Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov;27(11):101555.
doi: 10.1016/j.gim.2025.101555. Epub 2025 Aug 13.

Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder

Amber S E van Oirsouw  1 , Pavla Nedbalova  2 , Miroslava Hancarova  3 , Jan Prchal  4 , Darina Prchalova  5 , Marketa Vlckova  5 , Sarka Bendova  5 , Kristin G Monaghan  6 , Lisa M Dyer  6 , Yanmin Chen  6 , Deanna Alexis Carere  6 , Emma A M Te Bogt  1 , Heather Fisher  7 , Angela E Scheuerle  8 , Stephanie Riley  9 , Mahim Jain  9 , Weiyi Mu  10 , Joann N Bodurtha  10 , Albertien M van Eerde  1 , Marijn F Stokman  11 , Nicola Longo  12 , Meena Balasubramanian  13 , Michael Spiller  14 , Gregory Costain  15 , Charlotte von der Lippe  16 , Kristian Tveten  16 , Marianne Jortveit  17 , Øystein L Holla  16 , Bertrand Isidor  18 , Benjamin Cogné  18 , Kevin E Glinton  19 , Blake Vuocolo  19 , Roberta Ann Sierra  19 , Brad Angle  20 , Kelly Bontempo  20 , Klaas Koop  21 , Rachel Rabin  22 , John Pappas  22 , David A Staffenberg  23 , Pascal Joset  24 , Peter Miny  24 , Isabel Filges  24 , Abdulrazak Alali  25 , Kara Vitalone  26 , Jill A Rosenfeld  27 , Weimin Bi  27 , Samuel Bradbrook  28 , Renee Perrier  28 , Subhadra Ramanathan  29 , June-Anne Gold  30 , María Palomares Bralo  31 , María Ángeles Gómez-Cano  32 , Ann Haskins Olney  33 , Shelly Nielsen  33 , Alban Ziegler  34 , Dominique Bonneau  34 , Clément Prouteau  34 , Ange-Line Bruel  35 , Charlotte Caille-Benigni  36 , Laëtitia Lambert  37 , Andrea C Yu  38 , Nathaniel H Robin  39 , Dana Goodloe  39 , Jan Fischer  40 , Joseph Porrmann  40 , Yvonne D Hennig  41 , Rami Abou Jamra  42 , Isabella Herman  43 , Ivy R Johnson  33 , Lucas Hérissant  44 , Guillaume Jouret  44 , Koen L I van Gassen  1 , Ellen van Binsbergen  1 , Bert van der Zwaag  1 , Alwin Kamermans  1 , Renske Oegema  1 , Zdenek Sedlacek  5 , Michaela Fenckova  45 , Richard H van Jaarsveld  46
Affiliations
Free article

Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder

Amber S E van Oirsouw et al. Genet Med. 2025 Nov.
Free article

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Jill A. Rosenfeld and Weimin Bi: the Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. Deanna Alexis Carere, Yanmin Chen, Lisa M. Dyer, and Kristin G. Monaghan are employees of GeneDx. Weiyi Mu has consulted for UCB. All other authors declare no conflicts of interest.

LinkOut - more resources