title: The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations.
abstract: 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.
  
  
  
  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.
  
  
  
  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%).
  
  
  
  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.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Chun-An
authors.identifier: 0000-0002-2148-7490
authors.initials: CA
authors.lastname: Chen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Daniëlle G M
authors.initials: DG
authors.lastname: Bosch
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Marwan
authors.identifier: 0000-0001-5664-7987
authors.initials: M
authors.lastname: Shinawi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.affiliation: Genetics, Kaiser-Permanente Fresno Medical Center, Clovis, California, USA.
authors.forename: John
authors.identifier: 0000-0002-6644-6385
authors.initials: J
authors.lastname: Mann
authors.affiliation: Nicklaus Children's Hospital, Miami, Florida, USA.
authors.forename: Parul
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authors.lastname: Jayakar
authors.affiliation: Riley Hospital for Children, Indianapolis, Indiana, USA.
authors.forename: Katelyn
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authors.lastname: Payne
authors.affiliation: Riley Hospital for Children, Indianapolis, Indiana, USA.|Departments of Neurology, Medical and Molecular Genetics, and Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Laurence
authors.identifier: 0000-0002-0327-8062
authors.initials: L
authors.lastname: Walsh
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Moss
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Schreiber
authors.affiliation: University of Minnesota Health, Minneapolis, Minnesota, USA.
authors.forename: Cheri
authors.initials: C
authors.lastname: Schoonveld
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Kristin G
authors.identifier: 0000-0002-2185-0691
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: South West Thames Regional Genetics Service, St. George's Healthcare NHS Trust, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Elmslie
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Ganka
authors.initials: G
authors.lastname: Douglas
authors.affiliation: Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: F Nienke
authors.identifier: 0000-0003-4113-6505
authors.initials: FN
authors.lastname: Boonstra
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Millan
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Dianalee
authors.initials: D
authors.lastname: McKnight
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Gabriele
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authors.lastname: Richard
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: VMP Genetics, LLC, Atlanta, Georgia, USA.|University of Georgia, Athens, Georgia, USA.
authors.forename: Fran
authors.initials: F
authors.lastname: Kendall
authors.affiliation: Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, USA.
authors.forename: Keri
authors.initials: K
authors.lastname: Ramsey
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Kwame
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authors.lastname: Anyane-Yeboa
authors.affiliation: Nyack Hospital, Nyack, New York, USA.
authors.forename: Elfrida
authors.initials: E
authors.lastname: Malkin
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.|Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Wendy K
authors.identifier: 0000-0002-2259-6162
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Ochsner Clinic Foundation, New Orleans, Louisiana.
authors.forename: Dmitriy
authors.identifier: 0000-0003-3438-5685
authors.initials: D
authors.lastname: Niyazov
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Juan M
authors.identifier: 0000-0002-1094-3913
authors.initials: JM
authors.lastname: Pascual
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walkiewicz
authors.affiliation: Division of Pediatric Neurology, Akron Children's Hospital, Akron, Ohio, USA.
authors.forename: Vivekanand
authors.initials: V
authors.lastname: Veluchamy
authors.affiliation: McMaster University Medical Center, Hamilton, Ontario, Canada.
authors.forename: Chumei
authors.identifier: 0000-0002-0373-8356
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA.
authors.forename: Fuki M
authors.initials: FM
authors.lastname: Hisama
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bert B A
authors.identifier: 0000-0001-7772-7855
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Schaaf
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D051838:COUP Transcription Factor I / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree
chemical_list: D051838:COUP Transcription Factor I; C497589:NR2F1 protein, human