Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder

Authors

Amber S. van Oirsouw, Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Pavla Nedbalova, Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia in Ceske Budejovice, Ceske Budejovice, Czech Republic.
Miroslava Hancarova, Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. Electronic address: miroslava.hancarova@lfmotol.cuni.cz.
Jan Prchal, Laboratory of NMR Spectroscopy, University of Chemistry and Technology, Prague, Czech Republic.
Brad Angle, Advocate Health - MidwestFollow
Kelly Bontempo, Advocate Health - MidwestFollow
et al

Recommended Citation

van Oirsouw ASE, Nedbalova P, Hancarova M, et al. Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder. Genet Med. 2025;27(11):101555. doi:10.1016/j.gim.2025.101555

Affiliations

Advocate Children's Hospital Park Ridge

Abstract

Purpose: XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome, however no monogenic XPO1-related disorder has been described to date.

Materials and methods: We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We employed Drosophila to study XPO1 function in development and habituation learning.

Results: A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants and half have coding variants (10 missense and 1 in-frame deletion variant). We find an overlapping phenotype, consistent with a monogenic neurodevelopmental disorder (NDD). We demonstrate XPO1 functions in development by ubiquitous and neuron-specific knockdown in Drosophila. GABAergic neuron specific knockdown flies demonstrated impaired habituation.

Conclusion: Our results establish XPO1 as a novel dominant monogenic NDD gene and demonstrate a central role for XPO1 in development.

Document Type

Article

PubMed ID

40819229