A pathogenic NR2F1 gene variant disrupts transcriptional activity and causes severe neurodevelopmental delay in Bosch-Boonstra-Schaaf syndrome.

Introduction: Nuclear receptor subfamily 2, group F, member 1 (NR2F1) gene variations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome. The NR2F1 genotype correlates with its phenotype; variants within the DNA-binding domain may cause severe psychomotor developmental disorders. However, the mechanisms underlying these phenotypes remain unclear.

Methods: Whole-exome sequencing was performed on the proband and her parents DNA. Candidate variants were verified by Sanger sequencing and bioinformatics analyses. Molecular dynamics simulations were performed to predict structural changes in the mutant NR2F1 protein. A dual-luciferase assay was used to analyze the variant's effect on transcriptional activation.

Results: The proband was a 10-month-old girl with severe motor and cognitive developmental delays accompanied by bilateral optic nerve pallor. Genetic testing revealed a novel NR2F1 gene variant, NM_005654.6: c.452T > A (p.Met151Lys). Bioinformatics analysis suggested that this variant alters the protein structure or function. The molecular dynamics analysis showed that this variant might affect the stability of the zinc finger structure within the NR2F1 DNA-binding domain. Dual-luciferase assays indicated this variant affects transcriptional activation.

Conclusions: The NR2F1 variant c.452T > A (p.Met151Lys) may genetically cause the severe clinical phenotypes observed in this patient. This finding expands the spectrum of NR2F1 variants.