Chun-An Chen1,2, Daniëlle G M Bosch3,4,5,6, Megan T Cho7, Jill A Rosenfeld1, Marwan Shinawi8, Richard Alan Lewis1,9, John Mann10, Parul Jayakar11, Katelyn Payne12, Laurence Walsh12,13, Timothy Moss14, Allison Schreiber14, Cheri Schoonveld15, Kristin G Monaghan7, Frances Elmslie16, Ganka Douglas7, F Nienke Boonstra4,6, Francisca Millan7, Frans P M Cremers3,5, Dianalee McKnight7, Gabriele Richard7, Jane Juusola7, Fran Kendall17,18, Keri Ramsey19, Kwame Anyane-Yeboa20, Elfrida Malkin21, Wendy K Chung20,22, Dmitriy Niyazov23, Juan M Pascual24, Magdalena Walkiewicz1, Vivekanand Veluchamy25, Chumei Li26, Fuki M Hisama27, Bert B A de Vries3,6, Christian Schaaf1,2,28. 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. 2. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. 3. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 4. Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands. 5. Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 6. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. 7. GeneDx, Gaithersburg, Maryland, USA. 8. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA. 9. Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA. 10. Genetics, Kaiser-Permanente Fresno Medical Center, Clovis, California, USA. 11. Nicklaus Children's Hospital, Miami, Florida, USA. 12. Riley Hospital for Children, Indianapolis, Indiana, USA. 13. Departments of Neurology, Medical and Molecular Genetics, and Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA. 14. Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA. 15. University of Minnesota Health, Minneapolis, Minnesota, USA. 16. South West Thames Regional Genetics Service, St. George's Healthcare NHS Trust, London, UK. 17. VMP Genetics, LLC, Atlanta, Georgia, USA. 18. University of Georgia, Athens, Georgia, USA. 19. Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, USA. 20. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. 21. Nyack Hospital, Nyack, New York, USA. 22. Department of Medicine, Columbia University Medical Center, New York, New York, USA. 23. Division of Medical Genetics, Department of Pediatrics, Ochsner Clinic Foundation, New Orleans, Louisiana. 24. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 25. Division of Pediatric Neurology, Akron Children's Hospital, Akron, Ohio, USA. 26. McMaster University Medical Center, Hamilton, Ontario, Canada. 27. Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA. 28. Texas Children's Hospital, Houston, Texas, USA.
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.
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.
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