This project aims to develop a strategy to use an extrachromosomal array approach for the humanization of Caenorhabditis elegans to generate worm models of disease. I propose to build a rapid pipeline to test if the human coding sequence (CDS) can rescue the complete loss of function of the corresponding worm ortholog. This can then be used to assess variants of uncertain significance (VUSs) identified in patients with neurodevelopmental disorders. I will test the efficacy of introducing the human coding sequence alone, worm-specific codon optimization and use of synthetic introns for expression to generate potential C. elegans disease models.