A severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome with a novel description of coloboma and septo-optic dysplasia, owing to a start codon variant in the NR2F1 gene

Am J Med Genet A. 2022 Mar;188(3):900-906. doi: 10.1002/ajmg.a.62569. Epub 2021 Nov 17.


Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare congenital syndrome characterized by a range of phenotypes including optic atrophy and intellectual disability among other features. Pathogenic variants in the NR2F1 (nuclear receptor subfamily 2 group F member 1) gene have been linked to this condition. A recent report has shown that pathogenic variants in the start codon lead to decreased expression of the NR2F1 protein and a relatively mild phenotype, similar to that seen in whole gene deletions, and due to the lack of the dominant negative effect. Here we describe a severe case of BBSOAS with an initiation codon missense variant. The developmental delay, seizures, optic atrophy are in keeping with features observed in this condition, however this is the first report to describe colobomas and septo-optic dysplasia as associated features potentially extending the phenotype linked to BBSOAS. In addition, this is the first description of a severe phenotype linked to a de novo missense variant in the start codon of the NR2F1 gene.

Keywords: Bosch-Boonstra-Schaaf optic atrophy syndrome; NR2F1; coloboma; intellectual disability; septo-optic dysplasia.

Publication types

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

MeSH terms

  • COUP Transcription Factor I / genetics
  • Codon, Initiator
  • Coloboma* / genetics
  • Humans
  • Intellectual Disability* / genetics
  • Optic Atrophies, Hereditary* / genetics
  • Optic Atrophy* / diagnosis
  • Optic Atrophy* / genetics
  • Septo-Optic Dysplasia* / diagnosis
  • Septo-Optic Dysplasia* / genetics


  • COUP Transcription Factor I
  • Codon, Initiator
  • NR2F1 protein, human