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Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify candidate risk genes and biological pathways

View ORCID ProfileThomas V. Fernandez, Zsanett P. Williams, Tina Kline, Shreenath Rajendran, Farhan Augustine, Nicole Wright, Catherine A. W. Sullivan, Emily Olfson, Sarah B. Abdallah, Wenzhong Liu, Ellen J. Hoffman, Abha R. Gupta, View ORCID ProfileHarvey S. Singer
doi: https://doi.org/10.1101/730952
Thomas V. Fernandez
aYale Child Study Center, Yale University School of Medicine, New Haven, CT, 06519, USA
bDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT, 06519, USA
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  • For correspondence: thomas.fernandez@yale.edu
Zsanett P. Williams
cDepartment of Psychiatry, Vanderbilt University School of Nursing, Nashville, TN, 37237, USA
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Tina Kline
dDepartments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
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Shreenath Rajendran
dDepartments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
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Farhan Augustine
dDepartments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
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Nicole Wright
aYale Child Study Center, Yale University School of Medicine, New Haven, CT, 06519, USA
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Catherine A. W. Sullivan
eDepartment of Pediatrics, Yale University School of Medicine, New Haven, CT, 06519, USA
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Emily Olfson
aYale Child Study Center, Yale University School of Medicine, New Haven, CT, 06519, USA
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Sarah B. Abdallah
aYale Child Study Center, Yale University School of Medicine, New Haven, CT, 06519, USA
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Wenzhong Liu
aYale Child Study Center, Yale University School of Medicine, New Haven, CT, 06519, USA
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Ellen J. Hoffman
aYale Child Study Center, Yale University School of Medicine, New Haven, CT, 06519, USA
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Abha R. Gupta
aYale Child Study Center, Yale University School of Medicine, New Haven, CT, 06519, USA
eDepartment of Pediatrics, Yale University School of Medicine, New Haven, CT, 06519, USA
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Harvey S. Singer
dDepartments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
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  • ORCID record for Harvey S. Singer
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ABSTRACT

Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children (“primary” stereotypies, CMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with CMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging variants in CMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in CMS probands show significant overlap with those in Tourette syndrome, ASD candidate genes, and those in ASD probands with high stereotypy scores. Furthermore, exploratory biological pathway and gene ontology analysis highlight histone demethylation, organism development, cell motility, glucocorticoid receptor pathway, and ion channel transport. Continued sequencing of CMS trios will identify more risk genes and allow greater insights into biological mechanisms of stereotypies across diagnostic boundaries.

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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 August 13, 2019.
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Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify candidate risk genes and biological pathways
Thomas V. Fernandez, Zsanett P. Williams, Tina Kline, Shreenath Rajendran, Farhan Augustine, Nicole Wright, Catherine A. W. Sullivan, Emily Olfson, Sarah B. Abdallah, Wenzhong Liu, Ellen J. Hoffman, Abha R. Gupta, Harvey S. Singer
bioRxiv 730952; doi: https://doi.org/10.1101/730952
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Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify candidate risk genes and biological pathways
Thomas V. Fernandez, Zsanett P. Williams, Tina Kline, Shreenath Rajendran, Farhan Augustine, Nicole Wright, Catherine A. W. Sullivan, Emily Olfson, Sarah B. Abdallah, Wenzhong Liu, Ellen J. Hoffman, Abha R. Gupta, Harvey S. Singer
bioRxiv 730952; doi: https://doi.org/10.1101/730952

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