Comprehensivegeneticcharacterizationofprimaryimmunodeficiency
InternationalresearchteaminvolvingtheClusterofExcellencePMIexploresthegeneticsofprimaryimmunodeficiencies(PID)onanunprecedentedscale.
 
So-calledprimaryimmunodeficiencies(PID)areagroupofrareimmunesystemdeficiencies,whicharebasedonamalfunctionoftheimmunesystem.Amongotherthings,theycanleadtorecurringandoftenlife-threateninginfectionsinthoseaffected.Inaddition,patientshaveanincreasedriskofautoimmunereactions,inwhichtheimmunesystemattackstheownbody,aswellasanincreasedriskofcancer.Primaryimmunodeficienciesarerare:itisestimatedthatonepersonin10,000isaffected.Theycandifferconsiderablyincharacteristicsandprogression,whichmakesitparticularlydifficulttodiagnoseprimaryimmunodeficiencies.ThecurrentassumptionisthatmostofthePIDsarebasedonageneticdefect.Somegeneticchangesareinherited,andsomedevelopspontaneously.Butitisoftendifficulttodetermineasinglegenemutationasthecauseoftheimmunodeficiency,sincenoteveryonewiththisgenemutationwillsufferfromthedisease.AninternationalresearchteaminvolvingresearchersfromtheInstituteofClinicalMolecularBiology(IKMB)atKielUniversity(CAU)hasnowpresentedacomprehensivegenomeanalysisofPIDpatientswhichprovidesnewinsightsintothegeneticchangesassociatedwithPID.Theteam,ledbyresearchersatCambridgeUniversity,publishedtheirnewfindingsthisWednesdayinNature.
Throughdetailedanalysisofthewholegenomesequencing(WGS)ofpatients,theresearcherswereabletoconfirmnumerousraregenemutationsfrompreviousstudiesintoPID,andtoidentifyadditionalgenesthataremutatedinpatientsbutnotinhealthypeople.Furthermore,changestothegeneticmaterialintheso-calledgeneregulatoryregionshavebeenidentified,whichcontributetothedevelopmentofdiseases.Unlikeothergenes,theseregionsarenon-coding-i.e.theydonotcontaintheactualgeneticcodingforproteins-butinsteadregulatetheexpressionoftheothergenesintoproteins.Theobservedeffectofchangestothegeneregulatoryregionsprovidesanexplanationforwhythediseasedoesntoccurinallpeoplewhocarryknowndisease-causinggenemutations.Thenewly-identifiedgeneticpatternsofgenemutationsthatcausePIDprovidethebasisforbettergeneticdiagnosisofPIDinthefuture."Thisdiversediseasehasneverbeforebeeninvestigatedsocomprehensivelyandwithsuchdepthofanalysis,asinthisnewstudy,"explainedco-authorProfessorDavidEllinghaus,ascientistattheIKMBandamemberoftheClusterofExcellence"PrecisionMedicineinChronicInflammation"(PMI)."Thisrepresentsanimportantsteptowardsamoredetailedunderstandingoftheprimaryimmunodeficiencies.Thebetterweknowthegeneticcausesofthisdisease,thebetterandmorepreciselywecandiagnoseandtreatPIDpatientsinthefuture,"addedEllinghaus.
Basedonanalysesofthecompletegenomesofindividualpatientsandtheirimmediaterelatives,theresearchersinvestigatedindetailhowfrequently-occurring,knowngenevariantstogetherwithraregenevariantshaveanimpactontheimmunesystem,andhowtheyinfluenceeachother.Forexample,theyanalyzedthegenomeofapatientwhosemothercarriedararegenevariantanddidnotsufferfromPID,butinsteadhadanautoimmunedisease.Inadditiontotheraregenevariantinheritedfromtheirmother,thePIDpatientalsoinheritedacommongenevariantfromtheirfather,whichhastodatebeenassociatedwithrheumatoidarthritis.Incontrast,thebrotherofthePIDpatientonlyinheritedthecommongenevariantfromtheirfather,andhasnosymptomsofPID.Thejointinfluenceofacommonandarareriskvarianthaspresumablyledtothesevereimmunesystemdeficiency.Thisexampleillustrateswhythecharacteristicsandsymptomsofthediseasecanvarysosignificantlyfrompersontoperson,evenwithinthesamefamily. 
Co-authorDr.EvaEllinghaus,ascientistattheIKMBandamemberoftheClusterofExcellencePMI,hadalreadyconductedpriorinternationalresearchwork,togetherwithotherPMIclustermembers,intothegeneticsofpatientswithcommonvariableimmunodeficiency(CVID,oneofthemostcommonformsofthePIDgroupofdisorders).Thedatawasre-analyzedforthenewly-completedstudy,andprovidedimportantadditionalinsightsintothegeneticsofPID."Atthetime,ouranalysiswasthelargestgeneticinvestigationintoCVID.Wegeneticallyanalyzedmorethan770patientsandidentifiedanewriskgeneforthedisease,calledCLEC16A.Inthecurrentstudy,wehavedeterminedthatgeneticriskvariantsinCLEC16AincreasetheriskofbothPIDaswellasautoimmunedisorders,"saidDr.EvaEllinghaus.
Onthebasisofthesenewresearchfindings,itcouldbepossibleinfuturetoidentifyspecificgenevariantsandgeneticpatternsinindividualpatients,throughindividualWGSanalysis,andtherebybetterdiagnosethepresenceofaPIDdiseasethaniscurrentlypossible."Thenewstudyisanimportantsteptowardsprecisionmedicine,i.e.individualizedmedicine,forprimaryimmunodeficiencies,"saidProf.DavidEllinghaus."Becausethesediseasesaresodiverseintheirexpressionandatthesametimesorare,itisallthemoreimportantthateachpatientistreatedindividually,"addedEllinghaus.
Contakt:
Prof.DavidEllinghaus
InstituteofClinicalMolecularBiology(IKMB),CAUundUKSH,CampusKiel.
 0049431-50015131
 d.ellinghaus@ikmb.uni-kiel.de
Throughthedetailedanalysisofcompletegenomesofpatientswithaprimaryimmunedeficiency(PID),theresearchherswereabletoconfirmalargenumberofraregenealterationsfrompreviousstudiesandidentifyadditionalgenesthatarealteredindiseasedindividualscomparedtohealthyindividuals.
ProfessorDavidEllinghaus,juniorresearchgroupleader"BiomedicalInformaticsandGeneticRedefinitionofPhenotypes"attheInstituteofClinicalMolecularBiology(IKMB),CAUandUKSH,andmemberoftheClusterofExcellence„PrecisionMedicineinChronicInflammation“(PMI).
Dr.EvaEllinghaus,scientistattheInstituteofClinicalMolecularBiology(IKMB),CAUandUKSH,andmemberoftheClusterofExcellence„PrecisionMedicineinChronicInflammation“(PMI).
Originalpublication:
JamesE.D.Thaventhiranetal.:Wholegenomesequencingofasporadicprimaryimmunodeficiencycohort.Nature(2020).DOI10.1038/s41586-020-2265-1
FurtherInformationen:
JuniorResearchGroup"BiomedicalInformaticsandGeneticRedefinitionofPhenotypes",IKMB
ProfessorKenSmith'sGroup,UniversityofCambridge
AbouttheClusterofExcellencePMI
TheClusterofExcellence"PrecisionMedicineinChronicInflammation"(PMI)isbeingfundedfrom2019to2025throughtheGermanExcellenceStrategy(ExStra).Itsucceedsthe"InflammationatInterfacesCluster,whichwasalreadyfundedintwoperiodsoftheExcellenceInitiative(2007-2018).Around300membersfromeightinstitutionsatfourlocationsareinvolved:Kiel(KielUniversity,UniversityMedicalCenterSchleswig-Holstein(UKSH),MuthesiusUniversityofFineArtsandDesign,KielInstitutefortheWorldEconomy(IfW),LeibnizInstituteforScienceandMathematicsEducation(IPN)),Lbeck(UniversityofLbeck,UniversityMedicalCenterSchleswig-Holstein(UKSH)),Pln(MaxPlanckInstituteforEvolutionaryBiology)andBorstel(ResearchCenterBorstel-LeibnizLungCenter).
Thegoalistotranslateinterdisciplinaryresearchfindingsonchronicinflammatorydiseasesofbarrierorganstohealthcaremoreintensively,aswellastofulfilpreviouslyunsatisfiedneedsofthepatients.Threepointsareimportantinthecontextofsuccessfultreatment,andarethereforeattheheartofPMIresearch:theearlydetectionofchronicinflammatorydiseases,thepredictionofdiseaseprogressionandcomplications,andthepredictionofindividualresponsestotreatment.
Pressoffice
fbuhse@uv.uni-kiel.de+49(0)431/8804682https://precisionmedicine.de
ClusterofExcellence "PrecisionMedicineinChronicInflammation"
ScientificOffice
Head:Dr.habil.SusanneHolsteinPostal
Christian-Albrechts-Platz4,24118Kiel,Germany
Contact:SonjaPetermann
 +49(0)431880-4850,fax:+49(0)431880-4894
spetermann@uv.uni-kiel.de
Twitter:PMI@medinflame
Related Files
