MONO-ALLELIC VARIANTS IN THE NUCLEAR TRANSPORT RECEPTOR GENE XPO7 CAUSE A NEURODEVELOPMENTAL DISORDER WITH BRAIN ABNORMALITIES

Analyses of rare genetic variants have revealed converging risk factors between schizophrenia and neurodevelopmental disorders (NDDs). Recent exome sequencing studies of Schizophrenia have implicated rare coding variants of Exportin 7 (XPO7), a nucleo-cytoplasmic transport gating protein whose role in the brain remains poorly characterized. Through an international, multicenter collaboration, we identified both missense and truncating XPO7 variants in 25 individuals with pediatric NDDs using large-scale sequencing approaches. Affected subjects presented with a spectrum of motor and speech delays, mild to severe intellectual disability, behavioral problems, and hypotonia. Other symptoms included epilepsy, growth abnormalities, sensory impairments, and skeletal malformations.
3D structural modeling of XPO7 revealed that missense mutations were distributed across multiple protein domains without causing major predicted conformational disruptions. Functional assays demonstrated reduced expression of mutant XPO7 and enhanced cellular proliferation, consistent with a loss-of-function effect. A CRISPR–Cas9 knock-in mouse model carrying the recurrent R756W variant exhibited reduced brain volume, diminished excitatory synaptic transmission, and lowered intrinsic excitability of frontal cortical pyramidal neurons. Although dendritic spine density remained unaffected, dendritic arbor complexity was decreased. Neuronal density was elevated, in line with increased embryonic proliferation. NMDA receptor–mediated transmission was transiently elevated during juvenile stages, suggesting delayed synaptic maturation. Finally, heterozygous R756W mutant mice displayed altered anxiety-related behaviors.
These results identify XPO7 dysfunction as the basis of a previously unrecognized neurodevelopmental syndrome and establish its essential contribution to neuronal maturation and function. The convergence of XPO7 variants across NDDs and schizophrenia underscores its significance within the neurodevelopmental–psychiatric continuum.​​