@article{97dda2e1de0a4c2f8353efdd8036ef24,
title = "Kdm5a mutations identified in autism spectrum disorder using forward genetics",
abstract = "Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified Kdm5a as a candidate ASD gene. To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of thehippocampal transcriptome. To determine if KDM5A mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function.",
author = "{CAUSES Study} and Hayek, {Lauretta El} and Tuncay, {Islam Oguz} and Nadine Nijem and Jamie Russell and Sara Ludwig and Kiran Kaur and Xiaohong Li and Priscilla Anderton and Miao Tang and Amanda Gerard and Anja Heinze and Pia Zacher and Alsaif, {Hessa S.} and Aboulfazl Rad and Kazem Hassanpour and Abbaszadegan, {Mohammad Reza} and Camerun Washington and Dupont, {Barbara R.} and Louie, {Raymond J.} and Madeline Couse and Maha Faden and Rogers, {R. Curtis} and Jamra, {Rami Abou} and Elias, {Ellen R.} and Reza Maroofian and Henry Houlden and Anna Lehman and Bruce Beutler and Chahrour, {Maria H.}",
note = "Funding Information: We are grateful to the families for their participation in our study. We thank Daniel A Schmitz and Carlos A Pinzon-Arteaga for technical help and advice in designing the CRISPR knock-in experiment. We thank Chelsea Burroughs for assistance in preparing the Figures. The CAUSES Study investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Jan Friedman, Anna Lehman, Jill Mwe-nifumbo, Tanya Nelson, and Clara Van Karnebeek. The CAUSES Study was funded by Mining for Miracles, British Columbia Children{\textquoteright}s Hospital Foundation, and Genome British Columbia. This work was supported by the University of Texas Southwestern Medical Center and grants from the Welch Foundation and the Walter and Lillian Cantor Foundation to MHC. Publisher Copyright: {\textcopyright} El Hayek et al.",
year = "2020",
month = dec,
doi = "10.7554/eLife.56883",
language = "English (US)",
volume = "9",
pages = "1--25",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}