biostudies-literatureTepe BIntramural NIH HHSNICHD NIH HHSNIA NIH HHSNational Institute for Health Research (NIHR)NHGRI NIH HHSNINDS NIH HHSRosetreesNIGMS NIH HHSNIH HHS774-789https://www.ebi.ac.uk/biostudies/studies/S-EPMC10183469biostudies-literatureUnknown110(5)The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons American journal of human geneticsBi-allelic variants in INTS11 are associated with a complex neurological disorder.PMC10183469R01 GM134539R01 AG073260NIHR-RP-2016-07-019Z01 OD022005R24 OD022005U54 NS093793CF2 100018-CD2P50 HD105351CF2 100018-CD1R01 NS035129P30 HD024064RP-2016-07-019P50 HD103555R24 OD031447R01 HG009141UM1 HG008900Dasari SCole FSUndiagnosed Diseases NetworkLiu XZEmrick LTSolem EWener MGutierrez INovacic DMalicdan MCVFine AWorley KSutton SCunningham MAmendola LButte MJJobanputra VWalker MStoler JMJean-Marie OBennet JBonner DMoretti PMKlee EWWeisz-Hubshman MWeisz Hubshman MCooper CMLoo SKSmith ECHahn SCoakley TRPallais JCPalmer CGFieg ELPapp JCBellen HJAcosta MTPosey JELanza IRSilverman EKForghani IDayal JGJarvik GPVogel TPAdams DRTartaglia MDeardorff MDuncan LKrakow DZhao CByers PMartin MGAzamian MSBale JFisher PGFogel BLMahoney RRenteria GSinsheimer JSLanpher BCIzumi KScott DAMcCray ATPhillips JAWhitlock JNewman JHScott CRCogne BSweetser DAKoziura MAdam MAlvey JTran AAGochuico BMacnamara EFCarrasquillo OCobban LANickerson DBerg-Rood BPusey BNRaper ADavis JWegner DJMarth GCogan JDSchaechter JWang LKNicholas SKBivona STabor HKWenger TBejerano GJarvik JCraigen WJMight MBoyd BKennedy JIsasi RTucker BMWangler MFKaraviti LPak SZuchner SBayrak-Toydemir PHisama FMMartin BAHayes NLongo NKetkar SRosenfeld JAJamal FMao RLiu PSullivan KMamounas LAWallace SWambach JLalani SRDorrani NParker NHBlue ELanpher BPeter Chang TCLe Guillou XSaporta MOrengo JPThorson WTelischi FWheeler MTHing AHorike-Pyne MMartinez-Agosto JAKilich GBamshad MKurian MAZhang ZTekin MSchaefer GBEng CMD'Souza PHom JKravets EClark KNelson SFSmith KSLaMoure GLSybert VWalsh CAIntrone WKrasnewich DMBohnsack JUrv TKSchultz-Rogers LTifft CJWan JBaldridge DLewis RAHolm IASacco RSolomon BClark GDMak BCSchwab TAfenjar AMcCauley JRodan LHByrd WEKohane ISNieves-Rodriguez SBeck APerry KWPotocki LDrasinover VGrajewski ACrouse ABGlass IMochida GHWegner DDoss ALRives LCoggins MAndrews AKiley DKohler JNShashi VBehrens ETan ALMBotto LAshley EABacino CAChanprasert SEckstein DJSteel DBarbouth DBriere LCFernandez LQuinlan ARuzhnikov MBlanc PMaravilla KGilbert-Dussardier BBeggs AHMarwaha SNakano-Okuno MShohat MHuang YHamid RSchmitz CZastrow DBReuter CMBertini ESXiao CDai HRaja ANSpillmann RCGoßwein SSisco KSun AVanderver ABalasubramanyam ABurrage LCShin JBrown GSchoch KMarom RManolio TAToro CPace LGoldrich MPLee BHNeil JECassini TChao HTEsteves CHuang AOglesbee DVelinder MYang JMcConkie-Rosell AMorava EMacke ELMaduro VVYamamoto SViskochil DCarey JKrezel LSSampson JBLevitt RMerritt JLBademci GPais LSFalk MHigh FBernstein JABerry GTBican ABurke EABrokamp EKobren SNLam BLeBlanc KLam CRossignol FWalley NMRobertson AKHassey KGavrilova RCope HWard PAGranadillo De Luque JLEarl DMcGee EMagal NMacRae CAMefford HSullivan JADoherty DMirzaa GZarate YABurglen LRosenwasser NMaas RLColley HAGahl WALoscalzo JNiceta MWagner EJSchedl TJayadev SRao DAHadley DKanca ODi Donato NDipple KTepe BWolfe LAKorrick SRaskind WDell'Angelica ECGodfrey RATan QKWesterfield MDouine EDWahl CEPrabhakar PGolden-Grant KfalseBi-allelic variants in INTS11 are associated with a complex neurological disorder.The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons 2023-01-01T00:00:00Z2023 May2026-05-29T14:03:45.041Z2025-04-20T01:35:46.148ZS-EPMC101834693705471110.1016/j.ajhg.2023.03.012