Andersons pediatric cardiology 2278

SignificanteffortshavealreadyfocusedonevaluatingpostmortemDNA
samples.56–69,84Althoughthereisnear-universalconsensusthatsavingagenetic
samplefromthedecedentisthebestpractice,thereareseveralhurdlesto
overcome.Thesehurdlesincludethevariabilityinpracticeamongcoronersand
medicalexaminers’offices,theunderstandabledesireofthefamilytohavethe
bodyreleasedbacktotheircareforburialassoonaspossible,thedegradationof
DNAinpostmortemsamplespriortocollection,andthepracticalconsiderations
ofgettingmaterialsaved,stored,andDNAextractedeffectively.85–88
Table89.3tabulatestheyieldofpostmortemgeneticscreeningaftersudden
unexplaineddeath.Therecontinuestobediscussionwithinthefieldaboutthe
bestgeneticapproach.Somestudiesperformedgeneticscreeningpanelsusinga
small,predeterminedlistofgenesfirmlyimplicatedinsuddendeath.58,59,69
Othershaveusedwholeexomeorwholegenomesequencing,tosamplemore
broadlyacrossthegenome,usingcomputationaltoolstoevaluate100ormore
genes.55,57,89Ascostsofnext-generationsequencingdecrease,thelatter
approachislikelytobeincreasinglyavailable.However,theriskoflargerpanels
isthediscoveryofvariantsofunknownsignificanceorvariantsingeneswith
unclearapplicationtothecaseathand.
Table89.3
YieldofPathogenicandLikelyPathogenicVariantsinMolecular
AutopsyStudies
FirstAuthor,Year,
ReferenceNumber
Methner,201691
Winkel,201254
Lahrouchi,201770
Skinner,201164
Chugh,200458
Farrugia,201560
Wang,201468
DiPaolo,200459

Behr,200892
Tester,201266
Bagnall,201653
Nunn,201589
Anderson,201655
Christiansen,201657

NumberofGenes
Screened
64
3
77
5
5
23
6
5
11
6
131a
135
100
100

Numberof
Probands
71
44
302
52

12
16
274
10
57
173
490
59
32
61

YieldofPathogenicandLikely
PathogenicVariants(%)
3.7
11
13
15
16
19
20
20
21
26
27
29
32
34


aThenumberofgenestestedvariedwithinthestudy.

Definitionsofsuddenunexplaineddeathwereextractedfromeachpaperandwereindependently
reclassifiedassuddenunexplaineddeathorsuddenarrhythmicdeath,butnotrendexists
betweenthedefinitionsandtheyieldofvariants,sotheyarelistedsequentiallybyyield,notby
definition.

Interpretationofgeneticinformationcanbeexceptionallydifficultinsudden
unexplaineddeathcases.Arecentstudyin302suddenarrhythmicdeathcases
thatsearchedspecificallyforclinicallyactionablepathogenicorlikely
pathogenicvariantsfoundthatmolecularautopsycombinedwithclinical
evaluationincreasedthediagnosticyieldinsurvivingfamiliesfrom26%to
39%.70Familiesshouldbeforewarnedbeforemolecularautopsyisundertaken
thatgeneticinformationisadditiveandrarelydiagnosticinisolation.In
summary,geneticsequencingandinterpretationisaparallelprocessthatinforms
phenotypicworkup,butdoesnotreplaceit.AsFig.89.1shows,molecular
autopsycanbeperformedsimultaneouslywiththefamily'sphenotypicworkup,
usinggeneticinformationtoguidetheworkupasnecessary,butincorporating
phenotypicinformationtomakeafinaldiagnosisinthefamily.Fromthere,
clinicianscandeterminethevalueoflifestylemodifications,pharmacotherapy,
interventionaltherapy,andfamilycascadescreening.

EthicalConsiderationsandFutureDirections
(SeeAlsoChapter83)
Familiesrequirecarefulcounselingpriortogeneticscreeningafterasudden
deathepisode.Despiteeveryone'sbestintentions,therearepotentialdownsides
totestingsurvivingfamilymembersforageneticvariantthatisfoundinthe
decedent.IntheUnitedStates,federallaw(theGeneticInformation
NondiscriminationAct)prohibitsdiscriminationbyhealthinsurancecompanies,
grouphealthplans,employers,laborunions,andemploymentagenciesonthe
basisofgenetictestinginformation.Thislawdoesnotprotectagainstuseof

genetictestinginformationbycompaniesthatselllifeinsurance,disability
insurance,orlong-termcareinsurance.Inaddition,whilethedecedent's
insurancewilloccasionallycoverthecostofmolecularautopsy,thisisnot
universal,andprovidersshouldbetransparentwithfamiliesabouttheout-ofpocketcostsofmolecularautopsypriortoproceeding.90–92


ScreeningforAtherosclerotic
CardiovascularDiseaseRiskFactors
Thechronicprocessofatherosclerosisbeginsinearlylife,withinitialchanges
observedeveninthefetus.93Intwocontemporarystudies,Pathological
DeterminantsofAtherosclerosisinYouth94andtheBogalusaHeartStudy,95
autopsiesofyouthwhodiedfromunintentionalinjuryrevealedthattheseverity
andextentofatherosclerosisinchildhoodcorrelatedstronglywiththepresence
andintensityoftraditionalriskfactorssuchasdyslipidemia,hypertension,
obesity,tobaccosmokeexposure,anddiabetesmellitus.Multipleobservational
studiesindicatethatriskfactorsmeasuredinchildhoodpredictsubclinical
atherosclerosisinadulthood,oftenmorestronglythandoriskfactors96measured
inadulthood.Finally,thePrincetonLipidResearchClinicsFollow-upStudy
demonstratedthatthemetabolicsyndromeriskfactorclusterinchildhood
predictedactualclinicalcardiovasculardiseaseatages30to48years.97Taken
together,theseobservationscreateastrongchainofevidencelinkingriskfactor
developmentinearlychildhoodtoatheroscleroticcardiovasculardiseasein
adulthood.
Nevertheless,becauseofthelongperiodbetweenchildhoodandadultevents,
therearenorandomizedcontrolledtrialsofchildhoodscreeningforriskfactors
toreduceadultclinicalatheroscleroticcardiovasculardiseaseevents.Suchtrials
areunlikelytoeveroccur.Forthisreason,therehasbeensomedebateinthe
medicalcommunityabouttheutilityandcost-effectivenessofscreening,
particularlyregardingdyslipidemia.Thiswillbereviewedbelow.
Ofthetraditionalriskfactorsforatheroscleroticcardiovasculardisease,only

dyslipidemiascreeningwillbediscussedhere.Whileveryimportant,screening
fortheremainderoftheriskfactorsgenerallyoccursintheprimarycareclinic,
withmostcentersreferringpatientswiththeseriskfactorstononcardiology
specialists(nephrologyforhypertension,endocrinologyfordiabetes,weight
managementclinicforobesity)whenrequiredformanagement.Anexcellent
reviewoftheevidenceandexpertrecommendationsforscreeningfortheserisk
factorsinchildhoodcanbefoundinthe2011NationalHeart,Lung,andBlood
Institute(NHLBI)IntegratedGuidelinesforCardiovascularRiskReductionin
Children.98