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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

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, op...

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Autores principales: Kaiwar, Charu, Zimmermann, Michael T., Ferber, Matthew J., Niu, Zhiyv, Urrutia, Raul A., Klee, Eric W., Babovic-Vuksanovic, Dusica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701304/
https://www.ncbi.nlm.nih.gov/pubmed/28963436
http://dx.doi.org/10.1101/mcs.a002162
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author Kaiwar, Charu
Zimmermann, Michael T.
Ferber, Matthew J.
Niu, Zhiyv
Urrutia, Raul A.
Klee, Eric W.
Babovic-Vuksanovic, Dusica
author_facet Kaiwar, Charu
Zimmermann, Michael T.
Ferber, Matthew J.
Niu, Zhiyv
Urrutia, Raul A.
Klee, Eric W.
Babovic-Vuksanovic, Dusica
author_sort Kaiwar, Charu
collection PubMed
description 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.
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spelling pubmed-57013042017-12-04 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 Kaiwar, Charu Zimmermann, Michael T. Ferber, Matthew J. Niu, Zhiyv Urrutia, Raul A. Klee, Eric W. Babovic-Vuksanovic, Dusica Cold Spring Harb Mol Case Stud Research Report 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. Cold Spring Harbor Laboratory Press 2017-11 /pmc/articles/PMC5701304/ /pubmed/28963436 http://dx.doi.org/10.1101/mcs.a002162 Text en © 2017 Kaiwar et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Kaiwar, Charu
Zimmermann, Michael T.
Ferber, Matthew J.
Niu, Zhiyv
Urrutia, Raul A.
Klee, Eric W.
Babovic-Vuksanovic, Dusica
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701304/
https://www.ncbi.nlm.nih.gov/pubmed/28963436
http://dx.doi.org/10.1101/mcs.a002162
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