Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Novel NR2F1 variants likely disrupt DNA binding: molecular modeling in two cases, review of published cases, genotype-phenotype correlation, and phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome. Cold Spring Harb Mol Case Stud 2017 Nov;3(6)



Pubmed ID


Pubmed Central ID




Scopus ID

2-s2.0-85039764135   12 Citations


Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant disorder caused by mutations in the NR2F1 gene. There are presently 28 cases of BBSOAS described in the literature. Its common features include developmental delay, intellectual disability, hypotonia, optic nerve atrophy, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity, and thinning of the corpus callosum. Here we report two unrelated probands with novel, de novo, missense variants in NR2F1 The first is a 14-yr-old male patient with hypotonia, intellectual disability, optic nerve hypoplasia, delayed bone age, short stature, and altered neurotransmitter levels on cerebrospinal fluid testing. The second is a 5-yr-old female with severe developmental delay, motor and speech delay, and repetitive motion behavior. Whole-exome sequencing identified a novel missense NR2F1 variant in each case, Cys86Phe in the DNA-binding domain in Case 1, and a Leu372Pro in the ligand-binding domain in Case 2. The presence of clinical findings compatible with BBSOAS along with structural analysis at atomic resolution using homology-based molecular modeling and molecular dynamic simulations, support the pathogenicity of these variants for BBSOAS. Short stature, abnormal CNS neurotransmitters, and macrocephaly have not been previously reported for this syndrome and may represent a phenotypic expansion of BBSOAS. A review of published cases along with new evidence from this report support genotype-phenotype correlations for this disorder.

Author List

Kaiwar C, Zimmermann MT, Ferber MJ, Niu Z, Urrutia RA, Klee EW, Babovic-Vuksanovic D


Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Autism Spectrum Disorder
COUP Transcription Factor I
Child, Preschool
DNA-Binding Proteins
Developmental Disabilities
Genetic Association Studies
Intellectual Disability
Language Development Disorders
Models, Molecular
Muscle Hypotonia
Optic Atrophies, Hereditary
Optic Atrophy
Whole Exome Sequencing
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5