biostudies-literatureO'Donnell-Luria AHWellcome Sanger InstituteChildren's Hospital of PhiladelphiaNICHD NIH HHSBoston Children’s Hospital Faculty Development FellowshipRepublic of IrelandGerman Research SocietyNICHDCONICYTComprehensive Clinical Research NetworkNational Human Genome Research InstituteSkaggs-Oxford ScholarshipChile’s National Commission for Scientific and Technological ResearchMedical Research CouncilDietmar-Hopp-StiftungCambridge South RECBroad Center for Mendelian GenomicsBowel Cancer UKNational Institute for Health Research (NIHR)NHGRI NIH HHSUniversity of KielHealth Innovation Challenge FundWellcome TrustNational Institutes of Health’s National Institute of Child Health and Human Development1210-1222https://www.ebi.ac.uk/biostudies/studies/S-EPMC6556837biostudies-literatureUnknown104(6)We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.American journal of human geneticsHeterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.PMC655683772160007K12HD052896K12 HD052896HICF-1009-003WT 100127WT098051NF-SI-0510-10282HE5415/5-1HE5415/6-1HE5415/3-110/H0305/83HE5415/7-1R01 HD091846DFG WE4896/3-1UM1 HG008900MC_PC_160181DH1813319WE4896/4-1UM1HG008900R6-388REC GEN/284/12R01 HD073104R01 HG009141NF-SI-0515-1003518PG0019Ramos LLPMcNerlan STaylor JCNellaker CDouglas AGardiner CZak JSequeira CSkitt ZBarrett DMBrewer CEason JPaterson JWidaa SWoods GPendziwiat MVogel IPerson RClowes VTemple IKSteindl KLangman CFisher RHeredia RColgiu IFlinter FCollinson MNRosser EHawkins RAnjum UDabir TBrent STurner CFryer ATivey ARSchwarz NCoates AShearing EKini UMaegawa GHBJenkins LMorton JO'Shea RRoss ASarkar ABaty DMaher EAmburgey KO'Donnell-Luria AHRieß AArmstrong RMelchinger EUWragg CRoberts PBasinger AASaunders CPrescott KBrunstrom KPilz DTJarvis JEllis IRagge Nvan der Linden HFirth HVProcter AParker MJEiset SEReavey CHomfray TKelsell RSneddon LShaw-Smith CIslam LNevitt LMcWilliam CLuria VMcEntagart MMagee ACanham NHewitt SJohnson DBunyan DJBennett CPayne SSweeney ESelby AMarks KGoudie DDeciphering Developmental Disorders (DDD) StudyMcConnell VDean JClayton-Smith JKrishnappa NSquires MMiles EAhmed MCooper NBuchert RStewart HJones WDHobson EMontgomery TBaxter SLees MCilliers DSandford RStewart FDuban-Bedu BBurn JLavillaureix AMark PRLynch SAHeron DIsidor BHumphreys MD'Alessandro MFerrarini AHutton BVogt JRandall JPrigmore ECeulemans SShannon NDubourg CChatzimichali EJosifova DKingston HHelbig KLCole TCross GOgilvie CTomkins SAbou Jamra RGribble SVandersteen ACox HRoberts EWidjaja EMercimek-Andrews SThiffault IAitken SClarke ASampson JRankin JRoberts JRoberts GGreene PYates LDevlin GBohanna DMasruha MRKok FStraub VGreenhalgh LSingh TWentzensen IMPratt NDavidson RBevan APPoulton JRauch AGaunt LBarrett JCQuarrell OMiddleton AAwada JTurnpenny PPark SMvan Koningsbruggen SBarnicoat ADonaldson AHarrison RSveden AHarrison VNorman AHildyard LScurr IEscobar LFMcKee SHarrison LJoss SVasudevan PDonnai DSmith AFitzgerald TWSanchez-Valle ABlair ESmith KRamelli GPSifrim ABlyth MWeber YGMason LEElmslie FFry AAlvi MCrow YBitner-Glindzicz MWilliams NMohammed SHaack TBPatel CTischkowitz MWright MWilliams DTaylor RAccogli ASutton VIngram SShears DTaylor CGibbons RYau MHe LRahbari RBianchini CKaplanis JLongman CFaundes VSaggar AWakeling EPurnell HGoodship JJones ELachlan KRenieri AHurst JKroes HYDonnelly DDonnelly CLampe APhipps JDixit ABourn DCresswell LGreen ABerg JKirby GCulliton LDuncan AWellesley DMcWalter KSuri MDemurger FHeide SKraus AIrving MMiedzybrodzka ZBradley LGray EKumar VKAVarghese VArcher HKeren BKaemba BGill HKinning EMarcelis CLMParker MEvans KBourdon LMehta SPerrett DDobbie AMcLaughlin HMWood JCAmbridge KWilkinson EWilcox SJones PSwaminathan GJMcMullan DJRajan DFendick THashim MNava CCastle BEllard SBernhard BAkawi NClasper SAnderlid BMRaymond LBird LMFitzPatrick DRJackson AScott RSrour MHolden SEverest SDouzgou SPottinger Cde Vries DHollingsworth GWeber ACollins ANemeth ALim DMoore DMaye UWilson LFoulds NBayzetinova TMartin KChandler KKerr BTorokwa ACarre WHellens SKivuva EMurphy HRodan LHDavies SGhali NMcGowan ROng KRSamant STein MMcCann EHenderson AHurles MERice DThomson JMurday VSeller AVijayarangakannan PMcKay KConnell FSattar SBatstone PBanka SCurro ASingzon RCharles PVillard LTrauner DAKirk CSplitt MDeshpande CBalasubramanian MTysoe CNewbury-Ecob RPrice SMetcalfe KJonasson ARLu XMaas SMNaik SBrady AHelbig IWright CFTelegrafi ATreacy BDowling JJBaralle DSmol TSimonic IWhiteford MJoset PPais LSPridham AAzzarello-Burri SKazembe SPollard MRobert LMugalaasi HWallwark SMansour SClayton SSheridan EHolder SHolder MMale ASmithson SSchweiger SLowther GMcRae JFKing DKumar DSharif SLam WSyrbe STatton-Brown KMorgan SWaters JfalseHeterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.2019-01-01T00:00:00Z2019 Jun2024-02-15T18:04:05.919Z2021-02-20T04:41:29ZS-EPMC65568373107989710.1016/j.ajhg.2019.03.021