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Genomic diagnosis for children with intellectual disability and/or developmental delay

Kevin M. Bowling, Michelle L. Thompson, Michelle D. Amaral, Candice R. Finnila, Susan M. Hiatt, Krysta L. Engel, J. Nicholas Cochran, Kyle B. Brothers, Kelly M. East, David E. Gray, Whitley V. Kelley, Neil E. Lamb, Edward J. Lose, Carla A. Rich, Shirley Simmons, Jana S. Whittle, Benjamin T. Weaver, Amy S. Nesmith, Richard M. Myers, Gregory S. Barsh, E. Martina Bebin, Gregory M. Cooper
doi: https://doi.org/10.1101/084251
Kevin M. Bowling
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Michelle L. Thompson
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Michelle D. Amaral
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Candice R. Finnila
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Susan M. Hiatt
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Krysta L. Engel
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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J. Nicholas Cochran
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Kyle B. Brothers
3University of Louisville, Louisville, KY, USA
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Kelly M. East
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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David E. Gray
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Whitley V. Kelley
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Neil E. Lamb
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Edward J. Lose
2University of Alabama at Birmingham, Birmingham, AL, USA
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Carla A. Rich
3University of Louisville, Louisville, KY, USA
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Shirley Simmons
2University of Alabama at Birmingham, Birmingham, AL, USA
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Jana S. Whittle
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
4University of Alabama Huntsville, Huntsville, AL, USA
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Benjamin T. Weaver
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
2University of Alabama at Birmingham, Birmingham, AL, USA
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Amy S. Nesmith
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Richard M. Myers
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Gregory S. Barsh
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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E. Martina Bebin
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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Gregory M. Cooper
1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
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  • For correspondence: gcooper@hudsonalpha.org
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ABSTRACT

Purpose Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 310 of which were sequenced as proband-parent trios.

Methods Exomes were generated for 365 individuals (127 affected) and genomes were generated for 612 individuals (244 affected).

Results Diagnostic variants were found in 102 individuals (27%), with variants of uncertain significance in an additional 44 (11.8%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the diagnostic 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 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.

Conclusion Our results strongly support the value of genome sequencing as a first-choice diagnostic tool and means to continually advance clinical and research progress related to developmental disabilities, especially when coupled to rapid and free data sharing.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 03, 2016.
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Genomic diagnosis for children with intellectual disability and/or developmental delay
Kevin M. Bowling, Michelle L. Thompson, Michelle D. Amaral, Candice R. Finnila, Susan M. Hiatt, Krysta L. Engel, J. Nicholas Cochran, Kyle B. Brothers, Kelly M. East, David E. Gray, Whitley V. Kelley, Neil E. Lamb, Edward J. Lose, Carla A. Rich, Shirley Simmons, Jana S. Whittle, Benjamin T. Weaver, Amy S. Nesmith, Richard M. Myers, Gregory S. Barsh, E. Martina Bebin, Gregory M. Cooper
bioRxiv 084251; doi: https://doi.org/10.1101/084251
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Genomic diagnosis for children with intellectual disability and/or developmental delay
Kevin M. Bowling, Michelle L. Thompson, Michelle D. Amaral, Candice R. Finnila, Susan M. Hiatt, Krysta L. Engel, J. Nicholas Cochran, Kyle B. Brothers, Kelly M. East, David E. Gray, Whitley V. Kelley, Neil E. Lamb, Edward J. Lose, Carla A. Rich, Shirley Simmons, Jana S. Whittle, Benjamin T. Weaver, Amy S. Nesmith, Richard M. Myers, Gregory S. Barsh, E. Martina Bebin, Gregory M. Cooper
bioRxiv 084251; doi: https://doi.org/10.1101/084251

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