title: A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3.
abstract: Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.
authors.affiliation: Section of Child Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Hsiao-Tuan
authors.initials: HT
authors.lastname: Chao
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Mariska
authors.initials: M
authors.lastname: Davids
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Burke
authors.affiliation: Department of Pediatrics, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Pappas
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: McCarty
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Davis
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Wolfe
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tifft
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stong
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Travis K
authors.initials: TK
authors.lastname: Johnson
authors.affiliation: School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Coral G
authors.initials: CG
authors.lastname: Warr
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: mw147467@bcm.edu.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wangler
authors.affiliation: Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: maychristine.malicdan@nih.gov.
authors.forename: May Christine V
authors.initials: MCV
authors.lastname: Malicdan
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D001259:Ataxia / Q000235:genetics; D002490:Central Nervous System / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D005835:Genitalia / Q000002:abnormalities; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D013064:Speech Disorders / Q000235:genetics; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics
chemical_list: C000605678:EBF3 protein, human; D014157:Transcription Factors
keywords: COE3; Drosophila; ataxia; expressive speech disorder; hypotonia; inhibitory GABAergic neurons; intellectual disability; knot; transcription factor; vermian hypoplasia