1. De novo and biallelic DEAF1 variants cause a phenotypic spectrum
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Elysa J. Marco, Heather C Mefford, Stacey McGee, Christèle Dubourg, Edmund Cauley, Randi J Hagerman, Maria J. Nabais Sá, Bert B.A. de Vries, Rüdiger Lorenz, Elizabeth E. Palmer, Michael J. Parker, Arjan P.M. de Brouwer, Hester Y. Kroes, M. Chiara Manzini, Abbey A. Scott, Tara Montgomery, Naama Orenstein, Jeanne Amiel, Delphine Héron, Leonie A. Menke, Jonathan Berg, Sylvie Odent, Rachel Harrison, Philip J. Jensik, Rani Sachdev, Miranda Splitt, Tyler Mark Pierson, Jan Maarten Cobben, Ehsan Ghayoor Karimiani, Anneke T. Vulto-vanSilfhout, Roberto Colombo, Nayana Lahiri, Julian A. Martinez-Agosto, Evan P. McNeil, Boris Keren, John M. Graham, Chanika Phornphutkul, Reza Maroofian, Radboud University Medical Center [Nijmegen], Southern Illinois University [Carbondale] (SIU), Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, St George's, University of London, Geisel School of Medicine at Dartmouth, University Medical Center [Utrecht], University of California [Davis] (UC Davis), University of California, Nottingham University Hospitals NHS Trust, Northern Genetics Service, Newcastle University [Newcastle], University of New South Wales [Sydney] (UNSW), Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital, University of California [Los Angeles] (UCLA), Tel Aviv University [Tel Aviv], University of Dundee, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Amsterdam [Amsterdam] (UvA), Cedars-Sinai Medical Center, The George Washington University (GW), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Warren Alpert Medical School of Brown University, University of California (UC), Nottingham University Hospitals NHS Trust (NUH), Department of Pediatrics [Seattle, WA, USA], Tel Aviv University (TAU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), General Paediatrics, Paediatric Genetics, Amsterdam Reproduction & Development (AR&D), Sheffield Children's Hospital, St George‘s, University of London, University of Washington [Seattle]-Seattle Children’s Hospital [Seattle, WA, USA], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], George Washington University (GW), and AMS - Sports
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Adult ,Male ,Microcephaly ,Adolescent ,phenotype ,Developmental Disabilities ,genotype ,[SDV]Life Sciences [q-bio] ,Mutation, Missense ,Biology ,Young Adult ,03 medical and health sciences ,Neurodevelopmental disorder ,All institutes and research themes of the Radboud University Medical Center ,Genotype ,medicine ,Humans ,Exome ,Language Development Disorders ,Autistic Disorder ,Allele ,Child ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,030304 developmental biology ,Genetics ,0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,030305 genetics & heredity ,medicine.disease ,Phenotype ,neurodevelopmental disorder ,Human genetics ,DEAF1 ,DNA-Binding Proteins ,intellectual disability ,Child, Preschool ,Speech delay ,Autism ,Female ,medicine.symptom ,Transcription Factors - Abstract
International audience; Purpose To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. Methods We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype–phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. Results The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). Conclusion We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients. © 2019, American College of Medical Genetics and Genomics.
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- 2019
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