Genetics of the epilepsies-2 - 好大夫在线

来自 : 好大夫在线 发布时间：2021-03-25

Progressinmonogenicepilepsies

Monogenicepilepsiesincludebothfamilialepilepsiesandsevereepilepsiescausedbydenovomutationsinparticulargenes.Inbothgroups,massiveparallelsequencingtechnologieshavecontributedimmenselytogenediscovery.好大夫工作室儿科肖侠明

FamilialEpilepsies

Theyear2012witnessedtheanswertooneofepilepsygeneticsmostprominentmysteries:thegeneticsofBenignFamilialInfantileSeizures(BFIS).BFISrepresentsausuallybenignepilepsysyndromewithself-limitingseizuresinthe firstyear oflife.BFISisgeneticallyandphenotypicallydifferentfromBenignFamilialNeonatalSeizures(BFNS,KCNQ2,KCNQ3)andBenignFamilialNeonatal-InfantileSeizures(BFNIS,SCN2A).Eventhougha linkagetochromosome16 wasalready describedin1997[5],thegenehadescapeddetectionuntil2011.

Somewhatironically,theinitialgenefindingthroughNextGenerationSequencing(NGS)wasnotachievedinBFIS,butinparoxysmalkinesogenicdyskinesia(PKD),amovementdisorderthatisobservedinsomeBFISfamilies[6].PRRT2wassubsequentlyfoundtobethemaincauseofBFIS,explainingupto70%offamilies[7,8].FurthermorePRRT2mutationswerealsoidentifiedinseveralotherbenigninfantileepilepsies[9-11].Duringthecourseof2012,morethan20 publicationson PRRT2ininfantile epilepsieswerepublished,highlightingtheimportanceofthisgeneininfantileepilepsies.

TheidentificationofKCNT1mutationsinMalignantMigratingPartialSeizuresofInfancy(MMPSI)andsevereAutosomalDominantNocturnalFrontalLobeEpilepsy(ADNFLE)wasanothersurprisingfindinginthelast12months[12,13].MMPSIrepresentsasevereinfantileepilepsysyndromewithapeculiarelectroclinicalpattern.ADNFLE,incontrast,hasanonsetinadolescenceoradulthoodwithprominentfrontalseizures.MutationinCHRNA4,CHRNB2andCHRNA2areknowntocauseADNFLE[14].KCNT1mutationswerefoundthroughexomesequencingin6/12patientswithMMPSIincludingthreepatientswiththesamedenovomutation[13].FunctionalstudiessuggestthatthesemutationsresultsinanactivationoftheKCNT1channel,apotassiumchannelexpressedintheCentralNervousSystem.InfourfamilieswithsevereADNFLEandaccompanyingpsychiatricfeaturesandintellectualdisability,mutationsinKCNT1wereidentified[12].MMPSIandsevereADNFLEmightthereforerepresenttheextremesofanovel,unpredictedspectrumofepilepsyphenotypesduemutationsinasinglegene.

Epilepticencephalopathies

Genediscoveryinsevereearlyonsetepilepsies,theso-called“epilepticencephalopathies”, aimstoidentify denovovariantsorrecessivevariantsinsmallfamiliesorpatient-parenttriosusinggenome-widesequencingtechnology. Whenparentsareincludedinthesequencing,denovovariantscanbeassessedonagenome-widelevel, amethodthat hasbeenshowntobeeffectiveinseveralotherneurodevelopmentaldisorders[15-19].Usingwholegenome sequencingofafamilyquartet,SCN8AmutationswereidentifiedinafamilywithinfantileepilepticencephalopathyandSuddenUnexplainedDeathinEpilepsy(SUDEP,[20]).Inaddition,onestudyidentifiedmutationsinKCNQ2inOhtaharaSyndrome,anearlyonsetsevereepilepsy[21].Large-scalefamilysequencingortrio sequencinghavenotyet beenpublished, butdataoncomparablestudiesinautism,schizophreniaorintellectualdisabilityalreadyprovideafirstinsightintothismethod[15-19].Whiledenovomutationscanbeidentifiedinalmosteveryindividualsequenced,doublehitsinasinglegenearerareandrequiremodesttolargesamplesizesfordetection.Interestingly,uptohalfofthepatientsreportedinstudiesonautismandIDalsohadepilepsy.Hence,manyofthegenesrecurrentlyaffectedbydenovomutationsincludingCHD8andDYRK1Aalsorepresentinterestingcandidatesforseizuredisorders.Whilemanyoftherarevariantsmaynotbepathogenic,findingmutationsinaknownepilepsygeneorfindingdoublehitsareestablishedparadigmstoapproachfamilyexomesequencingdata.InDecember2012,theEpi4Kconsortium[2]presentedtheirfirstanalysisonlarge-scalefamilyexomesequencinginpatientswithInfantileSpasmsandLennox-Gastaut-SyndromewhowereidentifiedthroughtheEpilepsyPhenome/GenomeProject.TheEpi4Kresearchersanalyzed165patient-parenttriosfordenovomutationsonanexome-widelevelandfoundcausativevariantsin15%ofpatients[22,23].

ThegenesidentifiedincludedknowngenesforepilepticencephalopathiesincludingCDKL5,ARXandSTXBP1,butalsoseveralnovelgenes,whichrequirefurtherfollow-up.Insummary,thisfirstdatashowsthatthe methodsusedfor autism,schizophreniaandintellectualdisabilitycanbetranslatedtoidentifyinggenesinepilepsiesandthatdenovomutationssignificantlycontributetothegeneticmorbidityofepilepticencephalopathies.

Progressincomplexgeneticepilepsies

Thevastmajorityofepilepsiesarecomplexgenetic,i.e.astronggeneticcontributionisknownfromfamilyandtwinstudies[24,25],buttheepilepsiesarenotinheritedinamonogenicfashion.Theidentificationofgeneticriskfactorsincomplexgeneticepilepsiesoccursthroughassociationstudies,andtherecruitmentofsufficientlylargepatientcohortsforpowerfulassociationstudieshasbeenalong-standingweaknessofthefield.

Raregeneticvariants

Insightintothegeneticarchitectureofsporadicepilepsieshaslargelyoccurredthroughthestudyofcopynumbervariants,submicroscopicchromosomaldeletionsorduplications.Asurprisingfindingofthelastfiveyearshasbeentheidentificationofrecurrentmicrodeletionspredisposingtoawiderangeofneurodevelopmentaldisordersincludingautism,schizophreniaandintellectualdisability[26].Inaddition,manyofthesevariantswerefoundtobeinheritedfromunaffectedparents,apuzzlingfindinginthelightofthestronggeneticriskconferredbysomeofthesevariants[27].Inthelast12months,twopapershavebeenpublishedthatdescribeanalysesofthegeneticarchitectureofmicrodeletions.ApaperbyGirirarjanandcollaboratorsassayedtheroleofdoublehits,i.e.twoindependentcopynumbervariantsinpatientswithintellectualdisability,showingthatseveralmicrodeletionsassociatedwithdiseasepreferentiallyco-occurwithothermicrodeletionsinpatients[28]. Thispaper,buildinguponpreviouswork postulating adoublehitmodelforintellectualdisability[28],isafirststepinexplainingthegeneticsofneurodevelopmentaldisordersthrougholigogenicinheritance.However,thesestudieshavenotyetbeenextendedtopatientswithepilepsy.Afurtherpaperinvestigatedtheapparentcontradictionofassociationandsegregationforepilepsy-relatedmicrodeletionsanddeveloped modelsto translateoddsratioofrarevariantsintosegregationpatterns[29].Themainmessageofthismodelistheconclusionthatrarevariantswithanintermediateriskusuallyarenotexpectedtoshowaclearsegregationpatterninfamilies.RaregeneticvariantsinIdiopathicGeneralizedEpilepsywerealsoinvestigatedinastudybyHeinzenandcollaborators,whoaimedtoidentifyraregeneticsequencevariantsthroughexomesequencing[30].Theauthorsidentified3900raregeneticvariantsthroughexomesequencingof118IGEpatientsand242controlsandfollowedthesevariantsupinalargevalidationcohort.Novariantcouldbeidentifiedwithgenome-widesignificance,suggestingthatrarevariantsofintermediatefrequency(so-called“goldilocksvariants”) arenot asilyidentifiedincomplexgeneticepilepsies.TheauthorssuggestedthatthegeneticarchitectureofIGEmightbemoreheterogeneousandthatagene-basedapproachasopposedtoavariant-basedapproachmightbemoreadvantageous.