About the NR2F1 Gene

The NR2F1 gene (also called COUP-TF1), located at 5q15, encodes for a conserved orphan nuclear receptor protein and transcriptional regulator that plays a role in cortical patterning, neurogenesis, guidance of thalamocortical axons, arborization, and neurodevelopment of the eye and optic nerve. NR2F1 works as a homodimer and contains a DNA-binding domain (DBD) formed by two zinc-finger domains as well as a ligand-binding domain (LBD). Loss-of-function variants in NR2F1 are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome, a neurodevelopmental disorder. There are just over 100 known cases of BBSOAS worldwide as of February 2019.

Features of Bosch-Boonstra-Schaaf Optic Atrophy Syndrome

General

The phenotypic spectrum of BBSOAS is broad and variable, but the most well-established characteristics include developmental delay/intellectual disability and visual impairment (including optic nerve atrophy, optic nerve hypoplasia, and cortical visual impairment). Other common features include hypotonia, oromotor dysfunction, morphological changes of brain structures including thinning of the corpus callosum, and autism spectrum disorder. Individuals are also at an elevated risk of seizures, including infantile spasms.

Genotype-phenotype correlations have been proposed, with individuals with mutations in the DBD typically showing a more severe phenotype, and individuals with whole-gene deletions and truncating mutations tending to have moderate to mild symptoms. Individuals with point mutations outside of the DBD most often manifest the mildest phenotype.

BBSOAS is considered a static encephalopathy and has not been shown to be progressive/degenerative.

Inheritance Pattern

BBSOAS is an autosomal dominant disorder. The majority of cases are de novo, but familial cases are also known. The chance of unaffected parents with one affected child having a second affected child is less than 3%, while the chance of an affected parent having an affected child is 50%.    

Reference
Chen, C.-A. et al. The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype–phenotype correlations. Genet. Med. 18, 1143–1150 (2016).

Read the complete research article online Download the full research article PDF

Links For Further Research

Management of BBSOAS

The following tests and therapies are recommended patients who have been found to have a mutation in the NR2F1 gene:

Clinical Exams/Tests:

  1. Full, dilated eye examination from an ophthalmologist every two years
  2. Full hearing evaluation every two years
  3. Comprehensive psychological evaluation for autism:
    • ADI-R and ADOS testing performed by a certified clinical psychologist
  4. A brain MRI, recommended at 40 months or older

Other Therapies

  1. Physical Therapy 
  2. Occupational Therapy
  3. Speech Therapy

List of Features

  • Developmental delay/intellectual disability
  • Visual impairment
    • Optic nerve atrophy
    • Optic nerve hypoplasia
    • (and/or) Cortical visual impairment (CVI)
  • Hypotonia
  • Oromotor dysfunction
  • Thin corpus callosum
  • Repetitive behavior
  • Autism spectrum disorder
  • Seizures, including infantile spasms and febrile seizures
  • ADHD
  • Hearing impairment
  • Spasticity
  • Mild and inconsistent dysmorphic facial features