The Expanding Clinical Phenotype of Bosch-Boonstra-Schaaf Optic Atrophy Syndrome: 20 New Cases and Possible Genotype-Phenotype Correlations

Genet Med. 2016 Nov;18(11):1143-1150. doi: 10.1038/gim.2016.18. Epub 2016 Mar 17.

Abstract

Purpose: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations.

Methods: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis.

Results: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%).

Conclusion: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Autism Spectrum Disorder / complications
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / physiopathology
  • COUP Transcription Factor I / genetics*
  • Child
  • Child, Preschool
  • Female
  • Gene Deletion
  • Genetic Association Studies*
  • Humans
  • Male
  • Mutation, Missense
  • Optic Atrophy / complications
  • Optic Atrophy / genetics*
  • Optic Atrophy / physiopathology
  • Pedigree

Substances

  • COUP Transcription Factor I
  • NR2F1 protein, human