AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in a neurodevelopmental disorder with incomplete penetrance

AGAP1 is an Arf1 GAP that regulates endolysosomal trafficking. Damaging variants have been linked to cerebral palsy and autism. We report 3 new individuals with microdeletion variants in AGAP1. Affected individuals have intellectual disability (3/3), autism (3/3), dystonia with axial hypotonia (1/3), abnormalities of brain maturation (1/3), growth impairment (2/3) and facial dysmorphism (2/3). We investigated mechanisms potentially underlying AGAP1 neurodevelopmental impairments using the Drosophila ortholog, CenG1a. We discovered reduced axon terminal size, increased neuronal endosome abundance, and elevated autophagy at baseline. Given potential incomplete penetrance, we assessed gene-environment interactions. We found basal elevation in phosphorylation of the integrated stress-response protein eIF2 and inability to further increase eIF2-P with subsequent cytotoxic stressors. CenG1a-mutant flies have increased lethality from exposure to environmental insults. We propose a model wherein disruption of AGAP1 function impairs endolysosomal trafficking, chronically activating the integrated stress response, and leaving AGAP1-deficient cells susceptible to a variety of second hit cytotoxic stressors. This model may have broader applicability beyond AGAP1 in instances where both genetic and environmental insults co-occur in individuals with neurodevelopmental disorders. Summary statementWe describe 3 additional patients with heterozygous AGAP1 deletion variants and use a loss of function Drosophila model to identify defects in synaptic morphology with increased endosomal sequestration, chronic autophagy induction, basal activation of eIF2-P, and sensitivity to environmental stressors.