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.