OBJECTIVE: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. METHODS: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. RESULTS: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells. INTERPRETATION: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024.

Amsterdam University Medical Center University of Amsterdam Department of Clinical Genetics Amsterdam The Netherlands

Autism Research Center Peking University Health Science Center Beijing China

Baylor Genetics Houston TX USA

Center for Individualized Medicine Mayo Clinic Rochester MN USA

Center for Mendelian Genomics Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge MA USA

Center for Molecular and Chromosomal Genetics AP HP Sorbonne University Pitié Salpêtrière Hospital Paris France

Center for Pediatric Genomic Medicine Children's Mercy Hospital Kansas City MO USA

Center for Rare Diseases and Birth Defects Department of Woman and Child Health and Public Health Fondazione Policlinico Universitario A Gemelli IRCCS Rome Italy

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs FHU TRANSLAD CHU Dijon France

Département de Génétique AP HP Sorbonne Université Hôpital Trousseau and Groupe Hospitalier Pitié Salpêtrière Paris France

Department of Biochemistry and Genetics Angers University Hospital and UMR CNRS Angers France

Department of Biochemistry and Genetics University Hospital of Angers Angers France

Department of Clinical and Biological Sciences San Luigi Gonzaga University Hospital University of Torino Turin Italy

Department of Clinical Genetics and School for Oncology and Developmental Biology Maastricht UMC Maastricht The Netherlands

Department of Clinical Genetics Hôpital Jeanne de Flandre CHU Lille Lille France

Department of Clinical Genetics Maastricht University Medical Center Maastricht The Netherlands

Department of Clinical Genomics Mayo Clinic Rochester MN USA

Department of Genetics University of Groningen University Medical Center Groningen Groningen The Netherlands

Department of Genome Sciences University of Washington School of Medicine Seattle WA USA

Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands

Department of Medical Genetics Center for Medical Genetics School of Basic Medical Sciences Peking University Beijing China

Department of Medicine University of Toronto Toronto Canada

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA

Department of Molecular Genetics University of Toronto Toronto Canada

Department of Molecular Life Sciences University of Zurich Zurich Switzerland

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology Faculty of Medicine Comenius University Bratislava Slovakia

Department of Neurology University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Neurology Washington University School of Medicine St Louis MO USA

Department of Neurology Zvolen Hospital Zvolen Slovakia

Department of Neuropediatrics ATOS Klinik Heidelberg Heidelberg Germany

Department of Pathology and Laboratory Medicine Children's Mercy Hospitals Kansas City MO USA

Department of Pathology St Jude Children's Research Hospital Memphis TN USA

Department of Pediatric Neurology and Neurogenetic Referral Center AP HP Sorbonne Université Armand Trousseau Hospital Paris France

Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Department of Pediatrics Clinical Genetics and Metabolism Children's Hospital Colorado Aurora CO USA

Department of Pediatrics Guerin Children's at Cedars Sinai Medical Center Los Angeles CA USA

Department of Quantitative Health Sciences Research Mayo Clinic Rochester MN USA

Department of Research Center Hospitalier du Rouvray Rouen France

Dipartimento di Scienze Della Vita e Sanità Pubblica Università Cattolica del Sacro Cuore Rome Italy

Division of Genetics and Genomic Medicine St Louis Children's Hospital St Louis MO USA

Division of Genetics and Genomics The Manton Center for Orphan Disease Research Boston MA USA

Division of Laboratory Genetics and Genomics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Division of Medical Genetics Department of Internal Medicine Baylor Scott and White Medical Center Temple TX USA

Division of Neonatology Department of Pediatrics University of Miami Miller School of Medicine and Holtz Children's Hospital Jackson Health System Miami FL USA

Dr v Hauner Children's Hospital Department of Pediatric Neurology and Developmental Medicine LMU University of Munich Munich Germany

Genomics Health Services and Policy Research Program Li Ka Shing Knowledge Institute St Michael's Hospital Unity Health Toronto Toronto Canada

Howard Hughes Medical Institute University of Washington Seattle WA USA

INSERM UMR1231 équipe GAD Université de Bourgogne Franche Comté Dijon France

Institute for Advanced Study Technical University of Munich Garching Germany

Institute of Genomic Statistics and Bioinformatics University of Bonn Bonn Germany

Institute of Health Policy Management and Evaluation University of Toronto Toronto Canada

Institute of Human Genetics Klinikum rechts der Isar der TUM Munich Germany

Institute of Human Genetics Klinikum rechts der Isar School of Medicine Technical University of Munich Munich Germany

Institute of Human Genetics School of Medicine Technical University of Munich Munich Germany

Institute of Medical Biochemistry and Molecular Biology University Medicine Greifswald Greifswald Germany

Institute of Medical Biometry Informatics and Epidemiology University of Bonn Bonn Germany

Institute of Medical Genetics University of Zurich Schlieren Switzerland

Institute of Neurogenomics Helmholtz Zentrum Muenchen Neuherberg Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Jessenius Faculty of Medicine in Martin Comenius University Bratislava Martin Slovakia

Key Laboratory for Neuroscience Ministry of Education of China and National Health Commission of China Beijing China

Laboratory Medicine and Pathobiology University of Toronto Toronto Canada

Lunenfeld Tanenbaum Research Institute Sinai Health Toronto Canada

Medical Genetics Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Mitovasc Unit UMR CNRS 6015 INSERM 1083 Angers France

Molecular Genetics and Functional Genomics Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

Munich Cluster for Systems Neurology Munich Germany

Nantes Université CHU de Nantes Service de Génétique Médicale Nantes France

Nantes Université CHU Nantes CNRS INSERM l'institut du Thorax Nantes France

Neurogenetics Technische Universitaet Muenchen Munich Germany

Neuroscience Research Institute Peking University Beijing China

Normandie Univ UNIROUEN Inserm U1245 and CHU Rouen Department of Genetics and Reference Center for Developmental Disorders Rouen France

Pathology and Laboratory Medicine Mount Sinai Hospital Sinai Health Toronto Canada

The Fred A Litwin Family Centre in Genetic Medicine University Health Network and Sinai Health System Toronto Canada

Unité de Biologie et de Génétique Moléculaire Center Hospitalier Universitaire de Strasbourg Strasbourg France

Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares FHU TRANSLAD CHU Dijon Bourgogne Dijon France

Univ Lille CHU Lille RADEME Team Institut de Génétique Médicale Lille France

University Children's Hospital Paracelsus Medical University Salzburg Austria

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medRxiv. 2023 Jun 16:2023.06.13.23290941. doi: 10.1101/2023.06.13.23290941. PubMed

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