Background Intellectual disability (ID) represents a neurodevelopmental disorder, which is characterized by marked defects in the intellectual function and adaptive behavior, with an onset during the developmental period. ID is mainly caused by genetic factors, and it is extremely genetically heterogeneous. This study aims to identify the genetic cause of ID using trio‐WES analysis. Methods We recruited four pediatric patients with unexplained ID from non‐consanguineous families, who presented at the Department of Pediatrics, Guizhou Provincial People's Hospital. Whole‐exome sequencing (WES) and Sanger sequencing validation were performed in the patients and their unaffected parents. Furthermore, conservative analysis and protein structural and functional prediction were performed on the identified pathogenic variants. Results We identified five novel de novo mutations from four known ID‐causing genes in the four included patients, namely COL4A1 (c.2786T>A, p.V929D and c.2797G>A, p.G933S), TBR1 (c.1639_1640insCCCGCAGTCC, p.Y553Sfs*124), CHD7 (c.7013A>T, p.Q2338L), and TUBA1A (c.1350del, p.E450Dfs*34). These mutations were all predicted to be deleterious and were located at highly conserved domains that might affect the structure and function of these proteins. Conclusion Our findings contribute to expanding the mutational spectrum of ID‐related genes and help to deepen the understanding of the genetic causes and heterogeneity of ID.