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.

Autor:	Kaiwar C; Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona 85259, USA., Zimmermann MT; Department of Health Sciences Research, Mayo Clinic, Division of Biomedical Statistic and Informatics, Rochester, Minnesota 55905, USA., Ferber MJ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota 55905, USA., Niu Z; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota 55905, USA., Urrutia RA; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.; Department of Medicine, Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA., Klee EW; Department of Health Sciences Research, Mayo Clinic, Division of Biomedical Statistic and Informatics, Rochester, Minnesota 55905, USA.; Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota 55905, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA., Babovic-Vuksanovic D; Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota 55905, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Jazyk:	angličtina
Zdroj:	Cold Spring Harbor molecular case studies [Cold Spring Harb Mol Case Stud] 2017 Nov 21; Vol. 3 (6). Date of Electronic Publication: 2017 Nov 21 (Print Publication: 2017).
DOI:	10.1101/mcs.a002162
Abstrakt:	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. (© 2017 Kaiwar et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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