeventorhaveafamilyhistoryofthrombosis.22 Ithasbeensuggestedthatthisvariantresultsinincreasedthrombosisriskonlyinpatientswhohaveadditionalrisk factorssuchasotherprothromboticgeneticvariants.Forexample,thefrequencyofindividualscarryingbothafactorV Leidenalleleandtheprothrombingenemutationis1:1,000inthegeneralpopulationand15%inindividualswithVTE.22 Aswiththeotherprothromboticgeneticvariants,theroleofthismutationinarterialthrombosisisinconsistent.Clinical genetictestingisavailableforthisvariant. Hyperhomocysteinemia Homocystinuriaisararegeneticdiseasetransmittedinanautosomalrecessivepatternandmanifestsas thromboembolicdiseaseandprematureatherosclerosis.Incontrast,hyperhomocysteinemiaisrelativelycommon,with upto7%ofthepopulationshowinghomocysteineelevationstoalesserdegreethanthatseenwiththeMendelian diseaseofhomocystinuria.Althoughdebated,elevatedtotalhomocysteinelevelshavebeenshowntobeassociatedwith anincreasedriskofthromboembolicdiseaseincludingatheroscleroticdisease(seereviewbyDiMinnoetal.25) however,theseassociationsareconfoundedbymanyfactors.Therearemanyclinicalvariablesthatcancausemild moderateelevationsinhomocysteinelevels,includingnutritionaldeficiencies,medications,chronickidneyfailureand smoking,andgeneticfactorsalsoappeartoplayarole. ArelativelycommonvariantintheMTHFR(5,10methylenetetrahydrofolatereductase)gene,whichencodesanenzyme thatcatalyzestheconversionofhomocysteinetomethionine,hasbeenassociatedwithelevatedhomocysteinelevelsin individualswithlowfolateintake.22However,thedataimplicatingtheprothromboticroleofthispolymorphismare conflicting,andingeneral,itisnotthoughttobeasignificantcontributortoprothromboticrisk.Thus,genetictestingfor theMTHFRvariantisnotclinicallyindicated,androutinemeasurementofhomocysteinelevelsisnotindicated.However, althoughtherearenocleardatasupportingthisapproach,giventheabsenceofothermodifiablebiomarkersforrisk assessment,measurementofplasmahomocysteinelevelsmaybeconsideredinpatientspresentingwithveryearly onsetthromboticevents(includingatherosclerosis)andtreatmentwithvitaminsB6,B12,andfolateinitiatedforelevated levels.

ComplexDiseaseGenetics:GeneticsofAtherosclerosis
CADandrelatedatherosclerotictraitsareheritableinnature,asaremanyCADrelatedriskfactors.Earlystudieshave shownthathavingafirstdegreerelativewithCADincreasesanindividual'sriskofCAD,withincreasingrisktheyounger theageofonsetofthatrelative.26Despitethisstrongheritability,thegeneticarchitectureofCADandatherosclerosis remainsincompletelyunderstood.Thisismostlikelybecauseofthecomplex,polygenicriskmodelincludinggene environmentandgenegeneinteractions,underlyingnotonlyCAD,butalsoCADrelatedriskfactors.Regardless,given thatcurrentlyavailableclinicalriskmodelsdonotcompletelypredictriskofCADandCVevents,therehasbeengreat hopethatgeneticstudieswouldidentifymarkersthatwouldimproveclinicalriskmodels. Hundredsofcandidategenestudieshavebeenpublishedwithinconsistentandoftenmodestfindings.Inthesestudies, singleormultipleSNPsingenesinknownCAD/atherosclerosisbiologicalpathwaysaretestedforassociationwith presenceofdisease.Furthermore,whilesomehavedemonstratedstatisticalsignificance,themajorityofthesestudies havenotassessedindependentandincrementalassociationwithCVD.Whileacomprehensivereviewofgenes implicatedasassociatedwithCADorCVeventsisbeyondthescopeofthischapter,someofthemostrelevantgenes implicatedinCAD/CVDpathogenesisincludegenesinvolvedinlowdensitylipoproteincholesterolmetabolism(APOB, APOE,LDLR,HMGCR,ABCA1,andPCSK9),genesinvolvedinhighdensitylipoproteincholesterolmetabolism(LIPC, LPL,andCETP),andothergenes(ACE,MTHFR,andeNOS).27 Inaddition,applicationofarelativelynewtechnology,GWAS,hasenabledanagnostic"unbiased"approachto understandinggeneticriskforatherosclerosis.Thesestudieshaveconsistentlyidentifiedaregiononchromosome9p21 tobeassociatedwithCAD.28However,thesevariantsareverycommon(~20%ofthepopulationishomozygous),have unknownfunctionalconsequenceswithunclearbiologyofdiseasemediation,andconferonlymodestriskofCAD(odds ratios,1.21.6).Thus,itisbelievedthatmuchofthegeneticriskofatherosclerosisremainstobeelucidated.Morerecent GWAShaveidentifiedmorevariantsthatmayexplainsomeofthisunexplainedrisk.27 Whiletestingforsomeofthesegeneticvariantsisavailableonaresearchbasis,andhasbeguntobeofferedby commercialentities,itisnotcurrentlyindicatedforgeneralclinicalmanagement.Infact,thebest"genetic"testcurrently availableforassessingriskofCAD/atherosclerosisisadetailedfamilyhistorywithsubsequentinitiationofprimary preventivetherapies,asindicated. Novelgenetictechnologiesincludingepigenetics(heritablechangesintheexpressionofagenethatarecausedby mechanismsotherthanactualchangesintheDNAsequence,i.e.DNAmethylation),copynumbervariation(abnormal numberofcopiesofsectionsofDNAasopposedtosinglechangesseenwithSNPs),andDNAresequencingtoidentify moreraregeneticvariantsthatmaybeassociatedwithdisease.Oncethisgeneticarchitectureisclarifiedandshownto beincrementaltoclinicalriskmodelsfordisease,genetictestingmaybeappropriateinordertotargetmoreaggressive treatmentofCADriskfactors.

ComplexDiseaseGenetics:Arrhythmias
WhileMendeliangeneticarrhythmicdisordershavebeenpreviouslycovered,withtheshiftinfocustocommoncomplex diseases,therehasbeenagrowinginterestinunderstandingthegeneticsofarrhythmicdisorderssuchassudden cardiacdeath.Thesedisorders,whichappeartohaveageneticcomponent,arecharacterizedbyanunclearmodeof transmissionandareprobablytheresultofgeneenvironmentinteractionsthatremaintobeelucidated.Forexample, geneticvariantsthathavearelativelyhighfrequencyinthepopulation(i.e.,>5%prevalence),eitherwithinknowngenes thatcauseMendeliangeneticdisorders(i.e.,ionchannelgenes)orwithinothergenes,couldincreasetheriskof ventriculararrhythmiasinthecontextofreducedLVfunction. ThisnotionissupportedbyrecentGWASthathaveidentifiedcommonvariantswithintheseionchannelgenesaswellas withinnovelgenes,whichareassociatedwithhigherQTintervalsinageneralpopulationnotenhancedforlongQT. GiventheknownassociationoflongerQTintervals(evenwithinthenormalrange)withincreasedriskofsuddencardiac death,itcouldbehypothesizedthatthesesamegeneticvariantscouldincreaseriskofventriculararrhythmiasand suddencardiacdeath.Whilegenetictestingisnotclinicallyindicatedinthemanagementofthesecomplexdisorders, withthegrowingaccumulationofstudiesinthesedisorders,clinicaldecisionmakingmayincludegenetictestinginthe future.

CardiovascularPharmacogenomics
"Pharmacogenomics"canbedefinedasthestudyofgeneticvariationindrugresponse.29Intheeraof"personalized medicine,"pharmacogenomicsholdspromiseforenablingmorejudiciousdecisionsaboutwhichdrugandwhatdoseto useinagivenpatient.InCVD,thisparadigmissupportedbyseveralkeyexamplesofgeneticvariantsthathavebeen associatedwithdifferentialresponseto,orcomplicationsfrom,commonlyusedmedications. Warfarin Warfarinshowsmarkedheterogeneityintimeto,anddosageof,finaltherapeuticdose.Itismetabolizedpredominantly byacytochromeP450enzymeCYP2C9twocommonvariantsintheCYP2C9generesultinreducedenzymaticactivity (12%forCYP2C9*2and5%forCYP2C9*3).29Patientsharboringoneofthesecommongeneticvariantsrequireda lowerfinaldosefortherapeuticanticoagulationwithwarfarinandareatincreasedriskofbleedingcomplications.In combination,CYP2C9andanothergene,vitaminKepoxidereductasecomplexsubunit1(VKORC1)genotypes,explain 3040%ofthetotalvariationinthefinalwarfarindose.29 Observationalstudieshavesuggestedthatadditionofthesegenotypestoaclinicalalgorithmresultsinimproved outcomes,29whichhavebeensupportedbyresultsofclinicaltrials.30Infact,theFoodandDrugAdministration(FDA) hasrevisedthelabelonwarfarinandnowprovidesrangesofdosesbasedongenotypewiththesuggestionthatgenetic testingbeconsideredwhenprescribingthedrug.29Genetictestingforthesepolymorphismsisclinicallyavailable,and onlinealgorithmsareavailabletohelpthecliniciandeterminethebestwarfarindosewhengenotypedataareavailable (http://www.warfarindosing.org).Clinicaltrialsofpharmacogenomicwarfarindosingalgorithmsareongoing.However, emergingalternativeoralanticoagulantswithfixeddosingmayprecludefurtherdevelopmentofwarfarinalgorithms. Clopidogrel Manypatientssufferrecurrenteventsdespitetherapywithclopidogrel,amainstayantiplateletagentforavarietyofCV disorders,suggestingasyndromeofclopidogrelresistance.Clopidogrelisaninactiveprodrugrequiringhepatic activationviacytochromep450enzymesincludingCYP2C19.Anumberofdifferentallelesofthegeneencodingthis enzymehavebeenidentified(CYP2C19*2beingthemostcommon),whichresultinlossofenzymaticactivity.Patients carryingthosealleleshavereducedformationofclopidogrel'sactivemetaboliteandconsequentlyreducedplatelet inhibition.29Studieshaveconfirmedtheclinicalimplicationsofthisreducedplateletinhibitioncarriersofatleastone CYP2C19*2alleleexperiencea1.5foldincreaseinriskofCVdeath,MI,andstrokeintheyearoffollowupafterreceiving percutaneouscoronaryintervention(PCI)foracutecoronarysyndromeandtreatmentwithclopidogrel,ascomparedwith noncarriers.31 Carriersalsohaveuptoasixfoldincreasedriskofstentthrombosis.ThesefindingspromptedtheFDAtoadda"boxed warning"toclopidogrel,statingthatindividualswithaCYP2C19variantassociatedwithalowrateofmetabolismmight requiredoseadjustmentoruseofadifferentdrug.29Similarly,theAmericanCollegeofCardiologyFoundationand AmericanHeartAssociation(ACCF/AHA)haveissuedajointstatementsuggestingthatCYP2C19genotypingbe consideredforpatientstreatedwithclopidogrelwhoareatmoderateorhighriskforCVevents.29,32 Unfortunately,thedataregardinguseofalternativeagentsaresomewhatconflicting.Alargegeneticsubstudywithin thePLATO(PLATeletinhibitionandpatientOutcomes)trialofticagrelorversusclopidogrelfoundthatticagrelorresulted insuperioroutcomestoclopidogrelregardlessofCYP2C19genotype.Therewasahighereventrateincarriers randomizedtoclopidogrelcomparedwithnoncarrierswithin30daysofinitiationoftherapy,butthisdifferencedidnot bearoutoverthelongerterm.33 ClinicalgenetictestingforCYP2C19variantsisavailable,andshouldbeconsideredinmoderateorhighriskpatients. However,itstilldoesnothavewidespreaduseduetouncertaintyabouthowtotreatcarriersofthevariantanduncertainty abouttheclinicalutilityofgenotypinginreducingtheincidenceofCVevents.29Furtherstudiesareongoing. Statins Thereexistsheterogeneityintheresponsetostatins,suggestingaroleforgeneticfactors.AGWAShasuncovereda polymorphismintheSLCO1B1gene,encodinganorganicaniontransporterregulatingthehepaticuptakeofstatins, whichisstronglyassociatedwithriskofstatininducedmyopathy.34Whileclinicaltrialstoassesstheclinicalapplication ofthisgeneticvariantareongoing,thisvariantcouldprovetobehelpfulindeterminingwhichindividualsareatriskof developingmyopathypriortoplacingthemonastatin. Studieshavealsobeendonetounderstandpossiblegeneticvariationunderlyingtheheterogeneityinresponseto statinswithregardtoefficacy.Datahavesuggestedthatavariantinthekinesinlikefamily6(KIF6)gene(Trp719Arg)is associatedwithincidentCVDandamorebeneficialresponsetotherapywithstatins,andthatatorvastatinmaybe

superiortopravastatininpatientswithacutecoronarysyndromewhoarecarriersofthevariant.35 Suchdataprompteddevelopmentofawidelyusedcommerciallyavailabletest.However,thetesthasnotyetbeen approvedbytheFDAduetoinsufficientdatatodemonstratethesafetyandeffectivenessofthetestforuseinCVrisk assessment.Subsequentnestedstudieswithinclinicaltrialshaveshownnodifferenceinefficacyofcertainstatinsby KIF6genotype.35Further,thebiologicalmechanismshavenotbeenwellelucidated.Thus,theclinicalutilityofKIF6 genetictestingremainsunclear.

ComplexDiseaseGenetics:NongeneticBiomarkers
Workcontinuestomorethoroughlydefinethegeneticunderpinningsof"common"atheroscleroticCVD,butitisimportant tonotethatgeneticvariantsareimmutableandstaticthroughoutalifetime.Thepresenceofageneorgenevariantdoes notnecessarilyspecifythatadiseasephenotypewillbeobservedclinically.Somegenesareconstitutivelyexpressed whileforothers,regulationissensitivetotheenvironmentandexposures(e.g.,dietary,stress,hormonal,smoking,etc.). Thus,anindividual'sgenotypealonewillbeunlikelytoprovideriskstratificationforCVDeventsthatwouldbesufficientto guideindividualizedtreatmentstrategies.Assuch,agrowingnumberofstudieshaveidentifiednovelCVDbiomarkers usingemergingmoleculartechnologies,includingtranscriptomics,proteomics,andmetabolomics. RNAexpressionpatternsreflectactivetranscriptionofgeneticinformationatagivenpointintimeandmaybemore reflectiveofdiseasestateandactivitythanDNAbasedgeneticmarkers.Thus,geneexpressionmaybemorepredictive ofclinicaleventsinthenearterm.TheseRNAlevelscanbemeasuredinbiologicaltissuesandinperipheralblood throughuseofcommerciallyavailablegeneexpressionchips,whichrepresenttensofthousandsofgenes,socalled "transcriptomics."Bycomparingoneclinicalstatetoanother(e.g.,eventvs.noevent),onecanidentifyRNAmarkers associatedwithdiseaseaswellasfacilitatingbiologicalpathwaydiscovery.WhileworktoidentifyRNAmarkers predictingfutureCVeventsisongoing,studieshaverevealedthata23geneRNAsignaturereportingonmany inflammatorygenesmeasuredinperipheralbloodisassociatedwiththepresenceandseverityofCADinnondiabetic patients,36andhasbeendevelopedasacommerciallyavailabletest(CorusCAD,CardioDX,PaloAlto,CA). Metabolomicsisthestudyofthesmallmoleculemetabolitesthatarebyproductsofcellularmetabolismandisan emergingdisciplinethatmaybeparticularlyusefulfordiagnosisofhumandiseasesbecausechangesinmetabolite levelsprovideanintegratedphenotypic"readout"ofgenomic,transcriptomic,andproteomicvariation.Metabolomicshas beenusedtosuccessfullyidentifynovelmetabolicbiomarkersindependentlyassociatedwithinsulinresistanceand predictionofdiabetes,37andforCADandCVevents.38Noneofthesemarkersareavailableforclinicaltesting,but demonstratetheutilityofthisapproachforbiomarkerdiscovery. WhilethesenovelRNAandmetabolicbasedbiomarkersarenotFDAapprovedorroutinelyindicatedforthegeneralcare ofpatients,healthcareproviderswilllikelyseeagreaterintegrationofsuchtestsintoclinicalpractice.Futurestudieswill nodoubtidentifyadditionalnovelbiomarkersandimportantly,willneedtoassesstheincrementalutilityofthese biomarkersontopofmoreeasilymeasureableclinicalfactorsfordiagnosisorriskprediction.Validationofgenetic discoveries,alongwithintegrationoftheinformationtheyconveywithestablishedclinicalmodelsaswellasnewclinical biomarkersderivedfromthesenovelmoleculartechnologies,willbeessentialtoestablishutilityofgeneticsandother suchtechnologiesinclinicalpractice.

HumanGeneticResources
TheexplosionofhumangeneticsresearchbothincommoncomplexandMendelian geneticdisorderscanseemoverwhelming,buthealthcareprovidersneedtobe knowledgeableaboutthebasicsofthesediseases,inordertoappropriatelyidentify andreferhighriskpatientsandtheirfamilies,andforfacilitatingcriticalreviewofthe largenumberofstudiesthatcontinuetoemerge,suggestingnewgenomicmarkers forpotentialclinicaluse.Severalpublicgeneticwebsiteresourcesareavailableto aidtheclinicianandresearcherintheseendeavors(Table4).

Table4

PubliclyAvailableHumanGeneticWebsiteResources Table4

ConclusionsandFutureDirections
TheHumanGenomeProjectandothergeneticendeavorshavefueledmajoradvancesinourunderstandingofthe geneticsofCVD.CVhealthcareprovidersneedtohaveabasicknowledgeofhumangeneticconcepts,andclinical presentationsandscreeningimplicationsforfamilymembersforMendelianCVdisorders,inordertoidentifyatrisk individualsandtheirfamiliesandrefertoappropriatesubspecialtygeneticsclinicsforgeneticcounselingand considerationofgenetictesting.ThisknowledgewillalsohelpCVhealthcareprovidersinterprettheongoingworkon geneticandotherbiomarkersforcommon,complexCADandCVeventswheretheroleofgenetictestingislessclear. FuturestudieswillneedtoestablishthatDNAorRNAbasedtestsfordiagnosisofCADorriskpredictionforCVevents provideinformationaboveandbeyondthatprovidedbyconventionalriskfactors.Further,asthegeneticarchitectureof commonCVDisclarified,integrationwithnongeneticmolecularbiomarkerswilllikelybenecessarytoproducearobust modelforCVDriskpredictionandforunderstandingthemolecularmechanismsunderlyingthisriskmediation.

KeyPoints
MendelianCVDsincludeHCM,LQTS,Marfansyndrome,andfamilialDCM.Thesediseasesarecharacterizedby aclearmodeofinheritanceandoneorafewgenescausingthedisease,withmutationswithinthegenes showingstrongassociationwiththediseaseandmarkedphenotypiceffects. GenetictestingoftheaffectedindividualisoftenindicatedintheseMendelianCVgeneticdiseases,notfor diagnosticpurposes(diagnosisisusuallyaclinicaldiagnosis),butforfacilitatinggenetictestingandscreeningin atriskfamilymembers. WhenperforminggenetictestinginmostMendelianCVgeneticdiseases,thebestapproachisusuallytoperform afullscreenofallavailablegeneticvariantsintheindexcase,andthenperformfocusedtestingofonlythat geneticvariantinatriskfamilymembers. Marfansyndromeisaconnectivetissuedisorderinheritedinanautosomaldominantfashion,with95%ofcases causedbymutationsinthefibrillin1extracellularmatrixproteingene(FBN1),andpredisposestoaortic aneurysmsanddissections. FamilialDCMisaheterogeneousgeneticdisease,withvariablepresentations,reducedpenetrance,anddifferent modesofinheritance.Itiscausedbymutationsin33knowngenes,buttheseaccountforonly3035%ofcases thus,theroleofgenetictestingisunclear. FamilialHCMisarelativelycommongeneticdiseaseshowinganautosomaldominantmodeofinheritance causedbymutationsin1of14genesencodingcomponentsofthesarcomere,withgenetictestingidentifyingone ofthesemutationsin5075%ofcases.Thus,genetictestingcanbeusefulinhelpingtoconfirmadiagnosisand forguidingscreeninginatriskfamilymembers. FamilialHCMneedstobedifferentiatedfromLVhypertrophyresultingfromothergeneticdisorderssuchasFabry disease,amyloidosis,orothermetaboliccardiomyopathies,especiallyinyoungerindividuals. LQTSistypicallyautosomaldominantbutwithvariablepenetrance,andissubdividedinto12typesbasedonthe underlyingcausativegene.GenetictestingwillidentifyaknownLQTSmutationinapproximately75%ofcases, andthus,canhelpwithdiagnosisandforguidingscreeninginatriskfamilymembers. FactorVLeidenisageneticvariantthatcausesAPCresistanceandisthemostcommongeneticcauseofVTE, causingupto50%ofcases.Itistransmittedinanautosomaldominantfashion,andgenetictestingforthis geneticvariantisindicatedincertainpatientswithaVTE. Warfarinmetabolismisdeterminedpartiallybygeneticvariantsintwogenes,thehepaticcytochromep450 enzymeCYP2C9andVKORC1,whichexplain3040%ofthetotalvariationinfinalwarfarindose.Genetictesting forthesevariantsmayhelpwithachievingoptimalwarfarindosesmorequickly,andforimprovingoutcomes. Clopidogrelactivationismediatedpartiallythroughahepaticcytochromep450enzymecodedbythegene CYP2C19,andvariantsinthisgenehavebeenassociatedwithreducedplateletinhibitionandworseclinical outcomesinpatientstreatedwithclopidogrel.TheACCFandAHAsuggesttestingfortheseCYP2C19variants maybeindicatedforpatientstreatedwithclopidogrelwhoareatmoderateorhighriskforCVevents. CommonCVDssuchasCAD,MI,andatrialfibrillationdemonstrateamorecomplexmodelofgeneticriskthus, genetictestingisnotcurrentlyroutinelyindicatedinthesediseases. Novelgenomictechnologiesincludingepigenetics,copynumbervariationtesting,andDNAresequencingwill hopefullyhelprefinethegeneticarchitectureofthesecommonCVDsandfacilitatecreationofarobustrisk predictionmodel.

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Chapter2Exam
Visittheonlineversionoftheproducttoseethecorrectanswerandcommentary. 1. WhichofthefollowingisthemostcommongeneticcauseofVTE? A. ProteinSdeficiency. B. Prothrombin20210A. C. FactorVLeiden. D. MTHFRgeneticvariant.

2. InwhichofthefollowingCVDsisgenetictestingoftenindicated? A. CAD. B. FamilialDCM. C. LQTS. D. Atrialfibrillation.

3. Whichofthefollowingisthemostlikelycardiaccauseofexerciseinducedsyncope ina16yearoldpatient? A. Coronaryarteryanomaly. B. LQTS. C. FamilialDCM. D. HCM.

PleasevisittheonlineversiontoengageinthisExam. 1.ThecorrectanswerisC.FactorVLeidenisresponsibleforupto50%ofcasesofVTE, makingitthemostcommongeneticcauseofVTE.ItisrelativelycommoninCaucasian populations,withafrequencyofupto6%. AlthoughproteinSdeficiency,whichiscausedbymutationsintheproteinSgene,doescause VTE,thisisnotacommoncauseofdisease(prevalenceupto0.1%inthegeneralpopulation andupto7.3%inpatientswithVTE).Theprothrombin20210Avariantisarelativelycommon variantinthepopulation,withaprevalenceofupto18%inindividualswithathromboticeventor withafamilyhistoryofthrombosisitisthesecondmostcommongeneticcauseofVTE.A relativelycommonvariantintheMTHFRgenehasbeenassociatedwitharterialandvenous thrombosishowever,dataareconflictingandatbest,itconfersonlymodestriskofVTE. 2.ThecorrectanswerisC.GenetictestingwillidentifyaknownLQTSmutationinapproximately

75%ofcases,andthus,canhelpwithdiagnosis(especiallyinindividualswith"borderline" correctedQTintervals)andcanguidescreeninginatriskfamilymembers. WhilestudieshaveuncoveredhundredsofgeneticvariantsasassociatedwithCAD,thereareno genetictestscurrentlyindicatedforroutineevaluationofpatientswithCAD.Thismaychangein thefutureasstudiesevaluatemultiplegenesaspartofa"genescore"andmoregeneticvariants areuncoveredthroughnovelgenetictechnologies. Thereare33knowngenesthathavebeenimplicatedinfamilialDCM,butintotal,theyaccount foronly3035%ofcases.TheroleofroutinegenetictestinginfamilialDCMisuncleargiventhis lowyieldandnochangeinclinicalmanagementbasedongenetictesting(althoughifagenetic mutationisidentifiedinafamily,itcanhelpwithatriskfamilymemberstohelpdeterminetheir screeningregimen,i.e.,ifanatriskfamilymemberdoesnotcarrythefamilialmutation,then he/shedoesnotneedfurtherlongitudinalscreening). Atrialfibrillationisheritableinnature,andwhiletherearesomeformsofMendelian,monogenic atrialfibrillation,mostatrialfibrillationischaracterizedbyamorecomplexgeneticarchitecture, andthereisnocurrentroleforgenetictestingofthegeneticvariantsthathavebeenidentified. 3.ThecorrectanswerisD.HCMisarelativelycommondisorder(presentin1:500peoplein thegeneralpopulation),andisthemostcommoncauseofsuddendeathinyoungindividuals. Theremainderoftheanswerscanhaveexerciseinducedsyncopeasapresentingsymptom, butarealllesscommoninadolescentsthanHCM.