ArticleAmerican journal of human genetics2018
De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.
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Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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35citing papers in PubMed, 1 pooled it
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.Genes · 2023Pooled it
- Cellular stress triggers degradation and global redistribution of RNAPII.Science advances · 2026Article
- Computational stability analysis suggests binding-independent destabilization in pathogenic FBXO11 variants.Scientific reports · 2026Article
- Isolated absence epilepsy associated with a de novo FBXW7 missense variant in the F-box domain.Epilepsia open · 2026Article
- FBXO11 suppression rewires an NPM1-centered interactome influencing the progression of myelodysplastic syndrome.The Journal of clinical investigation · 2026Article
- From chromatin to proteostasis: multilevel gene regulation in Mendelian diseases.Frontiers in epigenetics and epigenomics · 2026Review
- FBXW7-Related Neurodevelopmental Disorder: Clinical Spectrum, Molecular Mechanisms, and Tumor Predisposition.Human mutation · 2026Review
- FBXO22 deficiency defines a pleiotropic syndrome of growth restriction and multi-system anomalies associated with a unique epigenetic signature.American journal of human genetics · 2025Article
- Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency.HGG advances · 2025Article
- Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders.Biomedicines · 2025Review
- FBXO11 variants are associated with intellectual disability and variable clinical manifestation in Chinese affected individuals.Journal of human genetics · 2024Article
- Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes.Nature communications · 2024Article
- Genetic factors associated with suicidal behaviors and alcohol use disorders in an American Indian population.Molecular psychiatry · 2024Article
- FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Genetic Factors Associated with Suicidal Behaviors and Alcohol Use Disorders in an American Indian Population.Research square · 2023Article
- Genetic Testing in Children with Developmental and Epileptic Encephalopathies: A Review of Advances in Epilepsy Genomics.Children (Basel, Switzerland) · 2023Review
- Article
- Somatic Development Disorders in Children and Adolescents Affected by Syndromes and Diseases Associated with Neurodysfunction and Hydrocephalus Treated/Untreated Surgically.International journal of environmental research and public health · 2022Article
- Defective protein degradation in genetic disorders.Biochimica et biophysica acta. Molecular basis of disease · 2022Review
- Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.American journal of human genetics · 2022Article
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Authors and funding
50 authors at 20 institutions in 13 countries.
Anne GregorInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Lynette G SadleirDepartment of Paediatrics and Child Health, University of Otago, Wellington 6242, New Zealand.
Reza AsadollahiInstitute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland; radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich," 8032 Zurich, Switzerland.
Silvia Azzarello-BurriInstitute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland; radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich," 8032 Zurich, Switzerland.
Agatino BattagliaStella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, 56128 Calambrone, Pisa, Italy.
Lilian Bomme OusagerDepartment of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
Paranchai BoonsawatInstitute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland; radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich," 8032 Zurich, Switzerland.
Ange-Line BruelINSERM U1231, LNC UMR1231 GAD, Burgundy University, 21079 Dijon, France.
Rebecca BuchertInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
Eduardo CalpenaClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Benjamin CognéDepartment of Medical Genetics, CHU Nantes, 44093 Nantes, France; l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, 44007 Nantes, France.
Bruno DallapiccolaGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
Felix DistelmaierDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
Frances ElmslieSouth West Thames Regional Genetics Service, St. George's, University of London, London SW17 0RE, UK.
Laurence FaivreINSERM U1231, LNC UMR1231 GAD, Burgundy University, 21079 Dijon, France; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, 21000 Dijon, France.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
Victoria HarrisonWessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.
Alex HendersonNorthern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne NE1 3BZ, UK.
David HuntWessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK.
Bertrand IsidorDepartment of Medical Genetics, CHU Nantes, 44093 Nantes, France.
Pascal JosetInstitute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland; radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich," 8032 Zurich, Switzerland.
Satoko KumadaDepartment of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo 183-0042, Japan.
Augusta M A LachmeijerDepartment of Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, the Netherlands.
Melissa LeesNorth East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London WC1N 3JH, UK.
Sally Ann LynchDept of Clinical Genetics, Temple Street Children's Hospital Dublin 1, D12 V004 Dublin, Ireland.
Francisco MartinezUnidad de Genética, Hospital Universitario y Politécnico La Fe, Avda Fernando Abril Martorell 106, 46026 Valencia, Spain.
Naomichi MatsumotoDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Carey McDougallDivision of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Heather C MeffordDivision of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Noriko MiyakeDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Candace T MyersDivision of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Sébastien MouttonINSERM U1231, LNC UMR1231 GAD, Burgundy University, 21079 Dijon, France; Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, 21000 Dijon, France.
Addie NesbittDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Antonio NovelliGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
Carmen OrellanaUnidad de Genética, Hospital Universitario y Politécnico La Fe, Avda Fernando Abril Martorell 106, 46026 Valencia, Spain.
Anita RauchInstitute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland; radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich," 8032 Zurich, Switzerland.
Monica RoselloUnidad de Genética, Hospital Universitario y Politécnico La Fe, Avda Fernando Abril Martorell 106, 46026 Valencia, Spain.
Ken SaidaDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Avni B SantaniDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ajoy SarkarNottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham NG5 1PB, UK.
Ingrid E SchefferDepartments of Medicine and Paediatrics, Austin Health and Royal Children's Hospital, The University of Melbourne, Parkville, VIC 3050, Australia.
Marwan ShinawiDivision of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Katharina SteindlInstitute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland; radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich," 8032 Zurich, Switzerland.
Joseph D SymondsPaediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Children, Glasgow G51 4TF, UK.
Elaine H ZackaiDivision of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
University of Washington Center for Mendelian Genomics
DDD StudyWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
André ReisInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Heinrich StichtInstitute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Christiane ZweierInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: christiane.zweier@uk-erlangen.de.
University of Zurich · CHChildren's Hospital of Philadelphia · USFriedrich-Alexander-Universität Erlangen-Nürnberg · DEHospital Universitari i Politècnic La Fe · ESYokohama City University · JPPrincess Anne Hospital · GBUniversity of Tübingen · DEUniversity of Washington · USAustin Health · AUBambino Gesù Children's Hospital · ITFondazione Stella Maris · ITGreat Ormond Street Hospital for Children NHS Foundation Trust · GBHeinrich Heine University Düsseldorf · DEInserm · FRInstitut du Thorax · FRIstituti di Ricovero e Cura a Carattere Scientifico · ITMaison des Sciences de l’Homme de Dijon · FRNewcastle upon Tyne Hospital · GBNottingham University Hospitals NHS Trust · GBOdense University Hospital · DK
Funding
UW Center for Mendelian GenomicsU54HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, NICKERSON, DEBORAH A · 2012 to 2015
$20.0MUW Center for Mendelian GenomicsUM1HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, LEAL, SUZANNE M · 2016 to 2020
$15.3MIntellectual and Developmental Disabilities Research CenterU54HD083091 · NICHD · UNIVERSITY OF WASHINGTON · PI GURALNICK, MICHAEL J · 2014 to 2019
$7.9MWashington University Intellectual and Developmental Disabilities Research Center-Administrative Down Syndrome SupplementU54HD087011 · NICHD · WASHINGTON UNIVERSITY · PI MOLEY, KELLE H · 2015 to 2019
$7.1MA Genomic Approach to EpilepsyR01NS069605 · NINDS · UNIVERSITY OF WASHINGTON · PI MEFFORD, HEATHER C. · 2010 to 2019
$4.9MNHGRI NIH HHS U54 HG006493NHGRI NIH HHS UM1 HG006493NICHD NIH HHS U54 HD083091NICHD NIH HHS U54 HD087011NINDS NIH HHS R01 NS069605
Abstract
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.
Indexed as
ChildExomeExome SequencingF-Box ProteinsFemaleGenetic Association StudiesGenetic VariationHumansIntellectual DisabilityMaleMicrocephalyNeurodevelopmental DisordersProteasome Endopeptidase ComplexProtein-Arginine N-MethyltransferasesUbiquitinationUbiquitin-Protein LigasesF-Box ProteinsFBXO11 protein, humanProteasome Endopeptidase ComplexProtein-Arginine N-MethyltransferasesUbiquitin-Protein LigasesFBXO11intellectual disabilityneurodevelopmental disorder
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