biostudies-literatureJeffries LIntramural NIH HHSNCATS NIH HHSNICHD NIH HHSCancer Research UKEpilepsy SocietyNIHHartwell FoundationMedical Research CouncilNational Institute for Health Research (NIHR)NHGRI NIH HHSHorizon 2020NINDS NIH HHSWellcome TrustNIH HHS101023https://www.ebi.ac.uk/biostudies/studies/S-EPMC10932913biostudies-literatureUnknown26(2)<h4>Purpose</h4>We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants.<h4>Methods</h4>The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells.<h4>Results</h4>Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recuGenetics in medicine : official journal of the American College of Medical GeneticsBiallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.PMC10932913MR/M009203/1S10 OD030363U24 NS120854MC_PC_14089U54 NS108874K02 NS112600ACF-2022-06-011NF-SI-0617-10154U01 NS134356U54 HD086984UL1 TR001878R01 NS131512MC_EX_MR/M009203/1NF-SI-0512-10113RP-2016-07-011R01 HG009141R01 HD102186UM1 HG008900R01 NS118522McNerlan SKeelagher RCole FSSwale ADouglas AMaleadyCrowe FGardiner CBorras SWener MNovacic DMalicdan MCVLincoln SAZwolinski SBrewer CPaterson JEason JCarpier JMWoods GTobias EWalker MClowes VJewell RTemple IKBennet JBonner DCaulfield MJWoods JDCooper-Charles LFisher RCooper CMHamblin ALoo SKSmith ECFlinter FHahn SRosser EScott RHSpooner WLau CCCarmichael JPapp JCSansbury FBleda MKelley EGJones LJDabir TArumugam PYu GTurner CHoward 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DABlair ESosinsky AFoulger RELucas CLDipple KBaple ERaskind WJi WBlyth MJohnston JMElmslie FGodfrey RAWesterfield MDouine EDWahl CEGolden-Grant KFry ADasari SStevens HEWright RWilliams NHu YMohammed SCraig CEHTischkowitz MWright MLiu XZWilliams EEmrick LTBonnemann CGWilliams DCallaway ASolem EGutierrez IMurdock DRSutton SShears DCunningham MMolenda AMcCormick DAmendola LButte MJStoler JMLester TGibbons RLynch SMoretti PMLongman CFaravelli FCoakley TRSaggar ALow KMcDonagh EMPallais JCFieg ELAcosta MTWakeling ELeigh SEAPatch CThomas ERAPosey JELanza IRJones ELachlan KRiesgo-Ferreiro PSilverman EKBradley TRuddy DMis EKOwens MForghani IYau SHurst JRoy SDonnelly DJarvik GPLampe AVogel TPAdams DRLeong IUSDixit ADeardorff MWitkowska KGropman ALDuncan LKrakow DBourn DZhao CGreen AByers PMartin MGBerg JRoy BBale JFisher PGCohen SWellesley DMcWalter KSuri MRenteria GGroden CAKraus ASinsheimer JSMiedzybrodzka ZIrving MScott DAde Burca ABradley LMcCray ATChao KRWhitlock JKhokha MKVarghese VMutch SOdhams CAScott CRSweetser DAClement EO'Driscoll MSavage KMcQuaid SKoziura MAlvey JTran AAMacnamara EFKinning ESigner RCobban LABaptista JNickerson DPullinger JLopez FJBerg-Rood BParker MHunt DOsio DMarth GLeach MEDobbie ASchaechter JWang LKNicholas SKWatters SAWenger TMorrow JSBejerano GDhar SUSieghart AJarvik JIsasi RSapp KTucker BMPak SJones WBayrak-Toydemir PMoutsianas LHayes NRosenfeld JACastle BJamal FMao RKasperaviciute DWallace SBernhard BWambach JBoardman-Pretty FClasper SRaymond LLalani SRJackson AScott RDorrani NPeter Chang TCJackson ESaporta MSillari CHHolden SOrengo JPComerford JThorson WTelischi FWheeler MTHorike-Pyne MUndiagnosed Disease NetworkDouzgou SJackson RPottinger CWeber ADarbinyan ABamshad MNemeth ALim DTekin MWilloughby JHom JKravets EReid ERahim TFresard LMoore DJeffries LBodek SWilson WChan GCSultana RWilson LSmith KRClark CSmith KSButler RJin HFoulds NKrasnewich DMWalsh CAWalsh EChandler KTifft CJKerr BLahnstein LLewis RAHolm IASacco RDeciphering Developmental DisordersClark GDHellens SStuckey AKivuva ESaade DSearle CRodan LHNorman AMKohane ISMcGowan RGhali NNieves-Rodriguez SBeck APorteous MRoworth WBriggs TOng KRSamson SLPotocki LGrajewski AMueller MDonkervoort SMcCann EKharbanda MHenderson ATucci AThomson JMercer CMurday VCoggins MAllen ZAndrews AKiley DKohler JNHenderson SLee HNath AAshley EADavids MLawson KChanprasert SMajcherska MMAlejandro MEEckstein DJBanka SHalai DBarbouth DLakhani SAFernandez LFerreira CSplitt MDeshpande CBalasubramanian MRuzhnikov MTysoe CRendon ANewbury-Ecob RPrice SPerez-Gil DLoughlin SAlbaba SLahiri NMarwaha SMetcalfe KHuang YBonnenmann CHamid RDai HKonstantino MRaja ANSisco KSun AVanderver AShin JNaik SBrown GBrady AHelbig IFinanger EPace LBrooks CChao HTBaralle DDaniels SHuang AHanchard NASimonic IYang JYamamoto SNugent KWhiteford MViskochil DGoldman AMHainline BELevitt RMerritt JLRobert LMugalaasi HHills ABican ABurke EAMansour SLam BLeBlanc KLam CWalley NMRobertson AKRogers TWard PAMcGee EStals KBaple ELBurkitt-Wright ESheridan EHolder SSullivan JAHolder MKamath ADoherty DMale ASmithson SSharif ACleary EMaas RLColley HALoscalzo JMulvihill JJJayadev SNguyen JNeed ACSawant KMak BLam WCampbell JWolfe LAKorrick SBrodsky NNDell'Angelica ECTatton-Brown KWilkie ATamburro CPfalseBiallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.<h4>Purpose</h4>We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants.<h4>Methods</h4>The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells.<h4>Results</h4>Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recu2024-01-01T00:00:00Z2024 Feb2026-06-01T05:09:00.146Z2025-04-05T10:19:42.977ZS-EPMC109329133794718310.1016/j.gim.2023.101023