Dis Model Mech. 2025 Oct 1;18(10): dmm052426. doi: 10.1242/dmm.052426

Models of Bosch-Boonstra-Schaaf optic atrophy syndrome reveal genotype-phenotype correlations in brain structure and behavior

Johann G Maass^1,2, Dominik Kamionek¹, Annabelle Mantilleri³, Susanne Theiss¹, Laura Dötsch¹, Felix Franke¹, Tim Schubert¹, Jonas G Scheck^4,5, Claudia Pitzer⁶, Paolo Piovani³, Michele Bertacchi³, Olivier Deschaux³, Anubhav Singh¹, Chun-An Chen⁷, Henning Fröhlich¹, Michèle Studer³, Christian P Schaaf¹

Affiliations
¹Institute of Human Genetics, Heidelberg University Clinic, 69120 Heidelberg, Germany.
²Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, USA.
³Institute of Biology Valrose (iBV), University Côte d’Azur (UCA), CNRS 7277, Inserm 1091, Avenue Valrose 28, Nice 06108, France.
⁴Neuroradiology Department, University Hospital Heidelberg, 69120 Heidelberg, Germany.
⁵Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁶Interdisciplinary Neurobehavioral Core, Heidelberg University, 69120 Heidelberg, Germany.
⁷Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

 Abstract

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare, autosomal dominant neurodevelopmental disorder caused by pathogenic variants in NR2F1, characterized by developmental delay, intellectual disability, optic nerve anomalies and autism spectrum disorder. Most pathogenic variants cluster within the highly conserved DNA-binding domain (DBD) or ligand-binding domain (LBD) of NR2F1 and are associated with variable clinical severity, suggesting a genotype-phenotype correlation. Although previous mouse models have provided important insights, comprehensive behavioral characterization remains limited. Here, we present two novel BBSOAS mouse models harboring patient-specific variants in the DBD (Nr2f1+/R139L) and LBD (Nr2f1+/E397*), alongside the established Nr2f1+/- model. We analyzed brain morphology and behavior to further expand the murine phenotype and investigate the genotype-phenotype correlation. We demonstrate that these models recapitulate key aspects of the BBSOAS phenotype, including deficits in cognition, social communication and motor function, and that the presence and severity of behavioral abnormalities are dependent on variant type. Our findings provide new evidence for a genotype-phenotype correlation associated with domain-specific NR2F1 variants and establish a robust platform for future mechanistic and therapeutic studies.

DOI: 10.1242/dmm.052426