Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder.
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van Oirsouw Amber S E, Nedbalova Pavla, Hancarova Miroslava, Prchal Jan, Prchalova Darina, Vlckova Marketa, Bendova Sarka, Monaghan Kristin G, Dyer Lisa M, Chen Yanmin, Carere Deanna Alexis, Te Bogt Emma A M, Fisher Heather, Scheuerle Angela E, Riley Stephanie, Jain Mahim, Mu Weiyi, Bodurtha Joann N, van Eerde Albertien M, Stokman Marijn F, Longo Nicola, Balasubramanian Meena, Spiller Michael, Costain Gregory, von der Lippe Charlotte, Tveten Kristian, Jortveit Marianne, Holla Øystein L, Isidor Bertrand, Cogné Benjamin, Glinton Kevin E, Vuocolo Blake, Sierra Roberta Ann, Angle Brad, Bontempo Kelly, Koop Klaas, Rabin Rachel, Pappas John, Staffenberg David A, Joset Pascal, Miny Peter, Filges Isabel, Alali Abdulrazak, Vitalone Kara, Rosenfeld Jill A, Bi Weimin, Bradbrook Samuel, Perrier Renee, Ramanathan Subhadra, Gold June-Anne, Palomares Bralo María, Ángeles Gómez-Cano María, Olney Ann Haskins, Nielsen Shelly, Ziegler Alban, Bonneau Dominique, Prouteau Clément, Bruel Ange-Line, Caille-Benigni Charlotte, Lambert Laëtitia, Yu Andrea C, Robin Nathaniel H, Goodloe Dana, Fischer Jan, Porrmann Joseph, Hennig Yvonne D, Abou Jamra Rami, Herman Isabella, Johnson Ivy R, Hérissant Lucas, Jouret Guillaume, van Gassen Koen L I, van Binsbergen Ellen, van der Zwaag Bert, Kamermans Alwin, Oegema Renske, Sedlacek Zdenek, Fenckova Michaela, van Jaarsveld Richard H
Аннотация
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.