De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism

Cold Spring Harb Mol Case Stud. 2017 Nov 21;3(6):a002097. doi: 10.1101/mcs.a002097. Print 2017 Nov.


Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B-cell Transcription Factor Family Member 3 (EBF3) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development. COE proteins are highly evolutionarily conserved and regulate neuronal specification, migration, axon guidance, and dendritogenesis during development and are essential for maintaining neuronal identity in adult neurons. Haploinsufficiency of EBF3 may affect brain development and function, resulting in developmental delay, intellectual disability, and behavioral differences observed in individuals with a deleterious variant in EBF3.

Keywords: autism; central hypotonia; intellectual disability, mild; moderate global developmental delay; neurogenic bladder.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Amino Acid Sequence / genetics
  • Ataxia / genetics
  • Autistic Disorder / genetics
  • Child
  • Child, Preschool
  • Conserved Sequence / genetics
  • Developmental Disabilities / genetics
  • Exome
  • Exome Sequencing / methods
  • Female
  • Humans
  • Infant
  • Intellectual Disability
  • Male
  • Muscle Hypotonia / genetics
  • Mutation
  • Neurodevelopmental Disorders / genetics
  • Prader-Willi Syndrome / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Young Adult


  • EBF3 protein, human
  • Transcription Factors