NR2F1 was first reported in relation to autosomal dominant Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) in 2014 (PMID: 24462372). BBSOAS is characterized by visual impairment due to optic nerve abnormalities and/or cortical visual impairment, developmental delay, and intellectual disability. Additional findings may include hypotonia, seizures, autism spectrum disorder or autistic features, and hearing defects (PMIDs: 24462372, 26986877, 32275123). NR2F1 variants, including missense, nonsense, frameshift and in-frame deletion variants, as well as large deletions, have been identified in over 50 individuals with BBSOAS (PMID: 32275123). Only 8 probands (PMIDs: 24462372, 26986877, 32275123) are included in this curation because the maximum score for genetic evidence has been reached. The disease mechanism is haploinsufficiency (PMIDs: 24462372, 26986877). However, a dominant-negative mechanism has been proposed for variants in the DNA binding domain (DBD) of the protein (PMIDs: 26986877, 32275123). Patients with variants in the DBD presented with more severe phenotypes, with increased prevalence of seizures and abnormal brain MRI findings compared to those with a deletion or coding variant outside of the DBD (PMIDs: 26986877, 32275123). This gene-disease relationship is also supported by experimental evidence, including a mouse model and in vitro expression studies (PMIDs: 31600777, 26986877).
In summary, NR2F1 is definitively associated with Bosch-Boonstra-Schaaf optic atrophy syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 16, 2022 (SOP Version 8).
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