van Oirsouw, A.S.E., Nedbalova, P., Hancarova, M., Prchal, J., Prchalova, D., Vlckova, M., Bendova, S., Monaghan, K.G., Dyer, L.M., Chen, Y., Carere, D.A., te Bogt, E.A.M., Fisher, H., Scheuerle, A.E., Riley, S., Jain, M., Mu, W., Bodurtha, J.N., van Eerde, A.M., Stokman, M.F., Longo, N., Balasubramanian, M., Spiller, M., Costain, G., von der Lippe, C., Tveten, K., Jortveit, M., Holla, Ø.L., Isidor, B., Cogné, B., Glinton, K.E., Vuocolo, B., Sierra, R.A., Angle, B., Bontempo, K., Koop, K., Rabin, R., Pappas, J., Staffenberg, D.A., Joset, P., Miny, P., Filges, I., Alali, A., Vitalone, K., Rosenfeld, J.A., Bi, W., Bradbrook, S., Perrier, R., Ramanathan, S., Gold, J.A., Bralo, M.P., Gómez-Cano, M.Á., Olney, A.H., Nielsen, S., Ziegler, A., Bonneau, D., Prouteau, C., Bruel, A.L., Caille-Benigni, C., Lambert, L., Yu, A.C., Robin, N.H., Goodloe, D., Fischer, J., Porrmann, J., Hennig, Y.D., Jamra, R.A., Herman, I., Johnson, I.R., Hérissant, L., Jouret, G., van Gassen, K.L.I., van Binsbergen, E., van der Zwaag, B., Kamermans, A., Oegema, R., Sedlacek, Z., Fenckova, M. & van Jaarsveld, R.H. (2025). Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder. Genetics in Medicine, 27(11):101555.
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.
Methods: We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We used 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 found an overlapping phenotype, consistent with a monogenic neurodevelopmental disorder. 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 neurodevelopmental disorder gene and demonstrate a central role for XPO1 in development.
Keywords
Dominant inheritance; Habituation; Mendelian disorders; Monogenic NDD; XPO1
