biostudies-literatureDore RSwiss National Science FoundationNIDA NIH HHSNational Institutes of HealthWellcome Trust101506https://www.ebi.ac.uk/biostudies/studies/S-EPMC12260708biostudies-literatureUnknown27(9)<h4>Purpose</h4>Synaptic communication deficits are central to many neurodevelopmental disorders. However, for rare monogenic conditions, these disorders remain poorly defined, with limited understanding of their molecular etiology. A homozygous frameshift variant in the synaptic cell adhesion molecule ELFN1 was reported in a family with 3 affected siblings with epileptic encephalopathy, alongside a missense variant of uncertain significance in a cohort study involving a family with intellectual disability. Therefore, we sought to evaluate the role and mechanism of biallelic ELFN1 variants in disease pathogenesis.<h4>Methods</h4>We describe 8 newly identified individuals from 5 unrelated families, all carrying homozygous ELFN1 variants, including frameshift and in-frame deletions. By integGenetics in medicine : official journal of the American College of Medical GeneticsELFN1 deficiency: The mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy.PMC12260708R01 DA056414216615Anwar IDouglas JDasari SCole FSUndiagnosed Diseases NetworkChang CTEmrick LTMcRoy ESkelton TLudlam WGWener MMaroofian RNovacic DCallaway KAttaripour STaylor HRajagopalan RWorley KSutton SCuddapah VButte MJWalker MJobanputra VStoler JMEzell KDickson PJean-Marie OKarasozen YLeppig KABonner DGropman AAlves CSeto EVetrini FCoakley TRPallais JCFieg ELBellen HJAcosta MTHurst APosey JELanza IRAnsar MRebelo AKheirollahi MSilverman EKDargie NKSirugo GMiller DJarvik GPVogel TPAdams DRButterfield RMartin MGByers PShelkowitz EZahid MFisher PGFogel BLSuri MMahoney RAntonarakis SECopmans DLanpher BCScott DASmith CAVilain EPhillips JAWhitlock JMovsesyan NPetcharet LSweetser DAFrederiksen HWare SMAlvey JTran AADore RMacnamara EFCobban LANicholas TJAlmalvez MRaper ADavis JKorf BTarakad APaul ALiaqat KMarth GCogan JDAllenspach EMulvihill LDehghani MHoulden HTabor HKBivona SWenger TKarimiani EGPusey Swerdzewski BNGonzalez JMBejerano GMozaffar TMantcheva LMight MCraigen WJWangler MFPak SZuchner SHisama FMBayrak-Toydemir PMartin BALongo NKetkar SRosenfeld JASkraban CBalton EMao RSullivan KLiu PWambach JAlvarez RLLalani SRDorrani NParker NHBlue EBoyden SOrengo JPThorson WWheeler MTHing AHorike-Pyne MHenchcliffe CMartinez-Agosto JABaldwin EECarvalho GKilich GBennett JBamshad MGraham BHTekin MEng CMOreshkov SD'Souza PHom JKravets EPeart LHanchard NTreat KMNelson SFSmith KSHalley MCBrunori GSheppeard SSybert VLatchman KDelgado MKhorrami MIntrone WTifft CJBaldridge DLewis RADarr KSolomon BHolm IASolnica-Krezel LClark GDRodan LHAfzali BCorona RIKohane ISByrd WEBaldwin EBeck APotocki LMoretti PMirjalili MRCrouse ABGlass IMikati MWegner DMaghiro ACMartemyanov KARives LCoggins MAndrews AKiley DKohler JNShashi VBehrens ESandmeyer SVargas ABotto LAshley EABacino CAChanprasert SBarbouth DBriere LCQuinlan AMalicdan MVRuzhnikov MNy AStriano PWelt CKWood HBeggs AHMarwaha SNakano-Okuno MHuang YDecleve AHamid RFu JMitchell BReuter CMXiao CDai HSpillmann RCSisco KGoddard PCMartinez-Agosto JVanderver AGlanton EBalasubramanyam AShin JBurrage LCMorimoto MSchoch KMarom RUngar RASunyaev SREghbal FToro CAbdenur JSingh KPace LLee BHChao HTCassini TEsteves CHuang AOglesbee DVelinder MMcConkie-Rosell AStergachis AMaduro VVGanetzky RYamamoto SViskochil DCarey JSampson JBBademci GAkram SDamseh NSWard AHigh FBernstein JABerry GTTan QRader DJBurke EARodriguez MKobren SNLeBlanc KLam CRossignol FWalley NMMovahedinia MPinto E Vairo FHassey KWard PAVahidi Mehrjardi MYEarl DMacRae CAHubshman MWRosenthal EChinn IKlee EDoherty DMirzaa GCorner BConboy EAllworth AMaas RLMulvihill JJLoscalzo JGahl WASchedl TRao DAJayadev SSchimmenti LMcMinn ADipple KKanca OAl-Beshri ANeumann SWolfe LAOverbury RKorrick SRaskind WDell'Angelica ECBorja NWesterfield MWahl CESabaii MBarrick RfalseELFN1 deficiency: The mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy.<h4>Purpose</h4>Synaptic communication deficits are central to many neurodevelopmental disorders. However, for rare monogenic conditions, these disorders remain poorly defined, with limited understanding of their molecular etiology. A homozygous frameshift variant in the synaptic cell adhesion molecule ELFN1 was reported in a family with 3 affected siblings with epileptic encephalopathy, alongside a missense variant of uncertain significance in a cohort study involving a family with intellectual disability. Therefore, we sought to evaluate the role and mechanism of biallelic ELFN1 variants in disease pathogenesis.<h4>Methods</h4>We describe 8 newly identified individuals from 5 unrelated families, all carrying homozygous ELFN1 variants, including frameshift and in-frame deletions. By integ2025-01-01T00:00:00Z2025 Sep2026-05-09T17:54:51.423Z2026-04-08T01:08:35.793ZS-EPMC122607084057602310.1016/j.gim.2025.101506