Evidence map›Paper›PMID 35395208›Full record

ArticleAmerican journal of human genetics2022

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.

Sarah E M Stephenson, Gregory Costain, Laura E R Blok, Michael A Silk, Thanh Binh Nguyen, Xiaomin Dong, Dana E Alhuzaimi, James J Dowling, Susan Walker, Kimberly Amburgey and 96 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.

0numbers the graph read from it
0cells of the map it votes in
31citing papers in PubMed
6.5field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

31 citing papers in PubMed, 39 citations in OpenAlex.

  1. Review
  2. Article
  3. Article
  4. Article
  5. Article
  6. Role ofJournal of thoracic disease · 2026
    Article
  7. Article
  8. Review
  9. Review
  10. Article
  11. Tumors and their microenvironments: Learning from pediatric brain pathologies.Biochimica et biophysica acta. Reviews on cancer · 2025
    Review
  12. Review
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. MYCN in human development and diseases.Frontiers in oncology · 2024
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

106 authors at 20 institutions in 11 countries.

Sarah E M StephensonMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
Gregory CostainDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
Laura E R BlokDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525, the Netherlands.
Michael A SilkStructural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Australia Cancer Research Funding Facility for Innovative Cancer Drug Discovery, Bio21 Institute, University of Melbourne, Melbourne, VIC 3052, Australia; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Thanh Binh NguyenStructural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Australia Cancer Research Funding Facility for Innovative Cancer Drug Discovery, Bio21 Institute, University of Melbourne, Melbourne, VIC 3052, Australia; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Xiaomin DongMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
Dana E AlhuzaimiMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
James J DowlingDivision of Neurology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Susan WalkerProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Kimberly AmburgeyDepartment of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Neurology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Robin Z HayeemsChild Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Lance H RodanDivision of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States.
Marc A SchwartzDepartment of Pediatrics, Harvard Medical School, Boston, MA 02115, United States; Cancer and Blood Disorders Center, Boston Children's Hospital, Boston, MA 02115, United States; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115, United States; Broad Institute of MIT and Harvard, Cambridge, MA 02115, United States.
Jonathan PickerDivision of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Child and Adolescent Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States.
Sally A LynchDepartment of Clinical Genetics, Children's Health Ireland at Temple Street, Rotunda, Dublin D01 XD99, Ireland.
Aditi GuptaCenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, United States; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, United States.
Kristen J RasmussenDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States.
Lisa A SchimmentiDepartment of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, United States; Otolaryngology-Head and Neck Surgery (Ear, Nose, and Throat), Mayo Clinic, Rochester, MN 55905, United States; Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, United States.
Eric W KleeCenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, United States; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, United States; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, United States.
Zhiyv NiuDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, United States.
Katherine E AgreDepartment of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, United States.
Ilana ChiltonDepartment of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, United States.
Wendy K ChungDepartment of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, United States; Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, United States.
Anya Revah-PolitiInstitute for Genomic Medicine and Precision Genomics Laboratory, Columbia University Irving Medical Center, New York, NYk, 10032, United States.
P Y Billie AuDepartment of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Christopher GriffithDivision of Pediatrics, University of South Florida, Tampa, FL 33620, United States.
Melissa RacobaldoDivision of Pediatrics, University of South Florida, Tampa, FL 33620, United States.
Annick Raas-RothschildSackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel; Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.
Bruria Ben ZeevSackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel; Pediatric Neurology Unit, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.
Ortal BarelThe Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.
Sebastien MouttonCentre Pluridisciplinaire de Diagnostic PréNatal, Pôle Mère Enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, Nouvelle-Aquitaine 33401, France; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, Bourgogne-Franche-Comté 21000, France; INSERM U1231, Laboratoire de Neurosciences Cognitives, UMR 1231, Genetic of Development Anomalies, University of Burgundy, Dijon, Bourgogne-Franche-Comté 21078 France.
Fanny Morice-PicardReference Center for Genetic, Complex, and Rare Skin Disorders, Department of Pediatric Dermatology, Bordeaux University Hospital, Bordeaux, Nouvelle-Aquitaine 33000, France.
Virginie CarmignacINSERM U1231, Laboratoire de Neurosciences Cognitives, UMR 1231, Genetic of Development Anomalies, University of Burgundy, Dijon, Bourgogne-Franche-Comté 21078 France.
Jenny CornatonReference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, Bourgogne-Franche-Comté 21000, France.
Nathalie MarleLaboratoire de Génétique Chromosomique et Moléculaire, Pôle de Biologie, Centre Hospitalier Universitaire de Dijon, Dijon, Bourgogne-Franche-Comté 21000 France.
Orrin DevinskyNeurology Department, New York University Langone Medical Center, New York, NY 10016, United States.
Chandler StimachDepartment of Human Genetics, Emory Healthcare, Atlanta, GA 30322, United States.
Stephanie Burns WechslerDepartment of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, United States; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, 30322, United States.
Bryan E HainlineIndiana University School of Medicine, Indianapolis, Indiana 46202, United States; Indiana University Health Physicians, Indiana University, Indianapolis, Indiana 46202, United States.
Katie SappIndiana University School of Medicine, Indianapolis, Indiana 46202, United States; Indiana University Health Physicians, Indiana University, Indianapolis, Indiana 46202, United States.
Marjolaine WillemsReference Center for Developmental Disorders, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier University Hospital, Montpellier, Occitanie 34295, France.
Ange-Line BruelInserm UMR 1231, Genetics of Developmental Anomalies, University of Bourgogne, University Hospital Federation, Translational Medicine in Development Disorders, Dijon, Bourgogne-Franche-Comté 21078, France.
Kerith-Rae DiasNew South Wales Health Pathology East Laboratory, Prince of Wales Private Hospital, Sydney, NSW 2031, Australia; Neuroscience Research Australia, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia.
Carey-Anne EvansNew South Wales Health Pathology East Laboratory, Prince of Wales Private Hospital, Sydney, NSW 2031, Australia; Neuroscience Research Australia, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia.
Tony RoscioliNew South Wales Health Pathology East Laboratory, Prince of Wales Private Hospital, Sydney, NSW 2031, Australia; Neuroscience Research Australia, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia; Centre for Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales 2031, Australia.
Rani SachdevCentre for Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales 2031, Australia; School of Women's and Children's Health, University of New South Wales Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia.
Suzanna E L TempleNew South Wales Health Pathology East Laboratory, Prince of Wales Private Hospital, Sydney, NSW 2031, Australia; Neuroscience Research Australia, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia; Centre for Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales 2031, Australia.
Ying ZhuNew South Wales Health Pathology East Laboratory, Prince of Wales Private Hospital, Sydney, NSW 2031, Australia; Newcastle Genetics of Learning Disability Service, Hunter Genetics, Newcastle, New South Wales 2298, Australia.
Joshua J BakerDepartment of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States.
Ingrid E SchefferMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC 3084, Australia.
Fiona J GardinerEpilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC 3084, Australia.
Amy L SchneiderEpilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC 3084, Australia.
Alison M MuirDepartment of Pediatrics, University of Washington, Seattle, WA 98195, United States.
Heather C MeffordDepartment of Pediatrics, University of Washington, Seattle, WA 98195, United States.
Amy CrunkGeneDx, Gaithersburg, MD 20877, United States.
Elizabeth M HeiseGeneDx, Gaithersburg, MD 20877, United States.
Francisca MillanGeneDx, Gaithersburg, MD 20877, United States.
Kristin G MonaghanGeneDx, Gaithersburg, MD 20877, United States.
Richard PersonGeneDx, Gaithersburg, MD 20877, United States.
Lindsay RhodesGeneDx, Gaithersburg, MD 20877, United States.
Sarah RichardsGeneDx, Gaithersburg, MD 20877, United States.
Ingrid M WentzensenGeneDx, Gaithersburg, MD 20877, United States.
Benjamin CognéMedical Genetic Services, The Thorax Institute, INSERM, Centre National de la Recherche Scientifique, University Hospital of Nantes, Nantes, Pays de la Loire 44007, France.
Bertrand IsidorMedical Genetic Services, The Thorax Institute, INSERM, Centre National de la Recherche Scientifique, University Hospital of Nantes, Nantes, Pays de la Loire 44007, France.
Mathilde NizonMedical Genetic Services, The Thorax Institute, INSERM, Centre National de la Recherche Scientifique, University Hospital of Nantes, Nantes, Pays de la Loire 44007, France.
Marie VincentMedical Genetic Services, The Thorax Institute, INSERM, Centre National de la Recherche Scientifique, University Hospital of Nantes, Nantes, Pays de la Loire 44007, France.
Thomas BesnardMedical Genetic Services, The Thorax Institute, INSERM, Centre National de la Recherche Scientifique, University Hospital of Nantes, Nantes, Pays de la Loire 44007, France.
Amelie PitonMolecular Genetic Unit, Strasbourg University Hospital, Strasbourg, Illkirch-Graffenstaden 67000, France; Institute of Genetics and Molecular and Cellular Biology, INSERM U964, Centre National de la Recherche Scientifique, UMR 7104, University of Strasbourg, Illkirch-Graffenstaden, Grand Est 67400, France.
Carlo MarcelisDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525, the Netherlands.
Kohji KatoDepartment of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Chubu 467-8601, Japan; Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Chubu 464-860, Japan.
Norihisa KoyamaDepartment of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Chubu 441-8570, Japan.
Tomoo OgiDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Chubu 464-860, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Chubu 467-8601, Japan.
Elaine Suk-Ying GohLaboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON L5B 1B8, Canada.
Christopher RichmondVictorian Clinical Genetics Services, Melbourne, VIC 3052, Australia.
David J AmorMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia.
Jessica O BoyceMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
Angela T MorganMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
Michael S HildebrandMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC 3084, Australia.
Antony KaspiPopulation Health and Immunity Division, The Walter and Eliza Hall Institute for Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
Melanie BahloPopulation Health and Immunity Division, The Walter and Eliza Hall Institute for Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
Rún FriðriksdóttirdeCODE Genetics, Amgen, Reykjavik 101, Iceland.
Hildigunnur KatrínardóttirdeCODE Genetics, Amgen, Reykjavik 101, Iceland.
Patrick SulemdeCODE Genetics, Amgen, Reykjavik 101, Iceland.
Kári StefánssondeCODE Genetics, Amgen, Reykjavik 101, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
Hans Tómas BjörnssonFaculty of Medicine, University of Iceland, Reykjavik 101, Iceland; Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik 101, Iceland; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, United States.
Simone MandelstamDepartment of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Medical Imaging, The Royal Children's Hospital, Melbourne, VIC 3052, Australia.
Manuela MorleoTelethon Institute of Genetics and Medicine, Pozzuoli, Naples 80078, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli," Naples 80138, Italy.
Milena MarianiDepartment of Pediatrics, Azienda Socio Sanitaria Territoriale, Lariana Sant'Anna Hospital, San Fermo Della Battaglia, Como 22042, Italy.
TUDP Study Group
Marcello ScalaDepartment of Neurosciences, Rehabilitation, Opthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Liguria 16126, Italy; Istituto di Ricovero e Cura a Carattere Scientifico Giannina Gaslini Institute, Genoa, Liguria 16147, Italy.
Andrea AccogliDepartment of Neurosciences, Rehabilitation, Opthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Liguria 16126, Italy; Istituto di Ricovero e Cura a Carattere Scientifico Giannina Gaslini Institute, Genoa, Liguria 16147, Italy.
Annalaura TorellaTelethon Institute of Genetics and Medicine, Pozzuoli, Naples 80078, Italy.
Valeria CapraIstituto di Ricovero e Cura a Carattere Scientifico Giannina Gaslini Institute, Genoa, Liguria 16147, Italy.
Mathew WallisTasmanian Clinical Genetics Services, Royal Hobart Hospital, Hobart, Tasmania 7000, Australia.
Sandra JansenDepartment of Human Genetics, Amsterdam University Medical Centers, Vrije Universiteit Medical Center Amsterdam, Amsterdam, the Netherlands.
Quinten WeisfiszDepartment of Human Genetics, Amsterdam University Medical Centers, Vrije Universiteit Medical Center Amsterdam, Amsterdam, the Netherlands.
Hugoline de HaanDepartment of Human Genetics, Amsterdam University Medical Centers, Vrije Universiteit Medical Center Amsterdam, Amsterdam, the Netherlands.
Simon SadedinMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia.
Broad Center for Mendelian Genomics
Sze Chern LimMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia.
Susan M WhiteMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia.
David B AscherStructural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Australia Cancer Research Funding Facility for Innovative Cancer Drug Discovery, Bio21 Institute, University of Melbourne, Melbourne, VIC 3052, Australia; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Biochemistry, University of Cambridge, Cambridge, England CB2 1GA, United Kingdom.
Annette SchenckDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525, the Netherlands.
Paul J LockhartMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
John ChristodoulouMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia.
Tiong Yang TanMurdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia. Electronic address: tiong.tan@vcgs.org.au.
The University of Melbourne · AUInserm · FRMayo Clinic · USUNSW Sydney · AUdeCODE Genetics (Iceland) · ISAmsterdam University Medical Centers · NLBaker Heart and Diabetes Institute · AUBoston Children's Hospital · USHospital for Sick Children · CAIstituto Giannina Gaslini · ITRadboud University Nijmegen · NLVictorian Clinical Genetics Services · AUColumbia University Irving Medical Center · USIndiana University Health · USMurdoch Children's Research Institute · AUTel Aviv University · ILUniversity of South Florida · USUniversity of Toronto · CAUniversity of Washington · USAzienda Socio Sanitaria Territoriale Lariana · IT

Funding

Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M
NHGRI NIH HHS UM1 HG008900
6 · The paper itself

Abstract

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Indexed as

F-Box-WD Repeat-Containing Protein 7Neurodevelopmental DisordersUbiquitinationGerm CellsGerm-Line MutationHumansProteasome Endopeptidase ComplexUbiquitin-Protein LigasesF-Box-WD Repeat-Containing Protein 7FBXW7 protein, humanProteasome Endopeptidase ComplexUbiquitin-Protein Ligasesbrain malformationepilepsyF-box proteinFBXW7gastrointestinal issuesglobal developmental delayhypotoniaintellectual disabilitymacrocephalyNeurodevelopment

Identifiers

PMID35395208
PMCPMC9069070
OpenAlexW4223648791

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.