A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3

Hsiao-Tuan Chao; Mariska Davids; Elizabeth Burke; John G Pappas; Jill A Rosenfeld; Alexandra J McCarty; Taylor Davis; Lynne Wolfe; Camilo Toro; Cynthia Tifft; Fan Xia; Nicholas Stong; Travis K Johnson; Coral G Warr; Undiagnosed Diseases Network; Shinya Yamamoto; David R Adams; Thomas C Markello; William A Gahl; Hugo J Bellen; Michael F Wangler; May Christine V Malicdan

doi:10.1016/j.ajhg.2016.11.018

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. Epub 2016 Dec 22.

Authors

Hsiao-Tuan Chao¹, Mariska Davids², Elizabeth Burke³, John G Pappas⁴, Jill A Rosenfeld⁵, Alexandra J McCarty², Taylor Davis³, Lynne Wolfe⁶, Camilo Toro⁶, Cynthia Tifft⁶, Fan Xia⁷, Nicholas Stong⁸, Travis K Johnson⁹, Coral G Warr⁹; Undiagnosed Diseases Network; Shinya Yamamoto¹⁰, David R Adams⁶, Thomas C Markello⁶, William A Gahl⁶, Hugo J Bellen¹¹, Michael F Wangler¹², May Christine V Malicdan¹³

Collaborators

Undiagnosed Diseases Network:
David R Adams, Christopher J Adams, Mercedes E Alejandro, Patrick Allard, Euan A Ashley, Carlos A Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Alan H Beggs, Hugo J Bellen, Jonathan A Bernstein, David P Bick, Camille L Birch, Braden E Boone, Lauren C Briere, Donna M Brown, Matthew Brush, Lindsay C Burrage, Katherine R Chao, Gary D Clark, Joy D Cogan, Cynthia M Cooper, William J Craigen, Mariska Davids, Jyoti G Dayal, Esteban C Dell'Angelica, Shweta U Dhar, Katrina M Dipple, Laurel A Donnell-Fink, Naghmeh Dorrani, Dan C Dorset, David D Draper, Annika M Dries, David J Eckstein, Lisa T Emrick, Christine M Eng, Cecilia Esteves, Tyra Estwick, Paul G Fisher, Trevor S Frisby, Kate Frost, William A Gahl, Valerie Gartner, Rena A Godfrey, Mitchell Goheen, Gretchen A Golas, David B Goldstein, Mary Gracie G Gordon, Sarah E Gould, Jean-Philippe F Gourdine, Brett H Graham, Catherine A Groden, Andrea L Gropman, Mary E Hackbarth, Melissa Haendel, Rizwan Hamid, Neil A Hanchard, Lori H Handley, Isabel Hardee, Matthew R Herzog, Ingrid A Holm, Ellen M Howerton, Howard J Jacob, Mahim Jain, Yong-Hui Jiang, Jean M Johnston, Angela L Jones, Alanna E Koehler, David M Koeller, Isaac S Kohane, Jennefer N Kohler, Donna M Krasnewich, Elizabeth L Krieg, Joel B Krier, Jennifer E Kyle, Seema R Lalani, Lea Latham, Yvonne L Latour, C Christopher Lau, Jozef Lazar, Brendan H Lee, Hane Lee, Paul R Lee, Shawn E Levy, Denise J Levy, Richard A Lewis, Adam P Liebendorder, Sharyn A Lincoln, Carson R Loomis, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Thomas C Markello, Azamian S Mashid, Paul Mazur, Alexandra J McCarty, Allyn McConkie-Rosell, Alexa T McCray, Thomas O Metz, Matthew Might, Paolo M Moretti, John J Mulvihill, Jennifer L Murphy, Donna M Muzny, Michele E Nehrebecky, Stan F Nelson, J Scott Newberry, John H Newman, Sarah K Nicholas, Donna Novacic, Jordan S Orange, J Carl Pallais, Christina G S Palmer, Jeanette C Papp, Loren D M Pena, John A Phillips 3rd, Jennifer E Posey, John H Postlethwait, Lorraine Potocki, Barbara N Pusey, Rachel B Ramoni, Lance H Rodan, Sarah Sadozai, Katherine E Schaffer, Kelly Schoch, Molly C Schroeder, Daryl A Scott, Prashant Sharma, Vandana Shashi, Edwin K Silverman, Janet S Sinsheimer, Ariane G Soldatos, Rebecca C Spillmann, Kimberly Splinter, Joan M Stoler, Nicholas Stong, Kimberly A Strong, Jennifer A Sullivan, David A Sweetser, Sara P Thomas, Cynthia J Tift, Nathanial J Tolman, Camilo Toro, Alyssa A Tran, Zaheer M Valivullah, Eric Vilain, Daryl M Waggott, Colleen E Wahl, Nicole M Walley, Chris A Walsh, Michael F Wangler, Mike Warburton, Patricia A Ward, Katrina M Waters, Bobbie-Jo M Webb-Robertson, Alec A Weech, Monte Westerfield, Matt T Wheeler, Anastasia L Wise, Lynne A Worthe, Elizabeth A Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Patricia A Zornio

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: [email protected].
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: [email protected].

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.

Publication types

Case Reports

MeSH terms

Abnormalities, Multiple / genetics
Ataxia / genetics
Central Nervous System / abnormalities
Child
Child, Preschool
Developmental Disabilities / genetics
Female
Genitalia / abnormalities
Humans
Infant
Infant, Newborn
Intellectual Disability / genetics
Male
Muscle Hypotonia / genetics
Mutation*
Neurodevelopmental Disorders / genetics*
Speech Disorders / genetics
Syndrome
Transcription Factors / genetics*
Zinc Fingers / genetics

Substances

EBF3 protein, human
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding