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.
Bibliographical noteFunding Information:
C.P.S. is generously supported by the Joan and Stanford Alexander family. C.P.S. has received a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. R.A.L. is a senior scientific investigator for Research to Prevent Blindness, whose unrestricted funds to his department support part of these studies. This research is supported by the Intellectual and Developmental Disabilities Research Center (1U54 HD083092), Stichting ODAS (to F.N.B. and F.P.M.C.), Vereniging Bartim?us-Sonneheerdt (5781251 to F.N.B. and F.P.M.C.), Oogfonds (to F.P.M.C., F.N.B., and B.B.A.deV.), and LSBS (to F.P.M.C., F.N.B., and B.B.A.deV.). The authors are grateful to the individuals and their families for their support and for participating in our research study. They thank Ming-Jer Tsai and Mafei Xu for providing technical assistance and Huda Y. Zoghbi for valuable input, guidance, and discussion.
- developmental delay
- optic atrophy