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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
Criteria for Genetic testing Related to Epilepsy, GTAC, October 2016 Page 3
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
Criteria for Genetic testing Related to Epilepsy, GTAC, October 2016 Page 4
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