Novel NR2F1 variants likely disrupt DNA binding: molecular modeling in two cases, review of published cases, genotype-phenotype correlation, and phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome

Cold Spring Harb Mol Case Stud. 2017 Nov 21;3(6):a002162. doi: 10.1101/mcs.a002162. Print 2017 Nov.


Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in the NR2F1 gene. There are presently 28 cases of BBSOAS described in the literature. Its common features include developmental delay, intellectual disability, hypotonia, optic nerve atrophy, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, and thinning of the corpus callosum. Here we report two unrelated probands with novel, de novo, missense variants in NR2F1 The first is a 14-yr-old male patient with hypotonia, intellectual disability, optic nerve hypoplasia, delayed bone age, short stature, and altered neurotransmitter levels on cerebrospinal fluid testing. The second is a 5-yr-old female with severe developmental delay, motor and speech delay, and repetitive motion behavior. Whole-exome sequencing identified a novel missense NR2F1 variant in each case, Cys86Phe in the DNA-binding domain in Case 1, and a Leu372Pro in the ligand-binding domain in Case 2. The presence of clinical findings compatible with BBSOAS along with structural analysis at atomic resolution using homology-based molecular modeling and molecular dynamic simulations, support the pathogenicity of these variants for BBSOAS. Short stature, abnormal CNS neurotransmitters, and macrocephaly have not been previously reported for this syndrome and may represent a phenotypic expansion of BBSOAS. A review of published cases along with new evidence from this report support genotype-phenotype correlations for this disorder.

Keywords: amblyopia; aplasia/hypoplasia of the optic nerve; cortical visual impairment; decreased CSF homovanillic acid (HVA); microretrognathia; optic disc hypoplasia; oromotor apraxia; relative macrocephaly; severe muscular hypotonia; short stature.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Adolescent
  • Autism Spectrum Disorder / genetics
  • COUP Transcription Factor I / genetics*
  • COUP Transcription Factor I / metabolism*
  • Child
  • Child, Preschool
  • DNA
  • DNA-Binding Proteins / genetics
  • Developmental Disabilities / genetics
  • Exome / genetics
  • Female
  • Genetic Association Studies
  • Humans
  • Intellectual Disability / genetics
  • Language Development Disorders / genetics
  • Male
  • Models, Molecular
  • Muscle Hypotonia / genetics
  • Mutation / genetics
  • Optic Atrophies, Hereditary / genetics*
  • Optic Atrophies, Hereditary / metabolism
  • Optic Atrophy / genetics
  • Seizures / genetics
  • Whole Exome Sequencing


  • COUP Transcription Factor I
  • DNA-Binding Proteins
  • NR2F1 protein, human
  • DNA