Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We here describe genomic data from 371 affected individuals, 310 of which were sequenced as proband-parent trios. Exomes were generated for 127 probands (365 individuals) and genomes were generated for 244 probands (612 individuals). Diagnostic variants were found in 102 individuals (27%), with variants of uncertain significance (VUS) in an additional 44 (11.8%). We found that a family history of neurocognitive disease, especially the presence of an affected first-degree relative, strongly reduces the diagnosis rate, reflecting both the disease relevance and relative ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have thus far reclassified 15 variants, with 10.8% of families who initially received a VUS, and 4.7% of families who received no variant, subsequently given a diagnosis. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP. Our results strongly support the value of genome sequencing as a first-choice diagnostic tool and means to continually advance, especially when coupled to rapid and free data sharing, clinical and research progress related to developmental disabilities.