The advent of whole exome sequencing (WES) represents a significant breakthrough in clinical genetics, providing physicians with a powerful tool for etiological discovery. In order to better characterize the genetic landscape of neurodevelopmental disorders, we analyzed 46 patients in our pediatric neurogenetics clinic who underwent WES, characterizing their clinical features and molecular diagnoses. This was a heterogeneous mix of patients with a spectrum of neurodevelopmental disabilities. With WES, the overall diagnostic rate was 41.3% (n = 19). Eleven patients had a single autosomal dominant disorder, while seven patients had a single autosomal recessive disorder. The remaining subject had both an autosomal dominant disorder and autosomal recessive disorder. Of the positive cases, n = 16 had intellectual disability/developmental delay; n = 6 had a CP-like syndrome; and n = 3 had autism. The 19 patients with positive mutations exhibited a variety of neurological issues, including microcephaly (n = 8), seizures/epilepsy (n = 6), hypotonia (n = 15), dystonia (n = 7), and stereotyped repetitive behaviors (n = 7). On neuroimaging, these 19 subjects demonstrated a wide range of deficits, including delayed myelination/hypomyelination (n = 6) and cerebellar abnormalities (n = 7). Interesting discoveries emerged from the use of WES. A patient was found to have a pathogenic PANK2 mutation without an eye-of-the-tiger sign. Another individual with diagnosed with two rare genetic disorders. The high diagnostic yield of WES, and its role in elucidating nonspecific clinical presentations and atypical manifestations of disease, support the use of WES in pediatric neurology practices.