2. Academic Validation
  3. A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3

A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3

  • Am J Hum Genet. 2017 Jan 5;100(1):128-137. doi: 10.1016/j.ajhg.2016.11.018.
Hsiao-Tuan Chao 1,  Mariska Davids 2,  Elizabeth Burke 3,  John G Pappas 4,  Jill A Rosenfeld 5,  Alexandra J McCarty 2,  Taylor Davis 3,  Lynne Wolfe 6,  Camilo Toro 6,  Cynthia Tifft 6,  Fan Xia 7,  Nicholas Stong 8,  Travis K Johnson 9,  Coral G Warr 9,  Undiagnosed Diseases Network,  Shinya Yamamoto 10,  David R Adams 6,  Thomas C Markello 6,  William A Gahl 6,  Hugo J Bellen 11,  Michael F Wangler 12,  May Christine V Malicdan 13
Affiliations

Affiliations

  • 1 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.
  • 2 Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • 3 Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • 4 Department of Pediatrics, New York University Langone Medical Center, New York, NY 10016, USA.
  • 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6 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.
  • 7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77030, USA.
  • 8 Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
  • 9 School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.
  • 10 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.
  • 11 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.
  • 12 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.
  • 13 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.
PMID: 28017372 DOI: 10.1016/j.ajhg.2016.11.018
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.

Keywords

COE3; Drosophila; ataxia; expressive speech disorder; hypotonia; inhibitory GABAergic neurons; intellectual disability; knot; transcription factor; vermian hypoplasia.

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