biostudies-literatureMarcogliese PCNICHD NIH HHSNIMH NIH HHSNHGRI NIH HHSNINDS NIH HHSZonMwNIH HHSNIGMS NIH HHS110517https://www.ebi.ac.uk/biostudies/studies/S-EPMC8983390biostudies-literatureUnknown38(11)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 Cell reportsDrosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases.PMC8983390R25 GM069234R25 GM056929P50 HD103555F30 MH118804R24 OD022005U54 HD083092R01 HG009141T32 GM00752691617021F32 NS110174UM1 HG008900Harnish JMKeren BMarom RGerman RJBhadane PPerrin LDelanne JMau-Them FTChao HTStrehlow VChao YHKeller REngland EBrusco AGraves HKYamamoto STrajkova SFehr Svan Dooren MFSchwaibold EMCWangler MFBhavana VHPavinato LRosenfeld JALiu NLesca GChatron NLeiz SBarakat TSJangam SWilke MBrownstein CAHull BAndrews JHaelterman NAPlatzer KLee PTSukarova-Angelovska EHuang MCRosenhahn EGuerrini RBei DGerard AChung HLvan Slegtenhorst MMarcogliese PCDeal SLCourtin TMadden JALongley CMVetro ASabatier IAgrawal PBPan HKanca OManivannan SNRossetti LZMurali CNRoser TLuo XBrugger MfalseDrosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases.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 2022-01-01T00:00:00Z2022 Mar2026-05-31T18:02:25.744Z2025-04-05T22:20:00.871ZS-EPMC89833903529486810.1016/j.celrep.2022.110517