Journal article
Biallelic CRELD1 variants cause a multisystem syndrome including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections
Genetics in medicine, Vol.26(2), 101023
02/2024
DOI: 10.1016/j.gim.2023.101023
PMCID: PMC10932913
PMID: 37947183
Abstract
Purpose
We sought to delineate a multisystem disorder caused by recessive CRELD1 variants.
Methods
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.
Results
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 one recurrent variant, p.(Cys192Tyr), identified in 10 families. X. tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared to controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X. tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients as compared to healthy donors.
Conclusion
This patient cohort combined with experimental data provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.
Details
- Title: Subtitle
- Biallelic CRELD1 variants cause a multisystem syndrome including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections
- Creators
- Dimah Saade - University of IowaLauren Jeffries - ID Genomics (United States)Emily K. Mis - ID Genomics (United States)Kirsty McWalterSandra Donkervoort - National Institutes of HealthNina N. Brodsky - ID Genomics (United States)Jean-Marie Carpier - Yale UniversityWeizhen Ji - ID Genomics (United States)Cristian Ionita - Yale UniversityBhaskar Roy - Yale UniversityJon S. Morrow - Yale UniversityArmine Darbinyan - Yale UniversityKrishna IyerRitu B. Aul - Hospital for Sick ChildrenSiddharth Banka - St Mary's HospitalKatherine R. Chao - Broad InstituteLaura Cobbold - St George's, University of LondonStacey Cohen - Children's Hospital of PhiladelphiaHelena M. Custodio - University College LondonMargaret Drummond-Borg - Cook Children's Medical CenterFrances Elmslie - St George's, University of LondonErika Finanger - Oregon Health & Science UniversityBryan E. Hainline - Indiana University HealthIngo Helbig - Children's Hospital of PhiladelphiaStacy Hewson - Hospital for Sick ChildrenYing Hu - National Institute of Neurological Disorders and StrokeAdam Jackson - St Mary's HospitalDragana JosifovaMonica Konstantino - ID Genomics (United States)Meganne E. Leach - Oregon Health & Science UniversityBryan Mak - University of California, Los AngelesDavid McCormick - King's College HospitalElisabeth McGee - University of California, Los AngelesStanley Nelson - University of California, Los AngelesJoanne Nguyen - Cook Children's Medical CenterKimberly Nugent - CooperSurgical (United States)Lucy OrtegaHoward P. Goodkin - University of VirginiaElizabeth Roeder - Baylor College of MedicineSani Roy - Cook Children's Medical CenterKatie Sapp - Indiana University HealthSanjay M. Sisodiya - University College LondonKaren Stals - Royal Devon & Exeter NHS Foundation TrustShelley Towner - University of VirginiaWilliam Wilson - University of VirginiaMustafa K. Khokha - ID Genomics (United States)Carsten G. Bönnemann - National Institute of Neurological Disorders and StrokeCarrie L. Lucas - ID Genomics (United States)Saquib A. Lakhani - Yale UniversityMaria T. AcostaMargaret Adam - St Mary's HospitalDavid R. AdamsPankaj B. AgrawalMercedes E. AlejandroJustin AlveyLaura Amendola - St George's, University of LondonAshley AndrewsEuan A. AshleyMahshid S. AzamianCarlos A. BacinoGuney BademciEva BakerAshok BalasubramanyamDustin BaldridgeJim BaleMichael BamshadDeborah BarbouthPinar Bayrak-ToydemirAnita BeckAlan H. BeggsEdward BehrensGill BejeranoJimmy BennetBeverly Berg-RoodJonathan A. BernsteinGerard T. BerryAnna BicanStephanie BivonaElizabeth Blue - Baylor College of MedicineJohn BohnsackCarsten Bonnenmann - National Institute of Neurological Disorders and StrokeDevon BonnerLorenzo BottoBrenna BoydLauren C. BriereElly BrokampGabrielle BrownElizabeth A. Burke - Baylor College of MedicineLindsay C. BurrageManish J. ButtePeter ByersWilliam E. ByrdJohn CareyOlveen CarrasquilloTa Chen Peter ChangSirisak ChanprasertHsiao-Tuan ChaoGary D. ClarkTerra R. CoakleyLaurel A. CobbanJoy D. CoganMatthew CogginsF Sessions ColeHeather A. ColleyCynthia M. CooperWilliam J. CraigenAndrew B. CrouseMichael CunninghamPrecilla D'SouzaHongzheng DaiSurendra DasariMariska DavidsJyoti G. DayalMatthew DeardorffEsteban C. Dell'AngelicaShweta U. Dhar - St Mary's HospitalKatrina DippleDaniel DohertyNaghmeh DorraniEmilie D. DouineDavid D. DraperLaura Duncan - St George's, University of LondonDawn EarlDavid J. EcksteinLisa T. EmrickChristine M. Eng - National Institute of Neurological Disorders and StrokeCecilia EstevesTyra EstwickMarni FalkLiliana FernandezCarlos FerreiraElizabeth L. FiegLaurie C. FindleyPaul G. FisherBrent L. FogelIrman ForghaniLaure Fresard - ID Genomics (United States)William A. Gahl - University of VirginiaIan Glass - Yale UniversityRena A. GodfreyKatie Golden-GrantAlica M. GoldmanDavid B. GoldsteinAlana GrajewskiCatherine A. GrodenAndrea L. GropmanIrma GutierrezSihoun HahnRizwan HamidNeil A. HanchardKelly HasseyNichole HayesFrances High - St George's, University of LondonAnne Hing - Cook Children's Medical CenterFuki M. HisamaIngrid A. HolmJason HomMartha Horike-PyneAlden HuangYong HuangRosario IsasiFariha JamalGail P. JarvikJeffrey JarvikSuman JayadevJean M. Johnston - Yale UniversityLefkothea KaravitiEmily G. KelleyJennifer KennedyDana KileyIsaac S. KohaneJennefer N. KohlerDeborah KrakowDonna M. KrasnewichElijah KravetsSusan KorrickMary KoziuraJoel B. KrierSeema R. LalaniByron LamChristina LamBrendan C. LanpherIan R. LanzaC Christopher LauKimberly LeBlanc - CooperSurgical (United States)Brendan H. LeeHane LeeRoy Levitt - Cook Children's Medical CenterRichard A. LewisSharyn A. LincolnPengfei LiuXue Zhong LiuNicola LongoSandra K. LooJoseph LoscalzoRichard L. MaasEllen F. MacnamaraCalum A. MacRaeValerie V. MaduroMarta M. MajcherskaMay Christine V MalicdanLaura A. Mamounas - St George's, University of LondonTeri A. ManolioRong MaoKenneth MaravillaThomas C. MarkelloRonit MaromGabor MarthBeth A. Martin - Baylor College of MedicineMartin G. MartinJulian A. Martínez-AgostoShruti MarwahaJacob McCauleyColleen E. McCormackAlexa T. McCrayHeather MeffordJ Lawrence MerrittMatthew MightGhayda MirzaaEva MoravaPaolo M. MorettiMarie Morimoto - Yale UniversityJohn J. MulvihillDavid R. MurdockMariko Nakano-OkunoAvi Nath - King's College HospitalJohn H. NewmanSarah K. NicholasDeborah NickersonShirley Nieves-RodriguezDonna NovacicDevin OglesbeeJames P. OrengoLaura Pace - St George's, University of LondonStephen PakJ Carl PallaisJeanette C. PappNeil H. ParkerJohn A. PhillipsJennifer E. PoseyLorraine PotockiBarbara N. PuseyAaron QuinlanWendy RaskindArchana N. RajaDeepak A. RaoGenecee RenteriaChloe M. ReuterLynette RivesAmy K. RobertsonLance H. RodanJill A. RosenfeldNatalie RosenwasserMaura RuzhnikovRalph SaccoJacinda B. SampsonSusan L. SamsonMario SaportaC Ron ScottJudy SchaechterTimothy SchedlDaryl A. ScottPrashant SharmaJimann ShinRebecca SignerCatherine H. SillariEdwin K. SilvermanJanet S. SinsheimerKathy SiscoEdward C. SmithKevin S. SmithEmily Solem - ID Genomics (United States)Lilianna Solnica-KrezelJoan M. StolerNicholas StongJennifer A. SullivanAngela SunShirley SuttonDavid A. Sweetser - King's College HospitalVirginia SybertHolly K. TaborCecelia P. TamburroMustafa Tekin - ID Genomics (United States)Fred TelischiWilla ThorsonCynthia J. TifftCamilo ToroAlyssa A. TranBrianna M. TuckerTiina K. UrvAdeline VanderverMatt VelinderDave ViskochilTiphanie P. VogelColleen E. WahlStephanie WallaceNicole M. WalleyChris A. WalshMelissa WalkerJennifer WambachJijun WanLee-Kai WangMichael F. WanglerPatricia A. Ward - University of VirginiaDaniel WegnerMark WenerTara WengerKatherine Wesseling PerryMonte WesterfieldMatthew T. WheelerJordan WhitlockLynne A. WolfeJeremy D. WoodsShinya YamamotoJohn YangGuoyun YuDiane B. ZastrowChunli ZhaoStephan ZuchnerJ.C. AmbroseP. Arumugam - Indiana University HealthE.L. Baple - ID Genomics (United States)M. Bleda - National Institute of Neurological Disorders and StrokeF. Boardman-Pretty - Yale UniversityJ.M. BoissiereC.R. Boustred - Yale UniversityM.J. Caulfield - St Mary's HospitalG.C. ChanC.E.H. CraigL.C. DaughertyA. de BurcaA. DevereauG. Elgar - National Institute of Neurological Disorders and StrokeR.E. FoulgerT. Fowler - National Institute of Neurological Disorders and StrokeP. FurióTaríJ.M. HackettD. HalaiA. HamblinS. Henderson - ID Genomics (United States)J.E. Holman - Yale UniversityT.J.P. HubbardK. Ibáñez - Yale UniversityR. Jackson - St Mary's HospitalL.J. JonesD. KasperaviciuteM. Kayikci - National Institute of Neurological Disorders and StrokeL. Lahnstein - ID Genomics (United States)K. Lawson - ID Genomics (United States)S.E.A. LeighI.U.S. LeongF.J. LopezF. MaleadyCroweJ. Mason - University College LondonE.M. McDonagh - National Institute of Neurological Disorders and StrokeL. Moutsianas - ID Genomics (United States)M. Mueller - National Institute of Neurological Disorders and StrokeN. Murugaesu - ID Genomics (United States)A.C. Need - Oregon Health & Science UniversityC.A. Odhams - ID Genomics (United States)C. Patch - ID Genomics (United States)D. Perez-GilD. PolychronopoulosJ. Pullinger - University College LondonT. Rahim - National Institute of Neurological Disorders and StrokeA. RendonP. Riesgo-Ferreiro - Indiana University HealthT. Rogers - National Institute of Neurological Disorders and StrokeM. Ryten - National Institute of Neurological Disorders and StrokeK. Savage - ID Genomics (United States)K. Sawant - ID Genomics (United States)R.H. ScottA. SiddiqA. SieghartD. SmedleyK.R. Smith - Yale UniversityA. SosinskyW. SpoonerH.E. Stevens - University of VirginiaA. StuckeyR. SultanaE R A ThomasS.R. ThompsonA. TucciE. Walsh - ID Genomics (United States)S.A. Watters - ID Genomics (United States)M.J. Welland - St Mary's HospitalE. Williams - ID Genomics (United States)K. Witkowska - ID Genomics (United States)
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.26(2), 101023
- DOI
- 10.1016/j.gim.2023.101023
- PMID
- 37947183
- PMCID
- PMC10932913
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Grant note
- DOI: 10.13039/100000002, name: NIH; DOI: 10.13039/100006792, name: Hartwell Foundation; DOI: 10.13039/100010269, name: Wellcome Trust; DOI: 10.13039/100018693, name: Horizon 2020; DOI: 10.13039/501100000272, name: National Institute for Health Research; DOI: 10.13039/501100000289, name: Cancer Research UK; DOI: 10.13039/501100018726, name: Epilepsy Society
- Language
- English
- Electronic publication date
- 11/2023
- Date published
- 02/2024
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984507154702771
Metrics
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