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Burden Analysis of Rare Microdeletions Suggests a Strong Impact of Neurodevelopmental Genes in Genetic Generalised Epilepsies
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نویسنده
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lal d. ,ruppert a.-k. ,trucks h. ,schulz h. ,de kovel c.g. ,kasteleijn-nolst trenité d. ,sonsma a.c.m. ,koeleman b.p. ,lindhout d. ,weber y.g. ,lerche h. ,kapser c. ,schankin c.j. ,kunz w.s. ,surges r. ,elger c.e. ,gaus v. ,schmitz b. ,helbig i. ,muhle h. ,stephani u. ,klein k.m. ,rosenow f. ,neubauer b.a. ,reinthaler e.m. ,zimprich f. ,feucht m. ,møller r.s. ,hjalgrim h. ,de jonghe p. ,suls a. ,lieb w. ,franke a. ,strauch k. ,gieger c. ,schurmann c. ,schminke u. ,nürnberg p. ,sander t. ,mörzinger m. ,weckhuysen s. ,claes l. ,deprez l. ,smets k. ,van dyck t. ,deconinck t. ,klitten l.l. ,campus k. ,ostertag p. ,von spiczak s. ,kleefuß-lie a.a. ,gaus g. ,janz d. ,reif p.s. ,oertel w.h. ,hamer h.m. ,becker f.
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منبع
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plos genetics - 2015 - دوره : 11 - شماره : 5
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چکیده
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Genetic generalised epilepsy (gge) is the most common form of genetic epilepsy,accounting for 20% of all epilepsies. genomic copy number variations (cnvs) constitute important genetic risk factors of common gge syndromes. in our present genome-wide burden analysis,large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the affymetrix snp 6.0 array in european case-control cohorts of 1,366 gge patients and 5,234 ancestry-matched controls. we aimed to: 1) assess the microdeletion burden in common gge syndromes,2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions,and 3) identify potential candidate genes for gge. we found a significant excess of microdeletions in 7.3% of gge patients compared to 4.0% in controls (p = 1.8 x 10-7; or = 1.9). recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the gge cohort and showed a 7.5-fold increased burden (p = 2.6 x 10-17) relative to controls. microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (p = 8.0 x 10-18,or = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (p = 1.3 x 10-12,or = 4.1) were significantly enriched in the gge patients. microdeletions found only in gge patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (nrxn1,rbfox1,pcdh7,kcna2,epm2a,rorb,plcb1). our results demonstrate that the significantly increased burden of large and rare microdeletions in gge patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes,suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common gge syndromes. © 2015 lal et al.
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آدرس
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cologne center for genomics (ccg),university of cologne,cologne,germany,cologne excellence cluster on cellular stress responses in aging-associated diseases (cecad),university of cologne,cologne,germany,department of neuropediatrics,university medical center giessen and marburg,giessen,germany,epicure consortium, Germany, cologne center for genomics (ccg),university of cologne,cologne,germany,epicure consortium, Germany, cologne center for genomics (ccg),university of cologne,cologne,germany,epicure consortium,germany,cologne center for genomics,university of cologne,weyertal 115b,cologne,50931, Germany, cologne center for genomics (ccg),university of cologne,cologne,germany,epicure consortium, Germany, epicure consortium,germany,department of medical genetics,university medical center utrecht,utrecht,netherlands,netherlands section complex genetics,department of medical genetics,university medical center utrecht,str. 2.112 universiteitsweg 100,cg utrecht,3584, Netherlands, epicure consortium, Germany, epicure consortium,germany,department of medical genetics,university medical center utrecht,utrecht, Netherlands, epicure consortium,germany,department of medical genetics,university medical center utrecht,utrecht,netherlands,netherlands section complex genetics,department of medical genetics,university medical center utrecht,str. 2.112 universiteitsweg 100,cg utrecht,3584, Netherlands, epicure consortium,germany,department of medical genetics,university medical center utrecht,utrecht,netherlands,sein epilepsy institute in the netherlands,hoofddorp,netherlands,netherlands section complex genetics,department of medical genetics,university medical center utrecht,str. 2.112 universiteitsweg 100,cg utrecht,3584,netherlands,sein epilepsy institute in the netherlands,p.o. box 540,hoofddorp,2130am, Netherlands, epicure consortium,germany,department of neurology and epileptology,hertie institute of clinical brain research,university of tübingen,tübingen,germany,abteilung neurologie mit schwerpunkt epileptologie,hertie institut für klinische hirnforschung,universität tübingen,hoppe-seyler-str. 3,tübingen,72076, Germany, epicure consortium,germany,department of neurology and epileptology,hertie institute of clinical brain research,university of tübingen,tübingen,germany,abteilung neurologie mit schwerpunkt epileptologie,hertie institut für klinische hirnforschung,universität tübingen,hoppe-seyler-str. 3,tübingen,72076, Germany, epicure consortium,germany,department of neurology,university of munich hospital—großhadern,munich,germany,department of neurology,university of munich hospital-großhadern,munich, Germany, epicure consortium,germany,department of neurology,university of munich hospital—großhadern,munich,germany,department of neurology,university of munich hospital-großhadern,munich, Germany, epicure consortium,germany,department of epileptology,university clinics bonn,bonn,germany,department of epileptology,university clinics bonn,sigmund freud strasse 1,bonn,53105, Germany, epicure consortium,germany,department of epileptology,university clinics bonn,bonn,germany,department of epileptology,university clinics bonn,sigmund freud strasse 1,bonn,53105, Germany, epicure consortium,germany,department of epileptology,university clinics bonn,bonn,germany,department of epileptology,university clinics bonn,sigmund freud strasse 1,bonn,53105, Germany, epicure consortium,germany,department of neurology,charité university medicine,campus virchow clinic,berlin, Germany, epicure consortium,germany,department of neurology,charité university medicine,campus virchow clinic,berlin,germany,department of neurology,vivantes humboldt-klinikum,berlin,germany,department of neurology,charité university medicine,campus virchow clinic,humboldt university of berlin,augustenburger platz 1,berlin,13353, Germany, epicure consortium,germany,department of neuropediatrics,university medical center schleswig-holstein (kiel campus),kiel,germany,schwanenweg 20,kiel,24105, Germany, epicure consortium,germany,department of neuropediatrics,university medical center schleswig-holstein (kiel campus),kiel,germany,schwanenweg 20,kiel,24105, Germany, epicure consortium,germany,department of neuropediatrics,university medical center schleswig-holstein (kiel campus),kiel,germany,schwanenweg 20,kiel,24105, Germany, epicure consortium,germany,epilepsy-center hessen,department of neurology,philipps-university marburg,marburg,germany,epilepsy center frankfurt rhein-main,department of neurology,johann wolfgang goethe university frankfurt,frankfurt,germany,epilepsy-center hessen,department of neurology,philipps-university marburg,marburg,35043, Germany, epicure consortium,germany,epilepsy-center hessen,department of neurology,philipps-university marburg,marburg,germany,epilepsy center frankfurt rhein-main,department of neurology,johann wolfgang goethe university frankfurt,frankfurt,germany,epilepsy-center hessen,department of neurology,philipps-university marburg,marburg,35043, Germany, department of neuropediatrics,university medical center giessen and marburg,giessen, Germany, epicure consortium,germany,department of neurology,medical university of vienna,vienna, Austria, epicure consortium,germany,department of neurology,medical university of vienna,vienna,austria,department of clinical neurology, Australia, epicure consortium,germany,department of pediatrics and neonatology,medical university of vienna,vienna,austria,department of pediatrics and neonatology, Australia, epicure consortium,germany,department of neurology,danish epilepsy centre,dianalund,denmark,institute for regional health services,university of southern denmark,odense,denmark,research department,danish epilepsy centre,dianalund kolonivej 7,dianalund,4293,denmark,wilhelm johannsen centre for functional genome research,university of copenhagen,blegdamsvej 3,copenhagen n,2200, Denmark, epicure consortium,germany,department of neurology,danish epilepsy centre,dianalund,denmark,institute for regional health services,university of southern denmark,odense,denmark,research department,danish epilepsy centre,dianalund kolonivej 7,dianalund,4293, Denmark, epicure consortium,germany,neurogenetics group,vib department of molecular genetics,university of antwerp,antwerp,belgium,laboratory of neurogenetics,institute born-bunge,university of antwerp,antwerp,belgium,medical university of vienna,währinger gürtel 18-20,vienna,a-1090,austria,ib department of molecular genetics,university of antwerp,universiteitsplein 1,antwerpen,2610, Belgium, epicure consortium,germany,neurogenetics group,vib department of molecular genetics,university of antwerp,antwerp,belgium,laboratory of neurogenetics,institute born-bunge,university of antwerp,antwerp,belgium,medical university of vienna,währinger gürtel 18-20,vienna,a-1090,austria,ib department of molecular genetics,university of antwerp,universiteitsplein 1,antwerpen,2610, Belgium, institute of epidemiology and biobank popgen,christian albrechts university,kiel, Germany, institute of clinical molecular biology,christian-albrechts-university of kiel,kiel, Germany, institute of genetic epidemiology,helmholtz zentrum münchen—german research center for environmental health,neuherberg,germany,institute of medical informatics,biometry and epidemiology,and chair of genetic epidemiology,ludwig-maximilians-university,munich, Germany, institute of genetic epidemiology,helmholtz zentrum münchen—german research center for environmental health,neuherberg,germany,research unit of molecular epidemiology,helmholtz zentrum münchen—german research center for environmental health,neuherberg,germany,institute of epidemiology ii,helmholtz zentrum münchen—german research center for environmental health,neuherberg, Germany, interfaculty institute for genetics and functional genomics,ernst moritz arndt university,greifswald, Germany, department of neurology,university medicine greifswald,ernst moritz arndt university,greifswald, Germany, cologne center for genomics (ccg),university of cologne,cologne,germany,cologne excellence cluster on cellular stress responses in aging-associated diseases (cecad),university of cologne,cologne,germany,epicure consortium,germany,center for molecular medicine cologne (cmmc),university of cologne,cologne,germany,cologne center for genomics,university of cologne,weyertal 115b,cologne,50931, Germany, cologne center for genomics (ccg),university of cologne,cologne,germany,epicure consortium,germany,cologne center for genomics,university of cologne,weyertal 115b,cologne,50931,germany,department of neurology,charité university medicine,campus virchow clinic,humboldt university of berlin,augustenburger platz 1,berlin,13353, Germany, department of pediatrics and neonatology, Australia, medical university of vienna,währinger gürtel 18-20,vienna,a-1090,austria,ib department of molecular genetics,university of antwerp,universiteitsplein 1,antwerpen,2610, Belgium, medical university of vienna,währinger gürtel 18-20,vienna,a-1090,austria,ib department of molecular genetics,university of antwerp,universiteitsplein 1,antwerpen,2610, Belgium, medical university of vienna,währinger gürtel 18-20,vienna,a-1090,austria,ib department of molecular genetics,university of antwerp,universiteitsplein 1,antwerpen,2610, Belgium, medical university of vienna,währinger gürtel 18-20,vienna,a-1090,austria,ib department of molecular genetics,university of antwerp,universiteitsplein 1,antwerpen,2610, Belgium, medical university of vienna,währinger gürtel 18-20,vienna,a-1090,austria,ib department of molecular genetics,university of antwerp,universiteitsplein 1,antwerpen,2610, Belgium, medical university of vienna,währinger gürtel 18-20,vienna,a-1090,austria,ib department of molecular genetics,university of antwerp,universiteitsplein 1,antwerpen,2610, Belgium, research department,danish epilepsy centre,dianalund kolonivej 7,dianalund,4293, Denmark, department of neuropediatrics,university medical center schleswig-holstein, Germany, schwanenweg 20,kiel,24105, Germany, schwanenweg 20,kiel,24105, Germany, department of epileptology,university clinics bonn,sigmund freud strasse 1,bonn,53105, Germany, department of neurology,charité university medicine,campus virchow clinic,humboldt university of berlin,augustenburger platz 1,berlin,13353, Germany, department of neurology,charité university medicine,campus virchow clinic,humboldt university of berlin,augustenburger platz 1,berlin,13353, Germany, epilepsy-center hessen,department of neurology,philipps-university marburg,marburg,35043, Germany, epilepsy-center hessen,department of neurology,philipps-university marburg,marburg,35043, Germany, epilepsy-center hessen,department of neurology,philipps-university marburg,marburg,35043, Germany, abteilung neurologie mit schwerpunkt epileptologie,hertie institut für klinische hirnforschung,universität tübingen,hoppe-seyler-str. 3,tübingen,72076, Germany
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Authors
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