Significance Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world. Several common and rare genetic risk variants associated with PD pathogenesis have been identified, predominantly in persons of European descent, but the genetic contributions to familial PD are largely unknown for Han Chinese. Here, we present a trio-based study to explore the association between de novo-altered genes and early onset PD in Han Chinese. We found that the 12 genes with de novo mutations were biologically connected to each other and likely to be disease-risk genes. Further analyses using two independent cohorts revealed that NUS1 harbored more rare nonsynonymous variants, and subsequent functional studies on Drosophila proved its potential link to PD pathogenesis.