NR2F1database: 112 variants and 84 patients support refining the clinical synopsis of Bosch–Boonstra–Schaaf optic atrophy syndrome

Abstract

Pathogenic variants of the nuclear receptor subfamily 2 group F member 1 gene (NR2F1) are responsible for Bosch–Boonstra–Schaaf optic atrophy syndrome (BBSOAS), an autosomal dominant disorder characterized by optic atrophy associated with developmental delay and intellectual disability, but with a clinical presentation which appears to be multifaceted. We created the first public locus‐specific database dedicated to NR2F1. All variants and clinical cases reported in the literature, as well as new unpublished cases, were integrated into the database using standard nomenclature to describe both molecular and phenotypic anomalies. We subsequently pursued a comprehensive approach based on computed representation and analysis suggesting a refinement of the BBSOAS clinical description with respect to neurological features and the inclusion of additional signs of hypotonia and feeding difficulties. This database is fully accessible for both clinician and molecular biologists and should prove useful in further refining the clinical synopsis of NR2F1 as new data is recorded.

Novel NR2F1 variant identified by whole-exome sequencing in a patient with Bosch–Boonstra–Schaaf optic atrophy syndrome

“…To date, approximately 80 patients with BBSOAS have been published in the literature. [ 4 ] Monoallelic variants in the NR2F1 gene can cause BBSOAS. [ 5 ] Functional studies showed that NR2F1 is involved in neural development and differentiation, as well as in eye and optic nerve development in mouse models.…”

“…[ 2 3 ] According to a latest literature search, about 80 cases have been reported previously. [ 4 ] Here, we report the case of a 3-year-old infant boy with BBSOAS presenting with delayed development, intellectual disability, strabismus, nystagmus, and bilateral optic nerve atrophy. Whole-exome sequencing revealed a de novo novel heterozygous missense mutation (c.437G>A; p.Cys146Tyr) in exon 1 of the NR2F 1 gene.…”

Integrated genetic code expansion and structural bioinformatics reveal disrupted supramolecular assembly in a genetic disorder

“…Similar symptoms are shared by multiple BBSOAS patients, however, their degree of severity is variable, possibly depending on the location and type of the NR2F1 mutation (Bertacchi et al ., 2022; Billiet et al , 2022; Chen et al ., 2016; Rech et al ., 2020). Pathogenic BBSOAS mutations are principally located in the two most conserved functional domains of the protein: the DNA-binding domain (DBD) and the ligand-binding domain (LBD).…”

Nr2f1 controls mitochondrial dynamics in mouse adult-born hippocampal neurons

“…Most variants in the NR2F1 gene of patients described so far are deletions and/or mutations predominantly located in the DNA-binding domain (DBD). Most of the pathogenic variants lead to haploinsufficiency or dominant-negative effects, thus compromising and/or completely abolishing NR2F1 transcriptional regulatory activity (Chen et al , 2016; Bosch et al , 2016; Kaiwar et al , 2017; Rech et al , 2020; Billiet et al , 2021). Recently, alterations in mitochondrial energy supply due to a defective function of the electron transport chain (ETC), have been reported in muscle biopsies from two BBSOAS patients (Martín-Hernández et al , 2018; Hobbs et al , 2020), suggesting that altered NR2F1 transcriptional activity might lead to mitochondria-related functional defects.…”

“…In humans, NR2F1 has recently emerged as a disease gene: multiple NR2F1 pathological variants cause the Bosch-Boonstra-Schaaf optic atrophy-intellectual syndrome (BBSOAS; OMIM: 615722), a rare monogenic autosomal-dominant disorder characterized by multiple clinical features including global developmental delay, mild-to-severe intellectual disability (ID), optic nerve atrophy, seizures and traits characteristic of the autism spectrum disorder (ASD) (Bosch et al, 2014; Chen et al, 2016; Kaiwar et al, 2017). Most variants in the NR2F1 gene of patients described so far are deletions and/or mutations predominantly located in the DNA-binding domain (DBD) and lead to haploinsufficiency or dominant-negative effects, thus compromising and/or completely abolishing NR2F1 transcriptional regulatory activity (Billiet et al, 2021; Bosch et al, 2016; Chen et al, 2016; Kaiwar et al, 2017; Rech et al, 2020).…”