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

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TitreDrosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases
Type de publicationJournal Article
Year of Publication2022
AuteursMarcogliese PC, Deal SL, Andrews J, J. Harnish M, V. Bhavana H, Graves HK, Jangam S, Luo X, Liu N, Bei D, Chao Y-H, Hull B, Lee P-T, Pan H, Bhadane P, Huang M-C, Longley CM, Chao H-T, Chung H-lok, Haelterman NA, Kanca O, Manivannan SN, Rossetti LZ, German RJ, Gerard A, Schwaibold EMaria Chri, Fehr S, Guerrini R, Vetro A, England E, Murali CN, Barakat TStefan, van Dooren MF, Wilke M, van Slegtenhorst M, Lesca G, Sabatier I, Chatron N, Brownstein CA, Madden JA, Agrawal PB, Keren B, Courtin T, Perrin L, Brugger M, Roser T, Leiz S, Mau-Them FTran, Delanne J, Sukarova-Angelovska E, Trajkova S, Rosenhahn E, Strehlow V, Platzer K, Keller R, Pavinato L, Brusco A, Rosenfeld JA, Marom R, Wangler MF, Yamamoto S
JournalCELL REPORTS
Volume38
Pagination110517
Date PublishedMAR 15
Type of ArticleArticle
ISSN2211-1247
Résumé

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.
DOI10.1016/j.celrep.2022.110517