De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder

Autor: Lilian Bomme Ousager, Anne Gregor, Bruno Dallapiccola, Sébastien Moutton, Marwan Shinawi, Heather C Mefford, Eduardo Calpena, Satoko Kumada, Joseph D. Symonds, Candace T. Myers, Antonio Novelli, Melissa Lees, Bertrand Isidor, Tobias B. Haack, Augusta M. A. Lachmeijer, Francisco Martínez, Anita Rauch, André Reis, Carmen Orellana, Pascal Joset, Rebecca Buchert, Laurence Faivre, Naomichi Matsumoto, Frances Elmslie, Ajoy Sarkar, Katharina Steindl, Mónica Roselló, Ingrid E. Scheffer, Lynette G. Sadleir, Victoria Harrison, Agatino Battaglia, Alex Henderson, Sally Ann Lynch, Felix Distelmaier, Ange Line Bruel, Paranchai Boonsawat, Noriko Miyake, Heinrich Sticht, David Hunt, Carey McDougall, Addie I. Nesbitt, Silvia Azzarello-Burri, Avni Santani, Reza Asadollahi, Benjamin Cogné, Elaine H. Zackai, Ken Saida, Christiane Zweier
Přispěvatelé: Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], St. George's Hospital, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Newcastle Upon Tyne Hospitals NHS Trust, Temple Street Children's University Hospital [Dublin], Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Children’s Hospital of Philadelphia (CHOP ), Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Nottingham Regional Genetics Service [Nottingham, UK], City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], Departments of Medicine and Paediatrics (Austin Health and Royal Children’s Hospital), University of Melbourne-Austin Health, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Bioinformatik, Institut für Biochemie
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: American Journal of Human Genetics
American Journal of Human Genetics, Elsevier (Cell Press), 2018, 103 (2), pp.305-316. ⟨10.1016/j.ajhg.2018.07.003⟩
American Journal of Human Genetics, 103(2), 305. Cell Press
AMERICAN JOURNAL OF HUMAN GENETICS
r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe
instname
University of Washington Center for Mendelian Genomics 2018, ' De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder ', American Journal of Human Genetics, vol. 103, no. 2, pp. 305-316 . https://doi.org/10.1016/j.ajhg.2018.07.003
ISSN: 0002-9297
1537-6605
DOI: 10.1016/j.ajhg.2018.07.003⟩
Popis: International audience; 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.
Databáze: OpenAIRE
Externí odkaz: