Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder

Amber S.E. van Oirsouw; Pavla Nedbalova; Miroslava Hancarova; Jan Prchal; Darina Prchalova; Marketa Vlckova; Sarka Bendova; Kristin G. Monaghan; Lisa M. Dyer; Yanmin Chen; Deanna Alexis Carere; Emma A.M. te Bogt; Heather Fisher; Angela E. Scheuerle; Stephanie Riley; Mahim Jain; Weiyi Mu; Joann N. Bodurtha; Albertien M. van Eerde; Marijn F. Stokman; Nicola Longo; Meena Balasubramanian; Michael Spiller; Gregory Costain; Charlotte von der Lippe; Kristian Tveten; Marianne Jortveit; Øystein L. Holla; Bertrand Isidor; Benjamin Cogné; Kevin E. Glinton; Blake Vuocolo; Roberta Ann Sierra; Brad Angle; Kelly Bontempo; Klaas Koop; Rachel Rabin; John Pappas; David A. Staffenberg; Pascal Joset; Peter Miny; Isabel Filges; Abdulrazak Alali; Kara Vitalone; Jill A. Rosenfeld; Weimin Bi; Samuel Bradbrook; Renee Perrier; Subhadra Ramanathan; June Anne Gold; María Palomares Bralo; María Ángeles Gómez-Cano; Ann Haskins Olney; Shelly Nielsen; Alban Ziegler; Dominique Bonneau; Clément Prouteau; Ange Line Bruel; Charlotte Caille-Benigni; Laëtitia Lambert; Andrea C. Yu; Nathaniel H. Robin; Dana Goodloe; Jan Fischer; Joseph Porrmann; Yvonne D. Hennig; Rami Abou Jamra; Isabella Herman; Ivy R. Johnson; Lucas Hérissant; Guillaume Jouret; Koen L.I. van Gassen; Ellen van Binsbergen; Bert van der Zwaag; Alwin Kamermans; Renske Oegema; Zdenek Sedlacek; Michaela Fenckova; Richard H. van Jaarsveld

doi:10.1016/j.gim.2025.101555

Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder

Amber S.E. van Oirsouw
, Pavla Nedbalova
, Miroslava Hancarova
, Jan Prchal
, Darina Prchalova
, Marketa Vlckova
, Sarka Bendova
, Kristin G. Monaghan
, Lisa M. Dyer
, Yanmin Chen
, Deanna Alexis Carere
, Emma A.M. te Bogt
, Heather Fisher
, Angela E. Scheuerle
, Stephanie Riley
, Mahim Jain
, Weiyi Mu
, Joann N. Bodurtha
, Albertien M. van Eerde
, Marijn F. Stokman

Nicola Longo, Meena Balasubramanian, Michael Spiller, Gregory Costain, Charlotte von der Lippe, Kristian Tveten, Marianne Jortveit, Øystein L. Holla, Bertrand Isidor, Benjamin Cogné, Kevin E. Glinton, Blake Vuocolo, Roberta Ann Sierra, Brad Angle, Kelly Bontempo, Klaas Koop, Rachel Rabin, John Pappas, David A. Staffenberg, Pascal Joset, Peter Miny, Isabel Filges, Abdulrazak Alali, Kara Vitalone, Jill A. Rosenfeld, Weimin Bi, Samuel Bradbrook, Renee Perrier, Subhadra Ramanathan, June Anne Gold, María Palomares Bralo, María Ángeles Gómez-Cano, Ann Haskins Olney, Shelly Nielsen, Alban Ziegler, Dominique Bonneau, Clément Prouteau, Ange Line Bruel, Charlotte Caille-Benigni, Laëtitia Lambert, Andrea C. Yu, Nathaniel H. Robin, Dana Goodloe, Jan Fischer, Joseph Porrmann, Yvonne D. Hennig, Rami Abou Jamra, Isabella Herman, Ivy R. Johnson, Lucas Hérissant, Guillaume Jouret, Koen L.I. van Gassen, Ellen van Binsbergen, Bert van der Zwaag, Alwin Kamermans, Renske Oegema, Zdenek Sedlacek, Michaela Fenckova, Richard H. van Jaarsveld

Utrecht University
University of South Bohemia
Charles University
University of Chemistry and Technology, Prague
OPKO Health, Inc.
University of Texas Southwestern Medical Center
Kennedy Krieger Institute
Department of Neurology and Developmental Medicine
Johns Hopkins University
Radboud University Nijmegen
University of California at Los Angeles
University of Sheffield
Sheffield Children's NHS Foundation Trust
University of Toronto
Telemark Hospital
Sørlandet Hospital
L'institut du Thorax
CHU de Nantes
Baylor College of Medicine
Advocate Children's Hospital
New York University
University of Basel
West Virginia University
Akron Children's Hospital
Alberta Children's Hospital
University of Calgary
Loma Linda University Health
University of California at Irvine
Hospital Universitario La Paz
ITHACA-European Reference Network
University of Nebraska Medical Center
Université d'Angers
Université de Bourgogne
Institut national de la santé et de la recherche médicale
CH Troyes
Université de Lorraine
University of Ottawa
University of Alabama at Birmingham
Technische Universität Dresden
Leipzig University
Boystown National Research Hospital
Laboratoire National de Santé

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Article number	101555
Pages (from-to)	101555
Journal	Genetics in Medicine
Volume	27
Issue number	11
Early online date	13 Aug 2025
DOIs	https://doi.org/10.1016/j.gim.2025.101555
State	Published - Nov 2025
Externally published	Yes

Keywords

Dominant inheritance
Habituation
Mendelian disorders
Monogenic NDD
XPO1

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10.1016/j.gim.2025.101555

Cite this

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., ... van Jaarsveld, R. H. (2025). Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder. Genetics in Medicine, 27(11), 101555. Article 101555. https://doi.org/10.1016/j.gim.2025.101555

@article{40c99ad0dbae4ef780983f604b3b8e1b,

title = "Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder",

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",

author = "\{van Oirsouw\}, \{Amber S.E.\} and Pavla Nedbalova and Miroslava Hancarova and Jan Prchal and Darina Prchalova and Marketa Vlckova and Sarka Bendova and Monaghan, \{Kristin G.\} and Dyer, \{Lisa M.\} and Yanmin Chen and Carere, \{Deanna Alexis\} and \{te Bogt\}, \{Emma A.M.\} and Heather Fisher and Scheuerle, \{Angela E.\} and Stephanie Riley and Mahim Jain and Weiyi Mu and Bodurtha, \{Joann N.\} and \{van Eerde\}, \{Albertien M.\} and Stokman, \{Marijn F.\} and Nicola Longo and Meena Balasubramanian and Michael Spiller and Gregory Costain and \{von der Lippe\}, Charlotte and Kristian Tveten and Marianne Jortveit and Holla, \{{\O}ystein L.\} and Bertrand Isidor and Benjamin Cogn{\'e} and Glinton, \{Kevin E.\} and Blake Vuocolo and Sierra, \{Roberta Ann\} and Brad Angle and Kelly Bontempo and Klaas Koop and Rachel Rabin and John Pappas and Staffenberg, \{David A.\} and Pascal Joset and Peter Miny and Isabel Filges and Abdulrazak Alali and Kara Vitalone and Rosenfeld, \{Jill A.\} and Weimin Bi and Samuel Bradbrook and Renee Perrier and Subhadra Ramanathan and Gold, \{June Anne\} and \{Palomares Bralo\}, Mar{\'i}a and \{{\'A}ngeles G{\'o}mez-Cano\}, Mar{\'i}a and Olney, \{Ann Haskins\} and Shelly Nielsen and Alban Ziegler and Dominique Bonneau and Cl{\'e}ment Prouteau and Bruel, \{Ange Line\} and Charlotte Caille-Benigni and La{\"e}titia Lambert and Yu, \{Andrea C.\} and Robin, \{Nathaniel H.\} and Dana Goodloe and Jan Fischer and Joseph Porrmann and Hennig, \{Yvonne D.\} and \{Abou Jamra\}, Rami and Isabella Herman and Johnson, \{Ivy R.\} and Lucas H{\'e}rissant and Guillaume Jouret and \{van Gassen\}, \{Koen L.I.\} and \{van Binsbergen\}, Ellen and \{van der Zwaag\}, Bert and Alwin Kamermans and Renske Oegema and Zdenek Sedlacek and Michaela Fenckova and \{van Jaarsveld\}, \{Richard H.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = nov,

doi = "10.1016/j.gim.2025.101555",

language = "English",

volume = "27",

pages = "101555",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "11",

}

van Oirsouw, ASE, Nedbalova, P, Hancarova, M, Prchal, J, Prchalova, D, Vlckova, M, Bendova, S, Monaghan, KG, Dyer, LM, Chen, Y, Carere, DA, te Bogt, EAM, Fisher, H, Scheuerle, AE, Riley, S, Jain, M, Mu, W, Bodurtha, JN, van Eerde, AM, Stokman, MF, Longo, N, Balasubramanian, M, Spiller, M, Costain, G, von der Lippe, C, Tveten, K, Jortveit, M, Holla, ØL, Isidor, B, Cogné, B, Glinton, KE, Vuocolo, B, Sierra, RA, Angle, B, Bontempo, K, Koop, K, Rabin, R, Pappas, J, Staffenberg, DA, Joset, P, Miny, P, Filges, I, Alali, A, Vitalone, K, Rosenfeld, JA, Bi, W, Bradbrook, S, Perrier, R, Ramanathan, S, Gold, JA, Palomares Bralo, M, Ángeles Gómez-Cano, M, Olney, AH, Nielsen, S, Ziegler, A, Bonneau, D, Prouteau, C, Bruel, AL, Caille-Benigni, C, Lambert, L, Yu, AC, Robin, NH, Goodloe, D, Fischer, J, Porrmann, J, Hennig, YD, Abou Jamra, R, Herman, I, Johnson, IR, Hérissant, L, Jouret, G, van Gassen, KLI, van Binsbergen, E, van der Zwaag, B, Kamermans, A, Oegema, R, Sedlacek, Z, Fenckova, M & van Jaarsveld, RH 2025, 'Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder', Genetics in Medicine, vol. 27, no. 11, 101555, pp. 101555. https://doi.org/10.1016/j.gim.2025.101555

TY - JOUR

T1 - Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder

AU - van Oirsouw, Amber S.E.

AU - Nedbalova, Pavla

AU - Hancarova, Miroslava

AU - Prchal, Jan

AU - Prchalova, Darina

AU - Vlckova, Marketa

AU - Bendova, Sarka

AU - Monaghan, Kristin G.

AU - Dyer, Lisa M.

AU - Chen, Yanmin

AU - Carere, Deanna Alexis

AU - te Bogt, Emma A.M.

AU - Fisher, Heather

AU - Scheuerle, Angela E.

AU - Riley, Stephanie

AU - Jain, Mahim

AU - Mu, Weiyi

AU - Bodurtha, Joann N.

AU - van Eerde, Albertien M.

AU - Stokman, Marijn F.

AU - Longo, Nicola

AU - Balasubramanian, Meena

AU - Spiller, Michael

AU - Costain, Gregory

AU - von der Lippe, Charlotte

AU - Tveten, Kristian

AU - Jortveit, Marianne

AU - Holla, Øystein L.

AU - Isidor, Bertrand

AU - Cogné, Benjamin

AU - Glinton, Kevin E.

AU - Vuocolo, Blake

AU - Sierra, Roberta Ann

AU - Angle, Brad

AU - Bontempo, Kelly

AU - Koop, Klaas

AU - Rabin, Rachel

AU - Pappas, John

AU - Staffenberg, David A.

AU - Joset, Pascal

AU - Miny, Peter

AU - Filges, Isabel

AU - Alali, Abdulrazak

AU - Vitalone, Kara

AU - Rosenfeld, Jill A.

AU - Bi, Weimin

AU - Bradbrook, Samuel

AU - Perrier, Renee

AU - Ramanathan, Subhadra

AU - Gold, June Anne

AU - Palomares Bralo, María

AU - Ángeles Gómez-Cano, María

AU - Olney, Ann Haskins

AU - Nielsen, Shelly

AU - Ziegler, Alban

AU - Bonneau, Dominique

AU - Prouteau, Clément

AU - Bruel, Ange Line

AU - Caille-Benigni, Charlotte

AU - Lambert, Laëtitia

AU - Yu, Andrea C.

AU - Robin, Nathaniel H.

AU - Goodloe, Dana

AU - Fischer, Jan

AU - Porrmann, Joseph

AU - Hennig, Yvonne D.

AU - Abou Jamra, Rami

AU - Herman, Isabella

AU - Johnson, Ivy R.

AU - Hérissant, Lucas

AU - Jouret, Guillaume

AU - van Gassen, Koen L.I.

AU - van Binsbergen, Ellen

AU - van der Zwaag, Bert

AU - Kamermans, Alwin

AU - Oegema, Renske

AU - Sedlacek, Zdenek

AU - Fenckova, Michaela

AU - van Jaarsveld, Richard H.

PY - 2025/11

Y1 - 2025/11

N2 - 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.

AB - 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.

KW - Dominant inheritance

KW - Habituation

KW - Mendelian disorders

KW - Monogenic NDD

KW - XPO1

UR - https://www.scopus.com/pages/publications/105017402220

U2 - 10.1016/j.gim.2025.101555

DO - 10.1016/j.gim.2025.101555

M3 - Article

C2 - 40819229

AN - SCOPUS:105017402220

SN - 1098-3600

VL - 27

SP - 101555

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 11

M1 - 101555

ER -

Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder

Abstract

Keywords

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