Heterozygous CELF4 variants in the N-term region crucial for the RNA-binding activity lead to neurodevelopmental disorder and obesity.
Ange-Line Bruel, Anneke T Vulto-vanSilfhout, Fr��d��ric Bilan, Gwena��l Le Guyader, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Sophie Rondeau, Marl��ne Rio, Kristen N Lee, Adelyn Beil, Mohnish Suri, Fran��ois Guerin, Valentin Ruault, Alice Goldenberg, Fran��ois Lecoquierre, Nicole Bertsch, Rhonda Anderson, Xiao-Ru Yang, Micheil Inness, Emi Rikeros-Orozco, Maria Palomares-Bralo, Jennifer Cassady Hayek, Jennifer Cech, Ankita Jhuraney, Runjun D Kumar, Saadet Mercimek-Andrews, Anastasia Ambrose, Erin N Wakeling, Ingrid M Wentzensen, Erin Torti, Catherine Gooch, Laurence Faivre, Christophe Philippe, Yannis Duffourd, Antonio Vitobello, Christel Thauvin-Robinet
Author Information
Ange-Line Bruel: INSERM UMR 1231, G��n��tique des Anomalies du D��veloppement, Universit�� de Bourgogne Franche-Comt��, Dijon, France. ange-line.bruel@u-bourgogne.fr. ORCID
Anneke T Vulto-vanSilfhout: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Fr��d��ric Bilan: Department of Genetics, CHU de Poitiers, Poitiers, France.
Gwena��l Le Guyader: Department of Genetics, CHU de Poitiers, Poitiers, France. ORCID
Brigitte Gilbert-Dussardier: Department of Genetics, CHU de Poitiers, Poitiers, France. ORCID
Xavier Le Guillou: Department of Genetics, CHU de Poitiers, Poitiers, France. ORCID
Sophie Rondeau: Department of Genetics, Necker Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cit�� University, Paris, France.
Marl��ne Rio: Department of Genetics, Necker Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cit�� University, Paris, France. ORCID
Kristen N Lee: Department of Pediatrics, Division of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, MI, USA. ORCID
Adelyn Beil: Department of Pediatrics, Division of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, MI, USA.
Fran��ois Guerin: Service de P��diatrie, CH de La Rochelle, La Rochelle, France.
Valentin Ruault: Medical Genetics and Rare Diseases Department, Montpellier University Hospital, Montpellier, France.
Alice Goldenberg: Department of Genetics and Reference Center for Developmental Disorders, Rouen Normandie University, Inserm U12045 and CHU Rouen, FHU-G4 G��nomique, Rouen, France.
Fran��ois Lecoquierre: Department of Genetics and Reference Center for Developmental Disorders, Rouen Normandie University, Inserm U12045 and CHU Rouen, FHU-G4 G��nomique, Rouen, France. ORCID
Nicole Bertsch: The Community Health Clinic Shipshewana, Shipshewana, IN, USA.
Rhonda Anderson: The Community Health Clinic Shipshewana, Shipshewana, IN, USA.
Xiao-Ru Yang: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Micheil Inness: Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
Emi Rikeros-Orozco: Instituto de Gen��tica M��dica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain.
Maria Palomares-Bralo: Instituto de Gen��tica M��dica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain.
Jennifer Cassady Hayek: Seattle Children's Hospital, Seattle, WA, USA. ORCID
Jennifer Cech: Seattle Children's Hospital, Seattle, WA, USA.
Ankita Jhuraney: University of Washington Medical Center, Seattle, WA, USA.
Runjun D Kumar: University of Washington Medical Center, Seattle, WA, USA.
Saadet Mercimek-Andrews: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Anastasia Ambrose: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Erin N Wakeling: GeneDx, Gaitherburg, MD, USA.
Ingrid M Wentzensen: GeneDx, Gaitherburg, MD, USA.
Erin Torti: GeneDx, Gaitherburg, MD, USA.
Catherine Gooch: Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Laurence Faivre: INSERM UMR 1231, G��n��tique des Anomalies du D��veloppement, Universit�� de Bourgogne Franche-Comt��, Dijon, France. ORCID
Christophe Philippe: INSERM UMR 1231, G��n��tique des Anomalies du D��veloppement, Universit�� de Bourgogne Franche-Comt��, Dijon, France. ORCID
Yannis Duffourd: INSERM UMR 1231, G��n��tique des Anomalies du D��veloppement, Universit�� de Bourgogne Franche-Comt��, Dijon, France.
Antonio Vitobello: INSERM UMR 1231, G��n��tique des Anomalies du D��veloppement, Universit�� de Bourgogne Franche-Comt��, Dijon, France. ORCID
Christel Thauvin-Robinet: INSERM UMR 1231, G��n��tique des Anomalies du D��veloppement, Universit�� de Bourgogne Franche-Comt��, Dijon, France. ORCID
RNA-binding proteins play a key role in post-transcriptional events, such as mRNA splicing, transport, stability, translation and decay. Dysregulation of RNA life can have dramatic consequences. CELF RNA-binding proteins appear to be essential during embryo development. In this study, we identified 15 patients with heterozygous missense or loss-of-function variants in the CELF4 gene by exome or genome sequencing. All variants affecting the N-terminus of the protein are essential and sufficient for the RNA-binding and splicing activity or RRM domains. Most patients presented with neurodevelopmental disorders including global developmental delay/intellectual disability (11/14), seizures (9/15) and overweight/obesity (10/14) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype. This study highlights the essential role of CELF4 in development and its involvement as a novel etiology of neurodevelopmental disorders with obesity.
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Grants
Saadet Mercimek-Andrews/Physicians' Services Incorporated Foundation (PSI Foundation)
Mercimek-Andrews Saadet/Physicians' Services Incorporated Foundation (PSI Foundation)
Mercimek-Andrews Saadet/Physicians' Services Incorporated Foundation (PSI Foundation)
