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Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases

2022; Cell Press; Volume: 38; Issue: 11 Linguagem: Inglês

10.1016/j.celrep.2022.110517

2639-1856

Paul C. Marcogliese, Samantha L. Deal, Jonathan C. Andrews, J. Michael Harnish, Venkata Hemanjani Bhavana, Hillary K. Graves, Sharayu Jangam, Xi Luo, Ning Liu, Danqing Bei, Yu-Hsin Chao, Brooke Hull, Pei-Tseng Lee, Hongling Pan, Pradnya Bhadane, Mei‐Chu Huang, Colleen M Longley, Hsiao‐Tuan Chao, Hyunglok Chung, Nele A. Haelterman, Oguz Kanca, Sathiyanarayanan Manivannan, Linda Rossetti, Ryan J. German, Amanda Gerard, Eva Maria Christina Schwaibold, Sarah Fehr, Renzo Guerrini, Annalisa Vetro, Eleina England, Chaya N. Murali, Tahsin Stefan Barakat, Marieke F. van Dooren, Martina Wilke, Marjon van Slegtenhorst, Gaëtan Lesca, Isabelle Sabatier, Nicolas Chatron, Catherine A. Brownstein, Jill A. Madden, Pankaj B. Agrawal, Boris Keren, Thomas Courtin, Laurence Perrin, Melanie Brugger, Timo Roser, Steffen Leiz, Frédéric Tran Mau‐Them, Julian Delanne, Elena Sukarova-Angelovska, Slavica Trajkova, Erik Rosenhahn, Vincent Strehlow, Konrad Platzer, Roberto Keller, Lisa Pavinato, Alfredo Brusco, Jill A. Rosenfeld, Ronit Marom, Michael F. Wangler, Shinya Yamamoto,

Genomics and Phylogenetic Studies

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.