PT - JOURNAL ARTICLE AU - Kevin M. Bowling AU - Michelle L. Thompson AU - Michelle D. Amaral AU - Candice R. Finnila AU - Susan M. Hiatt AU - Krysta L. Engel AU - J. Nicholas Cochran AU - Kyle B. Brothers AU - Kelly M. East AU - David E. Gray AU - Whitley V. Kelley AU - Neil E. Lamb AU - Edward J. Lose AU - Carla A. Rich AU - Shirley Simmons AU - Jana S. Whittle AU - Benjamin T. Weaver AU - Amy S. Nesmith AU - Richard M. Myers AU - Gregory S. Barsh AU - E. Martina Bebin AU - Gregory M. Cooper TI - Genomic diagnosis for children with intellectual disability and/or developmental delay AID - 10.1101/084251 DP - 2017 Jan 01 TA - bioRxiv PG - 084251 4099 - http://biorxiv.org/content/early/2017/03/03/084251.short 4100 - http://biorxiv.org/content/early/2017/03/03/084251.full AB - Background Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.Methods Whole exome sequences (WES) were generated for 365 individuals (127 affected) and whole genome sequences (WGS) were generated for 612 individuals (244 affected).Results Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and 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 11.3% of families who initially were found to harbor a VUS, and 4.7% of families with a negative result, eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP.Conclusion Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.