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Am J Hum Genet. 2017 Jan 5;100(1):128-137. doi: 10.1016/j.ajhg.2016.11.018. Epub 2016 Dec 22.

A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3.

Collaborators (170)

Adams DR, Adams CJ, Alejandro ME, Allard P, Ashley EA, Bacino CA, Balasubramanyam A, Barseghyan H, Beggs AH, Bellen HJ, Bernstein JA, Bick DP, Birch CL, Boone BE, Briere LC, Brown DM, Brush M, Burrage LC, Chao KR, Clark GD, Cogan JD, Cooper CM, Craigen WJ, Davids M, Dayal JG, Dell'Angelica EC, Dhar SU, Dipple KM, Donnell-Fink LA, Dorrani N, Dorset DC, Draper DD, Dries AM, Eckstein DJ, Emrick LT, Eng CM, Esteves C, Estwick T, Fisher PG, Frisby TS, Frost K, Gahl WA, Gartner V, Godfrey RA, Goheen M, Golas GA, Goldstein DB, Gordon MGG, Gould SE, Gourdine JF, Graham BH, Groden CA, Gropman AL, Hackbarth ME, Haendel M, Hamid R, Hanchard NA, Handley LH, Hardee I, Herzog MR, Holm IA, Howerton EM, Jacob HJ, Jain M, Jiang YH, Johnston JM, Jones AL, Koehler AE, Koeller DM, Kohane IS, Kohler JN, Krasnewich DM, Krieg EL, Krier JB, Kyle JE, Lalani SR, Latham L, Latour YL, Lau CC, Lazar J, Lee BH, Lee H, Lee PR, Levy SE, Levy DJ, Lewis RA, Liebendorder AP, Lincoln SA, Loomis CR, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Malicdan MCV, Mamounas LA, Manolio TA, Markello TC, Mashid AS, Mazur P, McCarty AJ, McConkie-Rosell A, McCray AT, Metz TO, Might M, Moretti PM, Mulvihill JJ, Murphy JL, Muzny DM, Nehrebecky ME, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Orange JS, Pallais JC, Palmer CGS, Papp JC, Pena LDM, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Ramoni RB, Rodan LH, Sadozai S, Schaffer KE, Schoch K, Schroeder MC, Scott DA, Sharma P, Shashi V, Silverman EK, Sinsheimer JS, Soldatos AG, Spillmann RC, Splinter K, Stoler JM, Stong N, Strong KA, Sullivan JA, Sweetser DA, Thomas SP, Tift CJ, Tolman NJ, Toro C, Tran AA, Valivullah ZM, Vilain E, Waggott DM, Wahl CE, Walley NM, Walsh CA, Wangler MF, Warburton M, Ward PA, Waters KM, Webb-Robertson BM, Weech AA, Westerfield M, Wheeler MT, Wise AL, Worthe LA, Worthey EA, Yamamoto S, Yang Y, Yu G, Zornio PA.

Author information

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.

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

PMID:
28017372
PMCID:
PMC5223093
DOI:
10.1016/j.ajhg.2016.11.018
[Indexed for MEDLINE]
Free PMC Article

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