title: De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome.
abstract: Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study. The core phenotype includes moderate to severe intellectual disability, and many individuals exhibit cerebellar ataxia, subtle facial dysmorphism, strabismus, and vesicoureteric reflux, suggesting that EBF3 has a widespread developmental role. Pathogenic de novo variants identified in EBF3 include multiple loss-of-function and missense mutations. Structural modeling suggested that the missense mutations affect DNA binding. Functional analysis of mutant proteins with missense substitutions revealed reduced transcriptional activities and abilities to form heterodimers with wild-type EBF3. We conclude that EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation.
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Sleven
authors.affiliation: Program in Molecular Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Welsh
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Program in Molecular Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Mair E A
authors.initials: MEA
authors.lastname: Churchill
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Wright
authors.affiliation: Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Henderson
authors.affiliation: John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Peninsula Clinical Genetics Service, Exeter EX1 2ED, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Rankin
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Vogt
authors.affiliation: Department of Genetic Medicine, Belfast City Hospital, Belfast BT9 7AB, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Magee
authors.affiliation: Department of Genetic Medicine, Belfast City Hospital, Belfast BT9 7AB, UK.
authors.forename: Vivienne
authors.initials: V
authors.lastname: McConnell
authors.affiliation: Department of Clinical Genetics, Our Lady's Hospital, Crumlin, Dublin D12 N512, Ireland; Health Science Centre, School of Medicine & Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.affiliation: Department of Paediatric Neurology and Clinical Neurophysiology, Temple Street Children's University Hospital, Dublin 1, Ireland; Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland.
authors.forename: Mary D
authors.initials: MD
authors.lastname: King
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Cox
authors.affiliation: Department of Medical Genetics, Children's & Women's Health Centre of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
authors.forename: Linlea
authors.initials: L
authors.lastname: Armstrong
authors.affiliation: Department of Medical Genetics, Children's & Women's Health Centre of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Pathology and Laboratory Medicine, BC Children's and BC Women's Hospitals, Vancouver, BC V6H 3N1, Canada.
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Nelson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.affiliation: Department of Medical Genetics, Children's & Women's Health Centre of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
authors.affiliation: Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LJ, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Williams
authors.affiliation: Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LJ, UK.
authors.forename: Penny
authors.initials: P
authors.lastname: Clouston
authors.affiliation: Program in Molecular Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. Electronic address: hagmanj@njhealth.org.
authors.forename: James
authors.initials: J
authors.lastname: Hagman
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK; Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Windmill Road, Headington, Oxford OX3 7HE, UK. Electronic address: andrea.nemeth@ndcn.ox.ac.uk.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Németh
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001259:Ataxia / Q000235:genetics; D002170:Canada; D002648:Child; D004247:DNA / Q000378:metabolism; D002658:Developmental Disabilities / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D013285:Strabismus / Q000235:genetics; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006113:United Kingdom
chemical_list: C000605678:EBF3 protein, human; D014157:Transcription Factors; D004247:DNA