The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype–phenotype correlations Academic Article uri icon

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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.

authors

  • Li, Chumei
  • Chen, Chun-An
  • Bosch, Daniëlle GM
  • Cho, Megan T
  • Rosenfeld, Jill A
  • Shinawi, Marwan
  • Lewis, Richard Alan
  • Mann, John
  • Jayakar, Parul
  • Payne, Katelyn
  • Walsh, Laurence
  • Moss, Timothy
  • Schreiber, Allison
  • Schoonveld, Cheri
  • Monaghan, Kristin G
  • Elmslie, Frances
  • Douglas, Ganka
  • Boonstra, F Nienke
  • Millan, Francisca
  • Cremers, Frans PM
  • McKnight, Dianalee
  • Richard, Gabriele
  • Juusola, Jane
  • Kendall, Fran
  • Ramsey, Keri
  • Anyane-Yeboa, Kwame
  • Malkin, Elfrida
  • Chung, Wendy K
  • Niyazov, Dmitriy
  • Pascual, Juan M
  • Walkiewicz, Magdalena
  • Veluchamy, Vivekanand
  • Li, Chumei
  • Hisama, Fuki M
  • de Vries, Bert BA
  • Schaaf, Christian

publication date

  • November 2016