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

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

Research output: Contribution to journalArticle

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1143-1150
Number of pages8
JournalGenetics in Medicine
Volume18
Issue number11
DOIs
StatePublished - Nov 1 2016

Keywords

  • BBSOAS
  • developmental delay
  • NR2F1
  • optic atrophy

ASJC Scopus subject areas

  • Genetics(clinical)

Fingerprint Dive into the research topics of 'The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations'. Together they form a unique fingerprint.

  • Cite this

    Chen, C. A., Bosch, D. G. M., Cho, M. T., Rosenfeld, J. A., Shinawi, M., Lewis, R. A., Mann, J., Jayakar, P., Payne, K., Walsh, L., Moss, T., Schreiber, A., Schoonveld, C., Monaghan, K. G., Elmslie, F., Douglas, G., Boonstra, F. N., Millan, F., Cremers, F. P. M., ... Schaaf, C. (2016). The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations. Genetics in Medicine, 18(11), 1143-1150. https://doi.org/10.1038/gim.2016.18