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

Charu Kaiwar, Michael T. Zimmermann, Matthew J. Ferber, Zhiyv Niu, Raul A. Urrutia, Eric W Klee, Dusica Babovic-Vuksanovic

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalCold Spring Harbor molecular case studies
Volume3
Issue number6
DOIs
StatePublished - Nov 1 2017

Fingerprint

Optic Atrophy
Genetic Association Studies
DNA
Muscle Hypotonia
Optic Nerve
Intellectual Disability
Neurotransmitter Agents
Megalencephaly
Exome
Language Development Disorders
Corpus Callosum
Molecular Dynamics Simulation
Attention Deficit Disorder with Hyperactivity
Hearing
Virulence
Cerebrospinal Fluid
Seizures
Ligands
Bone and Bones
Mutation

Keywords

  • amblyopia
  • aplasia/hypoplasia of the optic nerve
  • cortical visual impairment
  • decreased CSF homovanillic acid (HVA)
  • microretrognathia
  • optic disc hypoplasia
  • oromotor apraxia
  • relative macrocephaly
  • severe muscular hypotonia
  • short stature

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{d9cc1d31705840649325009f53e99b0a,
title = "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",
abstract = "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.",
keywords = "amblyopia, aplasia/hypoplasia of the optic nerve, cortical visual impairment, decreased CSF homovanillic acid (HVA), microretrognathia, optic disc hypoplasia, oromotor apraxia, relative macrocephaly, severe muscular hypotonia, short stature",
author = "Charu Kaiwar and Zimmermann, {Michael T.} and Ferber, {Matthew J.} and Zhiyv Niu and Urrutia, {Raul A.} and Klee, {Eric W} and Dusica Babovic-Vuksanovic",
year = "2017",
month = "11",
day = "1",
doi = "10.1101/mcs.a002162",
language = "English (US)",
volume = "3",
journal = "Cold Spring Harbor molecular case studies",
issn = "2373-2873",
publisher = "Cold Spring Harbor Laboratory Press",
number = "6",

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TY - JOUR

T1 - Novel NR2F1 variants likely disrupt DNA binding

T2 - molecular modeling in two cases, review of published cases, genotype-phenotype correlation, and phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome

AU - Kaiwar, Charu

AU - Zimmermann, Michael T.

AU - Ferber, Matthew J.

AU - Niu, Zhiyv

AU - Urrutia, Raul A.

AU - Klee, Eric W

AU - Babovic-Vuksanovic, Dusica

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

KW - amblyopia

KW - aplasia/hypoplasia of the optic nerve

KW - cortical visual impairment

KW - decreased CSF homovanillic acid (HVA)

KW - microretrognathia

KW - optic disc hypoplasia

KW - oromotor apraxia

KW - relative macrocephaly

KW - severe muscular hypotonia

KW - short stature

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U2 - 10.1101/mcs.a002162

DO - 10.1101/mcs.a002162

M3 - Article

VL - 3

JO - Cold Spring Harbor molecular case studies

JF - Cold Spring Harbor molecular case studies

SN - 2373-2873

IS - 6

ER -