RT Journal Article
SR Electronic
T1 Genomic diagnosis for children with intellectual disability and/or developmental delay
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 084251
DO 10.1101/084251
A1 Kevin M. Bowling
A1 Michelle L. Thompson
A1 Michelle D. Amaral
A1 Candice R. Finnila
A1 Susan M. Hiatt
A1 Krysta L. Engel
A1 J. Nicholas Cochran
A1 Kyle B. Brothers
A1 Kelly M. East
A1 David E. Gray
A1 Whitley V. Kelley
A1 Neil E. Lamb
A1 Edward J. Lose
A1 Carla A. Rich
A1 Shirley Simmons
A1 Jana S. Whittle
A1 Benjamin T. Weaver
A1 Amy S. Nesmith
A1 Richard M. Myers
A1 Gregory S. Barsh
A1 E. Martina Bebin
A1 Gregory M. Cooper
YR 2017
UL http://biorxiv.org/content/early/2017/03/03/084251.abstract
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.