Neurodevelopmental disorders, a group of early-onset neurological disorders with significantly clinical and genetic heterogeneity, remain a diagnostic odyssey for clinical genetic evaluation. In a total of 45 parent-child trios/quads with these disorders that was ‘not yet diagnosed’ by the traditional testing methods, we assessed the diagnostic yield by the combined use of standardized phenotypes and whole-exome sequencing data. Using a standardized vocabulary of phenotypic abnormalities from Human Phenotype Ontology (HPO), we performed deep phenotyping for these pedigrees to characterize multiple clinical features that was extracted from Chinese electronic medical records (EMRs). By matching HPO terms with known human diseases or cross-species comparison, together with whole-exome sequencing data, we prioritized candidate mutations/genes that underlies these pedigrees. We obtained a diagnostic yield of 49% (22 out of 45) with probably or possibly genetic diagnosis, of which the compound heterozygosity and de novo mutations accounted for the half of the diagnosis. Of note, the pedigrees with probable or possible diagnosis accompanied with a greater number of phenotypes implicated in non-nervous systems. The combined use of deep phenotyping and whole-exome sequencing provide implications for etiological evaluation for neurodevelopmental disorders in the clinical setting.