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, David R. Adams, Christopher J. Adams, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Carlos A. BacinoAshok 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, Rachel B. Ramoni, Undiagnosed Diseases Network

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)128-137
Number of pages10
JournalAmerican Journal of Human Genetics
Volume100
Issue number1
DOIs
StatePublished - Jan 5 2017

Fingerprint

B-Lymphocytes
Homeobox Genes
Nervous System
Intellectual Disability
Transcription Factors
Urogenital Abnormalities
Speech Disorders
Mutation
Muscle Hypotonia
Genitalia
Zinc Fingers
Invertebrates
Ataxia
Neurodevelopmental Disorders
3'-(1-butylphosphoryl)adenosine
Diptera
Vertebrates
Phenotype
Survival
DNA

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Chao, H. T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., ... Undiagnosed Diseases Network (2017). A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. American Journal of Human Genetics, 100(1), 128-137. https://doi.org/10.1016/j.ajhg.2016.11.018

A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. / Chao, Hsiao Tuan; Davids, Mariska; Burke, Elizabeth; Pappas, John G.; Rosenfeld, Jill A.; McCarty, Alexandra J.; Davis, Taylor; Wolfe, Lynne; Toro, Camilo; Tifft, Cynthia; Xia, Fan; Stong, Nicholas; Johnson, Travis K.; Warr, Coral G.; Adams, David R.; Adams, Christopher J.; Alejandro, Mercedes E.; Allard, Patrick; Ashley, Euan A.; Bacino, Carlos A.; Balasubramanyam, Ashok; Barseghyan, Hayk; Beggs, Alan H.; Bellen, Hugo J.; Bernstein, Jonathan A.; Bick, David P.; Birch, Camille L.; Boone, Braden E.; Briere, Lauren C.; Brown, Donna M.; Brush, Matthew; Burrage, Lindsay C.; Chao, Katherine R.; Clark, Gary D.; Cogan, Joy D.; Cooper, Cynthia M.; Craigen, William J.; Davids, Mariska; Dayal, Jyoti G.; Dell'Angelica, Esteban C.; Dhar, Shweta U.; Dipple, Katrina M.; Donnell-Fink, Laurel A.; Dorrani, Naghmeh; Dorset, Dan C.; Draper, David D.; Dries, Annika M.; Eckstein, David J.; Emrick, Lisa T.; Ramoni, Rachel B.; Undiagnosed Diseases Network.

In: American Journal of Human Genetics, Vol. 100, No. 1, 05.01.2017, p. 128-137.

Research output: Contribution to journalArticle

Chao, HT, Davids, M, Burke, E, Pappas, JG, Rosenfeld, JA, McCarty, AJ, Davis, T, Wolfe, L, Toro, C, Tifft, C, Xia, F, Stong, N, Johnson, TK, Warr, CG, 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, Ramoni, RB & Undiagnosed Diseases Network 2017, 'A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3', American Journal of Human Genetics, vol. 100, no. 1, pp. 128-137. https://doi.org/10.1016/j.ajhg.2016.11.018
Chao HT, Davids M, Burke E, Pappas JG, Rosenfeld JA, McCarty AJ et al. A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. American Journal of Human Genetics. 2017 Jan 5;100(1):128-137. https://doi.org/10.1016/j.ajhg.2016.11.018
Chao, Hsiao Tuan ; Davids, Mariska ; Burke, Elizabeth ; Pappas, John G. ; Rosenfeld, Jill A. ; McCarty, Alexandra J. ; Davis, Taylor ; Wolfe, Lynne ; Toro, Camilo ; Tifft, Cynthia ; Xia, Fan ; Stong, Nicholas ; Johnson, Travis K. ; Warr, Coral G. ; Adams, David R. ; Adams, Christopher J. ; Alejandro, Mercedes E. ; Allard, Patrick ; Ashley, Euan A. ; Bacino, Carlos A. ; Balasubramanyam, Ashok ; Barseghyan, Hayk ; Beggs, Alan H. ; Bellen, Hugo J. ; Bernstein, Jonathan A. ; Bick, David P. ; Birch, Camille L. ; Boone, Braden E. ; Briere, Lauren C. ; Brown, Donna M. ; Brush, Matthew ; Burrage, Lindsay C. ; Chao, Katherine R. ; Clark, Gary D. ; Cogan, Joy D. ; Cooper, Cynthia M. ; Craigen, William J. ; Davids, Mariska ; Dayal, Jyoti G. ; Dell'Angelica, Esteban C. ; Dhar, Shweta U. ; Dipple, Katrina M. ; Donnell-Fink, Laurel A. ; Dorrani, Naghmeh ; Dorset, Dan C. ; Draper, David D. ; Dries, Annika M. ; Eckstein, David J. ; Emrick, Lisa T. ; Ramoni, Rachel B. ; Undiagnosed Diseases Network. / A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 1. pp. 128-137.
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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.",
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AU - Ashley, Euan A.

AU - Bacino, Carlos A.

AU - Balasubramanyam, Ashok

AU - Barseghyan, Hayk

AU - Beggs, Alan H.

AU - Bellen, Hugo J.

AU - Bernstein, Jonathan A.

AU - Bick, David P.

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AU - Boone, Braden E.

AU - Briere, Lauren C.

AU - Brown, Donna M.

AU - Brush, Matthew

AU - Burrage, Lindsay C.

AU - Chao, Katherine R.

AU - Clark, Gary D.

AU - Cogan, Joy D.

AU - Cooper, Cynthia M.

AU - Craigen, William J.

AU - Davids, Mariska

AU - Dayal, Jyoti G.

AU - Dell'Angelica, Esteban C.

AU - Dhar, Shweta U.

AU - Dipple, Katrina M.

AU - Donnell-Fink, Laurel A.

AU - Dorrani, Naghmeh

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AU - Dries, Annika M.

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KW - intellectual disability

KW - knot

KW - transcription factor

KW - vermian hypoplasia

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