Microcephaly is a neurodevelopmental disorder characterized by occipital frontal circumference (OFC) more than two standard deviations below the mean. It can be accompanied by comorbidities including intellectual disabilities, seizures, and other developmental phenotypes. Microcephaly is attributed to malnutrition and exposure to toxins or infection during pregnancy, but genetic mutations are also a leading cause. To investigate the genetic mechanisms behind microcephaly, our lab collaborates with a physician who has completed whole exome sequencing for two hundred microcephaly patients. He identified potentially pathogenic human variant genes, which we are studying using Drosophila melanogaster as our model organism. We screened for loss of function phenotypes through RNAi knockdown of fly orthologs to determine if these genes are necessary for brain development. In our primary screen, we knocked down the genes in neural stem cells or mature neurons and assessed third instar larval brain volume. Knockdown in either neural stem cells or neurons resulted in significantly reduced brain volume in approximately 25 percent of our genes, meaning that 25 percent of our fly orthologs may be associated with neurodevelopment. We then performed a secondary screen phenotyping the statistically significant genes to look for potential causes of decreased brain lobe volume. We hypothesize increased apoptosis and decreased stem cell proliferation as potential causes of decreased lobe volume. After we complete this screen, we will be attempting to rescue abnormal brain phenotypes with human wild type and patient variant genes. If rescue with human wild type reverses the phenotype, we can conclude that gene function is conserved between species and the gene functions in brain development. Additionally, if the patient variant gene does not rescue the phenotype, we will have strong evidence that the patient variant is pathogenic and contributes to microcephaly. This project is a step towards our ultimate goal of identifying novel genetic mechanisms of neurodevelopmental disorders.