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 Richard M. Myers
A1 Gregory S. Barsh
A1 E. Martina Bebin
A1 Gregory M. Cooper
YR 2016
UL http://biorxiv.org/content/early/2016/10/28/084251.1.abstract
AB 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.AbbreviationsDD/IDDevelopmental delay and/or intellectual disabilityVUSVariant of uncertain significanceWGSWhole genome sequencingWESWhole exome sequencingCSERClinical Sequencing Exploratory ResearchACMGAmerican College of Medical Genetics and Genomics