Novel de novo variant in EBF3 is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases

Cold Spring Harb Mol Case Stud. 2017 May;3(3):a001743. doi: 10.1101/mcs.a001743.


Pathogenic variants in EBF3 were recently described in three back-to-back publications in association with a novel neurodevelopmental disorder characterized by intellectual disability, speech delay, ataxia, and facial dysmorphisms. In this report, we describe an additional patient carrying a de novo missense variant in EBF3 (c.487C>T, p.(Arg163Trp)) that falls within a conserved residue in the zinc knuckle motif of the DNA binding domain. Without a solved structure of the DNA binding domain, we generated a homology-based atomic model and performed molecular dynamics simulations for EBF3, which predicted decreased DNA affinity for p.(Arg163Trp) compared with wild-type protein and control variants. These data are in agreement with previous experimental studies of EBF1 showing the paralogous residue is essential for DNA binding. The conservation and experimental evidence existing for EBF1 and in silico modeling and dynamics simulations to validate comparable behavior of multiple variants in EBF3 demonstrates strong support for the pathogenicity of p.(Arg163Trp). We show that our patient presents with phenotypes consistent with previously reported patients harboring EBF3 variants and expands the phenotypic spectrum of this newly identified disorder with the additional feature of a bicornuate uterus.

Keywords: bicornuate uterus; congenital strabismus; downturned corners of mouth; generalized neonatal hypotonia; hydronephrosis; hydroureter; low posterior hairline; microretrognathia; moderate global developmental delay; neurogenic bladder; poor speech; recurrent urinary tract infections; short stature; urethral stricture; vesicoureteral reflux.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • Developmental Disabilities / genetics
  • Exome
  • Female
  • Humans
  • Intellectual Disability / genetics
  • Language Development Disorders / genetics
  • Mutation / genetics
  • Mutation, Missense
  • Neurodevelopmental Disorders / genetics*
  • Phenotype
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • EBF3 protein, human
  • Transcription Factors
  • DNA