Criteria for Genetic testing Related to Epilepsy, GTAC, October 2016  Page 1 

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CriteriaforGeneticTestingRelatedtoEpilepsy

GeneticTestingAdvisoryCommittee(GTAC)RecommendationtotheMinistryofHealthandLong‐TermCare

GTACrecommendsthatgeneticstestsforepilepsybepubliclyfunded,undertheconditionsandperthecriteriaoutlinedinthisreport,includingthepatriationofallgenetictestingforepilepsytoOntariolaboratories.

October2016

Note:ThispublicationistechnicalinnatureandisavailableinEnglishonlyduetoitslimitedtargetedaudience.ThispublicationhasbeenexemptedfromtranslationundertheFrenchLanguageServicesAct.

Remarque:Cettepublicationestdenaturetechniqueetestdisponibleenanglaisuniquementenraisondesonpublicciblelimité.CettepublicationaétéexemptéedelatraductionenvertudelaLoisurlesservicesenfrançais.

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AboutTheGeneticTestingAdvisoryCommittee

Newgenetictestsarebeingrapidlydevelopedandpromotedashightechtoolstoimprovediagnosticmedicineandfacilitatepatienttreatment.Aformalevaluationprocessisrequiredtoassessthevalidityandeffectivenessofnewandexistinggeneticteststobettermanagehealthcarespending.

TheGeneticTestingAdvisoryCommittee(“GTAC”)wasestablishedinApril2014withathreeyearmandatetoreviewtheclinicalutilityandvalidityofgenetictestsandprovideadvicetotheMinistryofHealthandLong‐TermCare(“ministry”)ontheprovisionofgenetictestsinOntario.ThecreationofGTACisinkeepingwiththedirectionoftheExcellentCareforAllActandtheOntarioActionPlanforHealthCaretopromotethedeliveryofhigh‐qualityhealthcarebasedonthebestavailablescientificandclinicalevidence.

ThepurposeofGTACistoreviewandprovidereportsonexistingandnewgenetictests.Thesereports,inadditiontootherfactors(e.g.implementationfeasibility,availablefundingandresources,systemlevelimpacts,andsocialandethicalfactors)willguidetheministry’sdecision‐makingonpublicfundingofgenetictestsinOntario.

ReviewProcess

TheevaluationprocessforagenetictestisdeterminedbywhetherthetestistobeprovidedinOntarioorthroughtheOut‐of‐Country(OOC)ProgramExceptionalAccessprocess.

GeneralStreamProcess:OntarioGeneticTests

1. Genetictestselection2. Evidence‐basedanalysis

a. Literaturereviewofclinicalandacademicpublicationsonthegenetictest

b. Referraltoanexpertsub‐committeec. GTACdeliberationoftheavailableevidence

3. DraftGTACreportandrecommendationprepared4. PostingdraftinOpenforComment5. Assessmentofstakeholder/publiccomments6. PostingoffinalizedGTACreportandrecommendations

ExceptionalAccessProcess:OOCGeneticTest

1.OOCgenetictestapplication/submission2.AssigntoappropriateGTACmemberforevaluationandrecommendation3.OOCResponsetorequestingphysician.

WebsiteEnglish:http://www.health.gov.on.ca/en/pro/programs/gtac/French:http://www.health.gov.on.ca/fr/pro/programs/gtac/default.aspx

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Table of Contents 

1. Background.....................................................................................................................................................4

2. ExpertPanelObjective................................................................................................................................5

3. RecommendationSummary.....................................................................................................................6

4. Circumstancesthatwouldindicatetheneedforgenetictesting.............................................7

5. Requirementstoproceedtofocusedgenepanelsorcomprehensiveepilepsygenepanelspursuanttothedeterminationofageneticdiagnosisinadultsandchildrenwithepilepsy.....................................................................................................................10

6. Criteriaforfocusedgenepanelsorcomprehensiveepilepsygenepanelsinadultsandchildrenwithepilepsypursuanttothedeterminationofageneticdiagnosis.........................................................................................................................................................11

7. Conditionsthatdonotindicateaneedforgenetictesting.......................................................13

8. GenerallimitationsandconsiderationswithNGS‐basedpaneltests..................................14

Table1.ExamplesofPanelTestingavailablewhenthegeneticheterogeneityisconsideredlow......................................................................................................................................15

Table2.ExampleofPanelTestingavailableforpotentiallytreatableconditions....................16

Table3.ExamplesofPanelTestingwhenthegeneticheterogeneityisconsidered“high”andthediagnosis“clear”.....................................................................................................16

Table4.ExamplesofPanelTestingwhengeneticheterogeneityisconsidered“high”andtheclinicaldiagnosisis“unclear”...........................................................................17

AppendixA:EpilepsyGeneticTestingCriteriaWorkingGroup........................................................18

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1. Background

Epilepsyisachronicdiseasethatischaracterizedbyrecurrentunprovokedseizures.Withaprevalenceof4‐5per1000persons,epilepsyisthesecondmostcommonneurologicalcondition,withapproximately75,000adultsand15,000childrenlivingwithepilepsyinOntario1,2.TheOntarioBrainInstituteestimatesthereareapproximately6,100newphysician‐diagnosedcasesinOntarioeachyear(NgR,etal.BrainDisordersinOntario:Prevalence,Incidence,andCostsfromHealthAdministrativeData.Toronto,ON:InstituteforClinicEvalSci.2015).Whiletheexactproportionofepilepsiesoccurringsecondarytomonogenicandpolygenicmutationsiscurrentlyunknown,itisspeculatedthatupto75%ofepilepsieshaveageneticunderpinning.Incertainepilepticconditions,thelikelihoodofageneticetiologymaybeevenhigher,particularlytheepilepticencephalopathies3.Giventhatgenetictestingisindicatedinpatientswithmedicallyrefractoryepilepsyandthatthisgrouprepresents30%ofthosewithepilepsy,about30%ofcases,i.e.apotential~1830patientsperyear,couldproceedtogenetictesting.

1 BowenJM,SneadOCarter,ChandraK,BlackhouseG,GoereeR.EpilepsycareinOntario:aneconomicanalysisofincreasingaccesstoepilepsysurgery.OntHealthTechnolAssessSer[Internet].2012July;12(18):1‐41.Availablefrom:http://www.hqontario.ca/en/documents/eds/2012/econ‐epilepsy‐surgery.pdf2 http://www.ices.on.ca/Publications/Atlases‐and‐Reports/2015/Brain‐Disorders‐in‐Ontario3 Thomas,RHand2014;10:283–292.

BerkovicSF.Thehiddengeneticsofepilepsy—aclinicallyimportantnewparadigm.NatureReviewsNeurology.

Theimpactofageneticdiagnosisinapersonwithepilepsycanbequitesignificant.Accurategeneticdiagnosismaydirecttreatmenttowardsdiseasemodifyingtherapiesand/ormedicationsknowntobeeffectiveincertainepilepsysyndromes.Geneticdiagnosismayalsoelucidateaprognosisandlimitfurtherinvestigationsthathaveassociatedrisksandcost.Similarly,ageneticdiagnosismaysparepatientsthemorbidityandsocietythecosts,ofunnecessaryepilepsysurgery.Further,geneticdiagnosesoftenhelpidentifypotentialco‐morbiditiesallowingforoptimizationoftreatmentandtheavoidanceofunnecessarymorbidity.Aswell,withappropriategeneticdiagnosis,geneticcounselingforfuturepregnanciesisoftenpossible.Finally,ageneticdiagnosisbringsclosureandpeaceofmindtothefamiliesofthosewithageneticdiseasewhethertreatableornot.

Anegativegeneticresultinthediagnosticevaluationofepilepsyalsocarriesbenefit.Anegativetestmayallowthepatienttoproceedwithoutdelaytowardscriticaltherapies(suchasepilepsysurgery)thatwouldnotbeindicatedinmostgeneticepilepsies.Anegativegeneticresultthereforemayavoidlongdelaystoappropriatetreatments,delaysthatresultinpooroutcomes.

Thoughasignificantandgrowingbodyofliteratureimplicatesspecificgenesandmutationsinparticularepilepticconditions,thereislittlegeneralguidanceavailableonthecircumstancesinwhichgenetictestingisindicatedandtestselectioninordertoguideoptimaltestappropriatenessandbenefit4.

4 AchkaarE,OlsenHE,PoduriA,PearlPL.Thegeneticsoftheepilepsies.CurrNeurolNeurosciRep2015;15:39

Thefollowingcriteriahavebeendevelopedtoaidcliniciansindeterminingtheindicationsforgenetictesting(focusedgenepanels,orcomprehensiveepilepsygenepanels)inadultsandchildrenwithepilepsy.

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2. ExpertPanelObjective

Giventheabove,GTACconvenedanExpertPaneltodocumentcriteriathatwouldaidcliniciansindeterminingtheindicationsforgenetictestinginordertoguideoptimaltestappropriatenessandbenefit.

Thiswouldincludeinclusionandexclusioncriteriaaswellasrecommendationsfortheuseofdifferenttypesofpaneltests,guidedbyseveralfactors:

• Diagnosticprecision• Cost• TestSensitivity• TestSpecificityandavoidingdetectionofvariantsofunknownsignificance(VUS)

ThecommitteewouldliketothanktheExpertPanel(seeAppendixA)fortheirdiligenceandhardworkincreatingthisreport.TheCommitteeendorsestheExpertPanel’sfullreport,whichiscapturedintheremainderofthisdocument.

Toensureanopenandtransparentapproach,thereviewprocessincludedextensivestakeholderconsultationincluding:

‐ InputfromacademiccentresinOntario‐ Inputfrombroaderneurologysector‐ PublicpostingthroughtheCommittee’swebsite

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3. RecommendationSummary

GTACsupportstheExpertPanelrecommendations,asfollows:

1. Mandatoryprerequisitesfor:a. referraltoaDistrictorRegionalEpilepsyCentreforan epileptologyconsultation,b. geneticsconsultationiftherearedysmorphic features, andc. consultation with a clinical biochemical geneticist or a physician with training in

metabolic disorders if clinical features suggest an inborn error of metabolism.

2. Prerequisitediagnosticproceduresforallpatientsaswellasdiagnosticproceduresthataredependentuponclinicalcircumstance

3. Circumstancesinwhichgenetictestingisindicated

4. Conditionsunderwhichgenetictestingisnotindicated

5. Criteriaandexamplesfor:• singlegenetestingorfocusedgenepanelsthatmaybeutilizedwhenthegenetic

heterogeneityisconsideredlow• focusedgenepanelstobeusedforpotentiallytreatableconditions• genepanelstobeusedwhenthegeneticheterogeneityisconsidered“high”and

thediagnosisis“clear”• comprehensiveepilepsygenepanels,orwholeexomesequencingthatare

indicatedwhengeneticheterogeneityisconsidered“high”andtheclinicaldiagnosisis“unclear”

6. GenerallimitationsandconsiderationswithNGS‐basedpaneltests.Theseguidelinesprovideclaritytoguidethereaderastowhichtypesofpanelsshouldbeuseddependingupontheclinicalcircumstancecoupledwiththedegreeofgeneticheterogeneityasoutlinedabove.Ratherthanspecifyingwhichpanelstouse,optionsareprovidedfortheclinician(epileptologistorgeneticist)facedwithavarietyofclinicalcircumstancesandgenetichistory.

AdditionallyGTACsupportstheExpertPanel’srecommendationsforfuturestepsinordertomaximizeappropriatetesting:

• ThroughtheEpilepsyImplementationTaskForcetheworkinggroupcouldexplorearoleforepilepsycentrestoactasanetworkpromotingconsultationbetweenandamongstepileptologiststosupportoptimaltestselectionforpatients,regardlessofgeographiclocation.

• Patriationofallgenetictesting(including biochemcial genetic tests) forepilepsytoOntariolaboratories.Theworking groupwouldworkwiththeministryandOntariolaboratoriesonthedevelopment ofsmallersetofpanelstocovercircumstancesinwhichgenetictestingisindicated. Patriationwouldalsonurtureimportantdialoguebetweencliniciansandlaboratory directorsandpersonnelintestselection,analysisandinterpretation.

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4. Circumstancesthatwouldindicatetheneedforgenetictesting

1. Whentheclinicalfeatures(ageofonset,seizuresemiology,andEEGfeatures)areconsistentwithadistinctelectroclinicalsyndromeasdefinedbytheInternationalLeagueAgainstEpilepsy(ILAE),withtheexceptionofbenignepilepsysyndromes(See7below).Forexample:

• Epilepticencephalopathies(IncludesconditionssuchasOhtaharasyndrome,earlyonsetmyoclonicencephalopathy,Westsyndrome,malignantmigratingpartialseizures,etc.)

• Seizuresassociatedwithafeverasmajortrigger(excludingpatientsmeetingclinicalcriteriaforsimplefebrileseizures).Forexample:

o Dravetsyndromeo Generalizedepilepsywithfebrileseizuresplus

• Idiopathic(genetic)generalizedepilepsy(IGE)refractorytotreatment.Forexample:

o Earlyonsetabsenceepilepsyo Myoclonicepilepsywhereprogressive,associatedwithneurocognitive

regression,and/orismedicallyrefractory

2. WhentheprognosisbasedonclinicalandEEGfindingsispoororthelikelihoodoflethaloutcomeishigh.Forexample:

• Increasedfrequencyand/orseverityofseizures,riskforsuddenunexpecteddeathofepilepsy(SUDEP)

• Myoclonicepilepsywhereprogressive,associatedwithneurocognitiveregression,and/orismedicallyrefractory

• Epilepticencephalopathies(poorlycharacterizedonclinicalandsemiologicalgroundsandalackofdistinctivefeaturesontheEEG)

3. WhenepilepticseizuresarerefractorytomedicaltreatmentasdefinedbytheILAE.

• AnyotherformofIGErefractorytotreatment(especiallyimportantwhenthedifferentialincludesIGEorafrontallobeepilepsywithrapid,secondarilygeneralization)

• Sporadicfocalonsetpharmacoresistantepilepsy

4. Whenepilepsyisassociatedwithfeaturessuggestiveoftreatableinbornerrorsofmetabolism.

• Clinicalfeaturesstronglysuggestiveofaninbornerrorofmetabolism, for example:o Familyhistoryofknownconditiono Parentalconsanguinityo Newbornormetabolicscreeningidentifiesabiochemicalmarkerassociated

with“metabolic”epilepsy

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• Examplesofimportanttreatableconditionsinclude(Listisnotcomplete):o Pyridoxinedependentepilepsyo Pyridoxalphosphatedependentepilepsyo Creatinedeficiencysyndromeso Glucosetransporter(GLUT1)deficiencyo CerebralFolatedeficiency

Note: Biochemical biomarkers are generally more sensitive thangenomic approaches to ascertain these conditions; genomic testingshould not be relied on in isolation to RULE OUT such conditions.

5. Whenepilepsyisassociatedwithdistinctivepatternsofmalformationsofcorticaldevelopmentidentifiedonneuroimagingstudies.Forexample:

• Hemimegalencephaly• Lissencephaly• Schizencephaly• Subcorticalbandheterotopia(doublecortex)• Corticaldysplasiawithfocalepilepsy• Operculardysplasia/asymmetric,unilateralorbilateral• Holoprosencephaly• Agenesisofcorpuscallosum• Polymicrogyria• Periventricularheterotopia• TuberousSclerosis

6. Whenepilepsyisassociatedwithclinicalsignsofneurodegeneration.Neurodegenerationmaymanifestas:

• Developmentalregressioninchildren• Variablebutprogressiveneurologicalsymptomsofcognitiveimpairment,motor

disabilityand/orotherneurologicalsignsandsymptoms• Examplesinclude:

o AcquiredEpilepticAphasia(LandauKleffnersyndrome)o Epilepticencephalopathywithcontinuousspikewaveactivityinsleepo MECP2duplicationsyndromeandRettsyndromeo AtypicalRolandicepilepsywithlanguagedeficits+/‐cognitivedisabilityo Progressivemyoclonicepilepsies((Unverricht‐Lundborg,NCL,Laforabody,

sialidosis)

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7. Whenepilepsyisassociatedwithparoxysmalneurologicalfeatures.Forexample:

• Paroxysmaldyskinesias• Episodicataxias• Hemiplegicmigraine

8. Whenepilepsyisassociatedwithadditionalsyndromicfeaturessuchasdevelopmentaldelay/intellectualdisability,multiplecongenitalanomalies,dysmorphicfeatures.Forexample:

• AngelmanandAngelman‐likesyndromes• Pitt‐Hopkinssyndrome• Rettsyndrome,andsyndromeswithRett‐likefeatures• MowatWilson• X‐linkedEpilepsywithMentalRetardation• SyndromicMentalRetardationassociatedwithepilepsy• Tuberoussclerosis• Epilepsywithglobaldevelopmentaldelaysorautistictraitsunspecified/ornot

classified

9. Whenfamilialepilepsyispresent,definedasatleast2first‐degreefamilymemberswithrelatedepilepsysyndromes,unlesstheepilepsysyndromeisbenignaslistedunder7below.

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5. Requirementstoproceedtofocusedgenepanelsorcomprehensiveepilepsygenepanelspursuanttothedeterminationofageneticdiagnosisinadultsandchildrenwithepilepsy.

• Mandatoryprerequisiteso Iftheepilepsyisuncontrolled,referralto,orconsultationwith,aDistrictor Regional

EpilepsyCentreforanepileptologyconsultation(consistentwith ProvincialGuidelinesfortheManagementofEpilepsyinAdultsandChildren5)is required

o Ifepilepsyiswellcontrolledor if there are dysmorphic features, referraltoa clinical geneticist is required

o If there is developmental regression or other clinical features suggestive of an inborn error of metabolism, consultation with a biochemical geneticist or a physician with training in inherited metabolic disorders is strongly recommended.

• Diagnosticproceduresthatarealwaysindicatedbeforeproceedingtofocusedgenepanels,comprehensiveepilepsygenepanels

o EEG+/‐EEGvideoo Consultwithepileptologisto MRI+/‐MRS

• Diagnosticproceduresthataredependentuponclinicalcircumstance,butnotrequiredforprogressiontofocusedgenepanelsorcomprehensiveepilepsygenepanels

o Metabolic:Theseinvestigationsshouldbetailoredtothespecificclinicalpresentation(considerconsultation);commonlyemployedtestsmayinclude:MRspectroscopy,lactate,gasandlytes,glucose,ammonia,plasmaand/orCSFaminoacids,totalhomocysteine,urineorganicacids,acylcarnitineprofile,sulfitescreen,urineS‐sulfocysteine,uricacid,biotinidase,and/orurinealpha‐aminoadipicsemialdehyde,othertestsasclinicallyindicated

o Neonatal/infantileseizures:Considertrialofpyridoxine(B6),pyridoxalphosphate,andfolinicacid

o Cerebrospinalfluidstudies:routinecytology,glucose,lactate,aminoacids,considerneurotransmitters

o Chromosomalmicroarrayinpresenceofdevelopmentaldelay/intellectualdisabilitiesand/ordysmorphicfeatures

o Anyoftheseinvestigationsmaysuggestasinglegenetestoraspecificgenepanel,forexample,specificinbornerrorofmetabolismgene,corticalmalformationgenepanel,ormitochondrialgenepanel

o Notethatifanyofthesetestsareunderconsideration,oriftheresultswillrequireadditionalexpertiseforinterpretation,thismayindicateaneedforconsultationwithaclinicaland/orbiochemicalgeneticist

5EpilepsyImplementationTaskForce,ProvincialGuidelinesfortheManagementofEpilepsyinAdultsandChildren,Version1.0,January2015,CriticalCareServicesOntario(accessedFeb10,2016https://www.criticalcareontario.ca/Provincial Guidelines for theManagament of Epilepsy in Adults and Children)

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6. Criteriaforfocusedgenepanelsorcomprehensiveepilepsygenepanelsinadultsandchildrenwithepilepsypursuanttothedeterminationofageneticdiagnosis.

• IfClinicaldiagnosisisclearandgeneticheterogeneityislow,focusedgenepanelsareindicated.Forexample:

o Draveto Progressivemyoclonicepilepsyo CorticalMalformationpanelo Angelman‐likesyndromeo Rett‐likesyndrome

ExamplesofPanelsareprovidedinTable1

• Ifatreatableepilepsyisunderconsideration,aSTATepilepsypanelfocusedontreatableconditionsshouldbeconsidered(e.g.:earlyonsetepilepsy,inconjunctionwithorafterbiochemicalmarkershavebeentested).Examplesofimportanttreatableconditionsinclude(Listisnotcomplete):

o Pyridoxinedependentepilepsyo Pyridoxalphosphatedependentepilepsyo Creatinedeficiencysyndromeso Glucosetransporter(GLUT1)deficiencyo CerebralFolatedeficiencyo Serinebiosynthesisdisorders

ExampleofavailablePanelsaregiveninTable2

• Wheretheclinicaldiagnosisisclearandgeneticheterogeneityishigh(e.g.LennoxGastaut,Infantilespasms,epilepticencephalopathies),buttheclinicaldiagnosisisnotindicativeofatreatableconditioneitherafocusedgenepanelorcomprehensiveepilepsypanelshouldbedone.Forexample:

o Epilepticencephalopathies‐(Ohtaharasyndrome,Infantilespasms,malignantmigratingpartialseizures,LennoxGastautsyndrome,Dravetsyndrome)

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ExamplesofavailablepanelsareprovidedinTable3

• Iftheclinicaldiagnosisisnotclearandgeneticheterogeneityisunknown,eitherafocusedgenepanelorcomprehensiveepilepsypanelshouldbedone.Forexample:

o Seizuresassociatedwithafeverasmajortrigger‐FebrileSeizuresplus(Excludingpatientsmeetingclinicalcriteriaforsimplefebrileseizures)

o Generalizedepilepsywithfebrileseizurespluso Epilepsyinfemaleswithmentalretardation

o Epilepsysyndromesassociatedwithfocalandmultifocalseizureso Autosomaldominantnocturnalfrontallobeepilepsyo Familialtemporallobeepilepsywithauditoryfeatureso Familialfocalepilepsywithvariablefocio SporadicFocalonsetpharmacoresistantepilepsy

o Epilepsyassociatedwithregression/dysfunctioninlanguage/communication+/‐development

o AcquiredEpilepticAphasia(LandauKleffnersyndrome)o Epilepticencephalopathywithcontinuousspikewaveactivityinsleepo AtypicalRolandicepilepsywithlanguagedeficits+/‐cognitivedisabilityo Earlyonsetprogressivemyoclonicepilepsy

o Idiopathic(genetic)generalizedepilepsy(IGE)refractorytotreatmento Earlyonsetabsenceepilepsyo JuvenileMyoclonicepilepsywhereprogressive,associatedwithneurocognitive

regression,and/ormedicallyrefractoryo AnyotherformofIGErefractorytotreatment(especiallyimportantwhenthe

differentialincludesIGEorafrontallobeepilepsywithrapid,secondarilygeneralization).

ExamplesofAvailablePanelsaregiveninTable4

• Epilepsiessuggestiveofmitochondrialdiseasesorinthecontextofmitochondrialdiseases:pleaserefertothemitochondrialtestingdocument[seehttp://www.newbornscreening.on.ca/sites/default/files/ontario_mitochondrial_disease_testing_requisition.pdf).

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7. Conditionsthatdonotindicateaneedforgenetictesting

• Recognizableseizuresyndromewithbenigncourse• Benignchildhoodepilepsywithcentraltemporalspikes(previouslytermedbenign

rolandicepilepsy)• Mesialtemporallobeepilepsywithhippocampalsclerosis• TypicalChildhoodAbsenceepilepsy(althoughifearlyonsetormedicallyrefractory

shouldconsiderandtestforGLUT1deficiency)• Juvenilemyoclonicepilepsywellcontrolledonmedicationsandwithoutintellectual

disabilityoranysignsofneurodegeneration• AcquiredEpilepsy(Intheseconditions,epilepsyisoftenassociatedwithaprimary

neurologicalcondition,whichmayormaynothaveageneticbasis,buttheepilepsyisusuallyacquired.)Suchconditionsinclude:

o Posttraumaticepilepsyo Epilepsysecondarytoneonatal‐perinatalHIEandsequelaeo Epilepsyassociatedwithcerebralpalsyrelatedtoperiventricular

leukomalacia(PVL)o Epilepsysecondarytobraintumorsorsystemicmalignancyo Epilepsyassociatedwithcomplicationsofchemotherapy,post‐transplant

immunosuppressiono Epilepsyrelatedtoradiationtherapyo Epilepsyrelatedtoinfectionsofthecentralnervoussystem(CNS)(viral,

bacterial,TB,fungal)andcomplicationsthereofo EpilepsyassociatedwithCNSinflammation(autoimmune,vasculitis)

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8. GenerallimitationsandconsiderationswithNGS‐basedpaneltests

• Codingregions+10‐20basepairsflankingexonicsequencearetypicallycovered• Coveragemaynotbe100%(thoughtypically>97%)• Dependingoncapturemethod,exon1isoftenpoorlycovered.• Repeatsequence(s)presentwithinexonicsequencemaybedifficulttocall• Copynumbervariantsarealsonotreliablycalled• Limitedabilitytodetectmosaicism• Formany(most)panelsthemoleculardiagnosisrateisnotknown• Pre‐testcounsellingregardingpossibletestoutcomesisrequiredbeforeordering

genetictesting.Thisshouldincludediscussionofvariantsofuncertainsignificance,riskofincidentaland/orsecondaryfindings,and,asapplicable,consentforreturnofincidentaland/orsecondaryfindings.

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Table1.ExamplesofPanelTestingavailablewhenthegeneticheterogeneityisconsideredlow

Company NameofTestNo.Genes

ROICoverage

DepthofCoverage

Variantsofinterest

confirmedbysanger Cost

Turn‐around‐time

Sangersequencingavailable URLtoinformation

GeneDx ProgressiveMyoclonicEpilepsy 17 100% 15x yes 3340 4week Yeshttp://www.genedx.com/wp‐content/uploads/crm_docs/info_sheet_epilepsy_prog.pdf

GeneDx Tuberoussclerosispanel 2 100% 15x yes 2120 4weeks Yeshttp://www.genedx.com/wp‐content/uploads/2014/07/info_sheet_tsc1_tsc2.pdf

GeneDxCorticalBrainMalformationPanel 24 100% 15x yes 3088 8weeks Yes

http://www.genedx.com/wp‐content/uploads/2013/08/info_sheet_cortical‐malf.pdf

GeneDx Rett/AngelmanPanel 11 100% 15x yes 2560 4weeks yes

http://www.genedx.com/wp‐content/uploads/2013/08/Info_sheet_epilepsy_Rett_Angelman.pdf

GeneDx Holoprosencephaly 4 100% na na 20008‐10weeks yes

http://www.genedx.com/wp‐content/uploads/crm_docs/info_sheet_hls.pdf

MNGComprehensiveNeuronalMigrationDisorders 111 97% 30x asneeded 1850 8weeks yes

http://www.medicalneurogenetics.com/OpenTestSearch/TestDetail.aspx?Show=NGS387

Transgenomics Rett/AtypicalRett/Angelman 16 >99% 20x yes 3,92012‐16weeks yes

http://www.transgenomic.com/product/rettatypical‐rettangelman‐ngs‐panel/

TransgenomicsTuberousSclerosisComplexPanel 2 100% na na 3,396

2‐4weeks yes

http://www.transgenomic.com/product/tsc‐tuberous‐sclerosis‐complex/

Fulgent Rett/AngelmanNGSPanel 18 98‐99% 10x asneeded 19504‐6

weeks yeshttp://fulgentdiagnostics.com/test/rett‐angelman‐ngs‐panel/

AthenaDiagnostics

EpilepsyAdvancedSequencingEvaluation‐NeuronalMigrationdisorders 29 100% 20x asneeded 2995

4‐6weeks yes

http://athenadiagnostics.com/view‐full‐catalog/e/epilepsy‐advanced‐sequencing‐evaluation‐neuronal‐m

AthenaDiagnosticsCompleteTuberousSclerosisEvaluation 2 100% 20x asneeded 2995

4‐6weeks yes

http://athenadiagnostics.com/view‐full‐catalog/c/complete‐tuberous‐sclerosis‐evaluation

UniversityofChicagoGeneticservices

AngelmansyndromeTesting(Tier2) 4 100% 15x na 4400 4weeks yes

http://dnatesting.uchicago.edu/sites/default/files/01AS_67.pdf

UniversityofChicagoGeneticservices Rett/Angelman 21 100% 15x yes 4400

6‐8weeks yes

http://dnatesting.uchicago.edu/sites/default/files/01%20NGS%20Rett%20Angelman_10.pdf

UniversityofChicagoGeneticservices

BrainMalformation‐CerebralCorticolMalformation 46 100% 15x yes 3900 8weeks yes http://dnatesting.uchicago.edu/tests/641

UniversityofChicagoGeneticservices

BrainMalformation‐Holoprosencephaly 9 100% 15x yes 3500 8weeks yes

http://dnatesting.uchicago.edu/sites/default/files/01%20NGS%20HPE_1.pdf

UniversityofChicagoGeneticservices

BrainMalformation‐Lissencephaly 26 100% 15x yes 6000 8weeks yes

http://dnatesting.uchicago.edu/sites/default/files/01%20NGS%20lissencephaly_13.pdf

UniversityofChicagoGeneticservices

BrainMalformation‐Polymicrogyria 15 100% 15x yes 3700 8weeks yes

http://dnatesting.uchicago.edu/sites/default/files/01%20NGS%20Polymicrogyria_66.pdf

UniversityofChicagoGeneticservices Rett/AtypicalRett 4 100% na na 4400 4weeks yes

http://dnatesting.uchicago.edu/sites/default/files/01Atypical%20Rett_31.pdf

Centogene Dravetsyndrome 4 100% 30x yes 1,676 3weeks yeshttps://www.centogene.com/centogene/inc/testCatalogueDetail/factsheet/5100_Dravet_syndrome_panel_V1.pdf

CentogeneNeuronalMigrationdisorderPanel 43 100% 30x yes 4,400 5weeks yes

https://www.centogene.com/centogene/centogene‐test‐catalogue‐detail.php?test=NGS&ID=20122&search=Panel&disease=Neuronal_migration_disorders_panel

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Table2.ExampleofPanelTestingavailableforpotentiallytreatableconditions(forexample,GLUT1testing)

Company NameofTestNo.Genes

ROICoverage

DepthofCoverage

VariantsofinterestconfirmedbySanger Cost

Turn‐around‐time

Sangersequencingavailable URLtoinformation

GeneDx STATEpilepsyPanel 18 100% 15x yes 3824 2weeks Yes

http://www.genedx.com/wp‐content/uploads/2014/10/info_sheet_STAT_Epilepsy1.pdf

Table3.ExamplesofPanelTestingwhenthegeneticheterogeneityisconsidered“high”andthediagnosis“clear”(forexample,earlyinfantileepilepsyencephalopathy)

Company NameofTestNo.Genes

Pick‐uprate

ROICoverage

DepthofCoverage

VariantsofinterestconfirmedbySanger Cost

Turn‐around‐time

Sangersequencingavailable URLtoinformation

GeneDxInfantileEpilepsyPanel 53 22% 100% 15x yes 3824 4weeks Yes

http://www.genedx.com/wp‐content/uploads/crm_docs/info_sheet_epilepsy_infa.pdf

MNGEpilepticEncephalopathy 80 ‐‐ 97% 30x asneeded 1200 8weeks yes

http://www.medicalneurogenetics.com/OpenTestSearch/TestDetail.aspx?code=NGS386

AthenaDiagnostics

EpilepsyAdvancedSequencingEvaluation‐Epilepticencephalopathies 31 ‐‐ 100% 20x asneeded 2995

4‐6weeks yes

http://athenadiagnostics.com/view‐full‐catalog/e/epilepsy‐advanced‐sequencing‐evaluation‐epileptic

Prevention

EarlyEpilepticEncephalopathyNextgensequencing 66 ‐‐ 100% 20x yes 2327.5

3‐4weeks(upto45days) yes

https://www.preventiongenetics.com/clinical‐dna‐testing/test/early‐infantile‐epileptic‐encephalopathy‐nextgen‐sequencing‐ngs‐panel/2891/

UniversityofChicagoGeneticservices

EarlyInfantileEpilepticEncephalopathy 30 ‐‐ 100% 15x yes 4500 8weeks yes

http://dnatesting.uchicago.edu/sites/default/files/01%20NGS%20EIEE_20.pdf

Centogene

EarlyInfantileEpilepticEncephalopathy 14 ‐‐ 100% 30x yes 4,087 3weeks yes

https://www.centogene.com/centogene/inc/testCatalogueDetail/factsheet/5026_EIEE_panel_V1.pdf

CentogeneEpilepticEncephalopathy 49 ‐‐ 100% 30x yes 4,400 3weeks yes

https://www.centogene.com/centogene/centogene‐test‐catalogue‐detail.php?test=NGS&ID=20064&search=Panel&disease=Epileptic_encephalopathy_panel

ROICoverage:when100%,impliesaSangersequencingpanelorthatSangersequencingwasusedtocoverregionsofpoorcoverageinanNGSpanel

Criteria for Genetic testing Related to Epilepsy, GTAC, October 2016  Page 17 

Table4.ExamplesofPanelTestingwhengeneticheterogeneityisconsidered“high”andtheclinicaldiagnosisis“unclear”

Company NameofTestNo.Genes

Pick‐uprate

ROICoverage

DepthofCoverage

Variantsofinterestconfirmedbysanger Cost

Turn‐around‐time

Sangersequencingavailable URLtoinformation

GeneDx ComprehensiveEpilepsyPanel 70 16% 100% 15x yes 4600 4weeks Yeshttp://www.genedx.com/wp‐content/uploads/crm_docs/info_sheet_epilepsy_comp.pdf

GeneDx ChildhoodOnsetEpilepsy 50 ‐‐ 100% 15x yes 3824 4weeks Yeshttp://www.genedx.com/wp‐content/uploads/crm_docs/info_sheet_epilepsy_child.pdf

MNG ComprehensiveEpilepsy 168 ‐‐ 97% 30x asneeded 1850 8weeks yeshttp://www.medicalneurogenetics.com/OpenTestSearch/TestDetail.aspx?code=NGS385

TransgenomicsComprehensiveEpilepsyEvaluation 377 ‐‐ 97% 20x yes 4130 16weeks yes

http://www.transgenomic.com/product/comprehensive‐epilepsy‐evaluation‐ngs‐panel/

Transgenomics Febrileseizurepanel 6 ‐‐ 100% na n/a 4,200 2‐4weeks yeshttp://www.transgenomic.com/product/febrile‐seizure‐panel/

Transgenomics Femalefebrilepanel 7 ‐‐ 100% na n/a 4,725 2‐4weeks yeshttp://www.transgenomic.com/product/female‐febrile‐seizure‐panel/

Fulgent EpilepsyNGSPanel 343 ‐‐ 98‐99% 10x asneeded 1950 4‐6weeks yes http://fulgentdiagnostics.com/test/epilepsy‐ngs‐panel/

AthenaDiagnosticsEpilepsyAdvancedSequencingEvaluation 141 ‐‐ 100% 20x asneeded 3495 4‐6weeks yes

http://athenadiagnostics.com/view‐full‐catalog/e/epilepsy‐advanced‐sequencing‐evaluation#section1

AthenaDiagnostics

EpilepsyAdvancedSequencingEvaluation‐Generalized,absence,focal,myoclonic 36 ‐‐ 100% 20x asneeded 2995 4‐6weeks yes

http://athenadiagnostics.com/view‐full‐catalog/e/epilepsy‐advanced‐sequencing‐evaluation‐generalize

AthenaDiagnosticsEpilepsyAdvancedSequencingEvaluation‐Syndromic 26 ‐‐ 100% 20x asneeded 2995 4‐6weeks yes

http://athenadiagnostics.com/view‐full‐catalog/e/epilepsy‐advanced‐sequencing‐evaluation‐syndromic

AthenaDiagnosticsEpilepsyAdvancedSequencingEvaluation‐Infantilespasms 10 ‐‐ 100% 20x asneeded 2495 4‐6weeks yes

http://athenadiagnostics.com/view‐full‐catalog/e/epilepsy‐advanced‐sequencing‐evaluation‐infantile

AthenaDiagnostics

EpilepsyAdvancedSequencingEvaluation‐XLIntellectualdisability 27 ‐‐ 100% 20x asneeded 2495 4‐6weeks yes

http://athenadiagnostics.com/view‐full‐catalog/e/epilepsy‐advanced‐sequencing‐evaluation‐epilepsy‐i

Prevention

EarlyEpilepticEncephalopathy,DominantandXLNextgensequencing 26 ‐‐ 100% 20x yes 2845

3‐4weeks(upto45days) yes

https://www.preventiongenetics.com/clinical‐dna‐testing/test/early‐epileptic‐encephalopathy‐dominant‐and‐xlinked‐nextgen‐sequencing‐ngs‐panel/2739/

PreventionEarlyEpilepticEncephalopathy,RecessiveNextgensequencing 40 ‐‐ 100% 20x yes 1653

3‐4weeks(upto45days) yes

https://www.preventiongenetics.com/clinical‐dna‐testing/test/early‐infantile‐epileptic‐encephalopathy‐recessive‐nextgen‐sequencing‐ngs‐panel/2747/

UniversityofChicagoGeneticservices

InfantileandChildhoodEpilepsysequencing 94 ‐‐ 100% 15x yes 5000 8weeks yes

http://dnatesting.uchicago.edu/sites/default/files/01%20NGS%20Epilepsy_8.pdf

CentogeneEpilepsy(absence)inchildhoodpanel 6 ‐‐ 100% 30x yes 1,261 3weeks yes

https://www.centogene.com/centogene/centogene‐test‐catalogue‐detail.php?test=NGS&ID=20065&search=Panel&disease=Epilepsy_(absence)_in_childhood_panel

CentogeneEpilepsy(generalized)withfebrileseizures 6 ‐‐ 100% 30x yes 1,857 3weeks yes

https://www.centogene.com/centogene/centogene‐test‐catalogue‐detail.php?test=NGS&ID=20067&search=Panel&disease=Epilepsy_(generalized)_with_febrile_seizures_panel

CentogeneEpilepsy(partial)hereditarypanel 27 ‐‐ 100% 30x yes 4,400 3weeks yes

https://www.centogene.com/centogene/centogene‐test‐catalogue‐detail.php?test=NGS&ID=20066&search=Panel&disease=Epilepsy_(partial)_hereditary_panel

Courtagen epiSEEKComprehensive 447 ‐‐ 98.40% 20x asneeded 4110 4‐6weeks yeshttp://www.courtagen.com/test‐menu‐genetic‐test‐episeek.htm

Courtagen EpiSEEKFocus 76 ‐‐ 96% 20x asneeded 3375 4‐6weeks yes http://www.courtagen.com/test‐menu‐episeek‐focus.htm

Criteria for Genetic testing Related to Epilepsy, GTAC, October 2016  Page 18 

Appendix A: Epilepsy Genetic Testing Criteria Working Group 

Dr.CarterSneadIII PaediatricNeurologistTheHospitalforSickChildrenUniversityofToronto

Dr.DanielleAndrade NeurologistUniversityHealthNetwork(TorontoWesternHospital)TheHospitalforSickChildrenUniversityofToronto.

Dr.ElizabethDonner PediatricNeurologistHospitalforSickChildrenUniversityofToronto.

Dr.DavidDyment MedicalGeneticistChildren'sHospitalofEasternOntarioUniversityofOttawa

Dr.AsuriNarayanPrasad PediatricNeurologistChildren’sHospital,LondonHealthSciencesCentreUniversityofWesternOntario

Dr.SharanGoobie MedicalGeneticistChildren’sHospital,LondonHealthSciencesCentreUniversityofWesternOntario

Dr.KymBoycott MedicalGeneticistChildren'sHospitalofEasternOntarioUniversityofOttawa

Dr.MatthewLines MedicalGeneticistChildren'sHospitalofEasternOntarioUniversityofOttawa