Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | 110517 |
| Journal | Cell Reports |
| Volume | 38 |
| Issue number | 11 |
| DOIs | |
| State | Published - Mar 15 2022 |
Keywords
- autism spectrum disorder
- Drosophila melanogaster
- functional genomics
- GLRA2
- GluClalpha
- humanization
- missense variants
- rare genetic diseases
- T2A-GAL4
- TG4
- undiagnosed diseases
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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In: Cell Reports, Vol. 38, No. 11, 110517, 15.03.2022.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases
AU - Marcogliese, Paul C.
AU - Deal, Samantha L.
AU - Andrews, Jonathan
AU - Harnish, J. Michael
AU - Bhavana, V. Hemanjani
AU - Graves, Hillary K.
AU - Jangam, Sharayu
AU - Luo, Xi
AU - Liu, Ning
AU - Bei, Danqing
AU - Chao, Yu Hsin
AU - Hull, Brooke
AU - Lee, Pei Tseng
AU - Pan, Hongling
AU - Bhadane, Pradnya
AU - Huang, Mei Chu
AU - Longley, Colleen M.
AU - Chao, Hsiao Tuan
AU - Chung, Hyung lok
AU - Haelterman, Nele A.
AU - Kanca, Oguz
AU - Manivannan, Sathiya N.
AU - Rossetti, Linda Z.
AU - German, Ryan J.
AU - Gerard, Amanda
AU - Schwaibold, Eva Maria Christina
AU - Fehr, Sarah
AU - Guerrini, Renzo
AU - Vetro, Annalisa
AU - England, Eleina
AU - Murali, Chaya N.
AU - Barakat, Tahsin Stefan
AU - van Dooren, Marieke F.
AU - Wilke, Martina
AU - van Slegtenhorst, Marjon
AU - Lesca, Gaetan
AU - Sabatier, Isabelle
AU - Chatron, Nicolas
AU - Brownstein, Catherine A.
AU - Madden, Jill A.
AU - Agrawal, Pankaj B.
AU - Keren, Boris
AU - Courtin, Thomas
AU - Perrin, Laurence
AU - Brugger, Melanie
AU - Roser, Timo
AU - Leiz, Steffen
AU - Mau-Them, Frederic Tran
AU - Delanne, Julian
AU - Sukarova-Angelovska, Elena
AU - Trajkova, Slavica
AU - Rosenhahn, Erik
AU - Strehlow, Vincent
AU - Platzer, Konrad
AU - Keller, Roberto
AU - Pavinato, Lisa
AU - Brusco, Alfredo
AU - Rosenfeld, Jill A.
AU - Marom, Ronit
AU - Wangler, Michael F.
AU - Yamamoto, Shinya
N1 - Funding Information: We express our appreciation to the subjects and families for their participation in this study. We thank Nora Duran, Mark Durham, Shelley Gibson, Yuchun He, Matthew Lagarde, Wen-Wen Lin, and Dr. Karen Schulze for technical or administrative assistance. We thank Dr. Hugo Bellen for insightful scientific discussions and valuable comments on this manuscript. We sincerely thank the late Dr. Kenneth Scott for access to many of the human cDNAs used in this study. This work was primarily supported by a Simons Foundation Autism Research Initiative (SFARI) Functional Screen Award (368479) to M.F.W. and S.Y. Generation of human cDNA transgenic lines were in part supported by NIH/ORIP (R24OD022005). Confocal microscopy is supported in part by NIH/NICHD (U54HD083092) to the Intellectual and Developmental Disabilities Research Center (IDDRC) Neurovisualization Core at BCM. P.C.M. is supported by CIHR (MFE-164712) and the Stand by Eli Foundation. J.A. is supported by NIH/NINDS (F32NS110174). H.C. is supported by the Warren Alpert Foundation. R.M. is supported by NIH/NIGMS (T32GM07526-43) and through BCM Chao physician-scientist award. C.M.L. is part of the BCM Medical Scientist Training Program and McNair MD/PhD Student Scholars, supported by the McNair Medical Institute at the Robert and Janice McNair Foundation and NIH F30 Award (F30MH118804). B.H. is supported in part by the Postbaccalaureate Research Education Program NIGMS (R25 GM069234). H.T.C. received support by the American Academy of Neurology and CNCDP-K12. T.S.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. R.G. and A.V. received support from The DECODE-EE project (Health Research Call 2018; Tuscany Region) and are members of the European Reference Network EpiCARE. A.B. L. Pavinato, and S.T. received funding specifically appointed to Department of Medical Sciences from the Italian Ministry for Education, University and Research (Ministero dell'Istruzione, dell'Università e della Ricerca—MIUR) under the program “Dipartimenti di Eccellenza 2018–2022” project code D15D18000410001. For subject 10, sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. M.F.W. and S.Y. conceived and designed the project. P.C.M. J.A. S.L.D. and J.M.H. designed and conducted most fly experiments and analyzed the data. V.H.B. and Y.-H.C. performed cloning and mutagenesis. H.K.G. performed cloning and coordination. S.J. performed immunostaining and confocal microscopy. X.L. performed structural analysis and generated reagents. N.L. D.B. Y.-H.C. P.L. B.H. H.P. P.B. M.-C.H. C.M.L. H.-T.C. H.C. N.A.H. O.K. and S.N.M. contributed to reagent generation and some fly experiments. R.M. A.G. E.M. C.S. S.F. R.G. A.V. E.E. C.N.M. T.S.B. M.F.v.D. M.W. M.v.S. G.L. I.S. N.C. C.A.B. J.A.M. P.B.A. B.K. T.C. L. Perrin, M.B. T.R. S.L. F.T.M.-T. J.D. E.S.-A. S.T. E.R. V.S. K.P. R.K. L. Pavinato, and A.B. reported and described GLRA2 subjects. L.Z.R. R.J.G. and J.A.R. aided in subject matchmaking and collection and organization of patient data. P.C.M. J.A. S.L.D. J.M.H. R.M. M.F.W. and S.Y. wrote and revised the manuscript. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. Funding Information: We express our appreciation to the subjects and families for their participation in this study. We thank Nora Duran, Mark Durham, Shelley Gibson, Yuchun He, Matthew Lagarde, Wen-Wen Lin, and Dr. Karen Schulze for technical or administrative assistance. We thank Dr. Hugo Bellen for insightful scientific discussions and valuable comments on this manuscript. We sincerely thank the late Dr. Kenneth Scott for access to many of the human cDNAs used in this study. This work was primarily supported by a Simons Foundation Autism Research Initiative (SFARI) Functional Screen Award ( 368479 ) to M.F.W. and S.Y. Generation of human cDNA transgenic lines were in part supported by NIH /ORIP ( R24OD022005 ). Confocal microscopy is supported in part by NIH/ NICHD ( U54HD083092 ) to the Intellectual and Developmental Disabilities Research Center (IDDRC) Neurovisualization Core at BCM. P.C.M. is supported by CIHR ( MFE-164712 ) and the Stand by Eli Foundation . J.A. is supported by NIH/ NINDS ( F32NS110174 ). H.C. is supported by the Warren Alpert Foundation . R.M. is supported by NIH/ NIGMS ( T32GM07526-43 ) and through BCM Chao physician-scientist award . C.M.L. is part of the BCM Medical Scientist Training Program and McNair MD/PhD Student Scholars, supported by the McNair Medical Institute at the Robert and Janice McNair Foundation and NIH F30 Award ( F30MH118804 ). B.H. is supported in part by the Postbaccalaureate Research Education Program NIGMS (R25 GM069234). H.T.C. received support by the American Academy of Neurology and CNCDP-K12. T.S.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021 ), an Erasmus MC Fellowship 2017 , and Erasmus MC Human Disease Model Award 2018 . R.G. and A.V. received support from The DECODE-EE project (Health Research Call 2018; Tuscany Region) and are members of the European Reference Network EpiCARE. A.B., L. Pavinato, and S.T. received funding specifically appointed to Department of Medical Sciences from the Italian Ministry for Education , University and Research (Ministero dell’Istruzione, dell’Università e della Ricerca—MIUR) under the program “Dipartimenti di Eccellenza 2018–2022” project code D15D18000410001. For subject 10, sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 . Publisher Copyright: © 2022 The Authors
PY - 2022/3/15
Y1 - 2022/3/15
N2 - 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.
AB - 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.
KW - autism spectrum disorder
KW - Drosophila melanogaster
KW - functional genomics
KW - GLRA2
KW - GluClalpha
KW - humanization
KW - missense variants
KW - rare genetic diseases
KW - T2A-GAL4
KW - TG4
KW - undiagnosed diseases
UR - http://www.scopus.com/inward/record.url?scp=85126320885&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126320885&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2022.110517
DO - 10.1016/j.celrep.2022.110517
M3 - Article
C2 - 35294868
AN - SCOPUS:85126320885
SN - 2211-1247
VL - 38
JO - Cell Reports
JF - Cell Reports
IS - 11
M1 - 110517
ER -