ArticleCell reports2022
Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases.
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Article in Cell reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44citing papers in PubMed
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44 citing papers in PubMed, 52 citations in OpenAlex.
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Authors and funding
61 authors at 20 institutions in 7 countries.
Paul C MarcoglieseDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Samantha L DealJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Program in Developmental Biology, BCM, Houston, TX 77030, USA.
Jonathan AndrewsDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
J Michael HarnishDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
V Hemanjani BhavanaDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Hillary K GravesDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Sharayu JangamDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Xi LuoDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Department of Pediatrics, Division of Hematology/Oncology, BCM, Houston, TX 77030, USA.
Ning LiuDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77021, USA.
Danqing BeiDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Yu-Hsin ChaoDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Brooke HullDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Pei-Tseng LeeDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Hongling PanDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Pradnya BhadaneDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Mei-Chu HuangDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Colleen M LongleyJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Program in Developmental Biology, BCM, Houston, TX 77030, USA.
Hsiao-Tuan ChaoDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Department of Pediatrics, Division of Neurology and Developmental Neuroscience, BCM, Houston, TX 77030, USA; Department of Neuroscience, BCM, Houston, TX 77030, USA; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, TX 77030, USA; TCH, Houston, TX 77030, USA; Development, Disease Models & Therapeutics Graduate Program, BCM, Houston, TX 77030, USA.
Hyung-Lok ChungDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA.
Nele A HaeltermanDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Oguz KancaDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Sathiya N ManivannanDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Linda Z RossettiDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
Ryan J GermanDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Amanda GerardDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; TCH, Houston, TX 77030, USA.
Eva Maria Christina SchwaiboldInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Sarah FehrPraxis für Humangenetik Tübingen, Tübingen, Germany.
Renzo GuerriniNeuroscience Department, Children's Hospital Meyer-University of Florence, Florence, Italy.
Annalisa VetroNeuroscience Department, Children's Hospital Meyer-University of Florence, Florence, Italy.
Eleina EnglandThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Chaya N MuraliDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; TCH, Houston, TX 77030, USA.
Tahsin Stefan BarakatDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Marieke F van DoorenDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Martina WilkeDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Marjon van SlegtenhorstDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Gaetan LescaDepartment of Medical Genetics, Lyon University Hospital, Université Claude Bernard Lyon 1, Lyon, France; Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France.
Isabelle SabatierDepartment of Pediatric Neurology, Lyon University Hospitals, Lyon, France.
Nicolas ChatronDepartment of Medical Genetics, Lyon University Hospital, Université Claude Bernard Lyon 1, Lyon, France; Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France.
Catherine A BrownsteinDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Jill A MaddenDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
Pankaj B AgrawalDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Boris KerenGenetic Department, Pitié-Salpêtrière Hospital, APHP.Sorbonne Université, Paris 75013, France.
Thomas CourtinGenetic Department, Pitié-Salpêtrière Hospital, APHP.Sorbonne Université, Paris 75013, France.
Laurence PerrinGenetic Department, Robert Debré Hospital, APHP.Nord-Université de Paris, Paris 75019, France.
Melanie BruggerInstitute of Human Genetics, Technical University Munich, Munich, Germany.
Timo RoserDivision of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Lindwurmstraße 4, 80337 Munich, Germany.
Steffen LeizDepartment of Pediatrics and Adolescent Medicine, Hospital Dritter Orden, Munich, Germany.
Frederic Tran Mau-ThemINSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France; Laboratoire de Génétique, Innovation en Diagnostic Génomique des Maladies Rares UF6254, Plateau Technique de Biologie, CHU Dijon, 14 Rue Paul Gaffarel, BP 77908, 21079 Dijon, France.
Julian DelanneINSERM U1231, LNC UMR1231 GAD, Burgundy University, 21000 Dijon, France.
Elena Sukarova-AngelovskaDepartment of Endocrinology and Genetics, University Clinic for Children's Diseases, Medical Faculty, University Sv. Kiril i Metodij, Skopje, Republic of Macedonia.
Slavica TrajkovaDepartment of Medical Sciences, University of Torino, Turin, Italy.
Erik RosenhahnInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Vincent StrehlowInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Roberto KellerAdult Autism Center, Mental Health Department, Health Unit ASL Città di Torino, Turin, Italy.
Lisa PavinatoDepartment of Medical Sciences, University of Torino, Turin, Italy; Institute of Human Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Alfredo BruscoDepartment of Medical Sciences, University of Torino, Turin, Italy; Medical Genetics Unit, Città della Salute e della Scienza, University Hospital, Turin, Italy.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Baylor Genetics Laboratories, Houston, TX 77021, USA.
Ronit MaromDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; TCH, Houston, TX 77030, USA.
Michael F WanglerDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; TCH, Houston, TX 77030, USA; Development, Disease Models & Therapeutics Graduate Program, BCM, Houston, TX 77030, USA. Electronic address: mw147467@bcm.edu.
Shinya YamamotoDepartment of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Program in Developmental Biology, BCM, Houston, TX 77030, USA; Department of Neuroscience, BCM, Houston, TX 77030, USA; Development, Disease Models & Therapeutics Graduate Program, BCM, Houston, TX 77030, USA. Electronic address: yamamoto@bcm.edu.
Baylor College of Medicine · USErasmus MC · NLBoston Children's Hospital · USLeipzig University · DEInserm · FRMeyer Children's Hospital · ITNeurological Research Institute · USSorbonne Université · FRUniversité Claude Bernard Lyon 1 · FRAzienda Ospedaliera Citta' della Salute e della Scienza di Torino · ITBroad Institute · USHeidelberg University · DELudwig-Maximilians-Universität München · DEMünchen Klinik · DEPraxis für Humangenetik Tübingen · DETechnical University of Munich · DETexas Medical Center · USTorino e-district · ITUniversité de Lyon · FRUniversité Paris Cité · FR
Funding
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MInitiative for Maximizing Student Development (IMSD) ProgramR25GM056929 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI PEREIRA, FRED A · 1998 to 2023
$12.4MMEDICAL GENETICS RESEARCH FELLOWSHIP PROGRAMT32GM007526 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI Brendan Lee · 1985 to 2026
$11.4MPreclinical and Clincial OutcomesP50HD103555 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI MIRJANA MALETIC-SAVATIC · 2020 to 2026
$9.9MSteps towards a paternal gene activation therapy for Angelman syndromeU54HD083092 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI NELSON, DAVID LOREN, SAMACO, RODNEY C · 2014 to 2019
$7.8MYEARS 19 - 23: BCM POST-BACCALAUREATE RESEARCH EDUCATION PROGRAMR25GM069234 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI PEREIRA, FRED A · 2003 to 2024
$7.5MExpansion and characterization of the Drosophila Toolkit to study SARS-CoV-2R24OD022005 · OD · BAYLOR COLLEGE OF MEDICINE · PI BELLEN, HUGO J · 2016 to 2023
$7.4MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MThe role of Neuroligin 2 in the regulation of GABAergic interneuron activity and cortical inhibitionF30MH118804 · NIMH · BAYLOR COLLEGE OF MEDICINE · PI BRADY, COLLEEN MICHELLE · 2018 to 2022
$163kStructural and behavioral impact of ASD-associated variants of NRXN1 in Drosophila melanogaster.F32NS110174 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI ANDREWS, JONATHAN · 2018 to 2020
$162kNHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG008900NICHD NIH HHS P50 HD103555NICHD NIH HHS U54 HD083092NIGMS NIH HHS R25 GM056929NIGMS NIH HHS R25 GM069234NIGMS NIH HHS T32 GM007526NIH HHS R24 OD022005NIMH NIH HHS F30 MH118804NINDS NIH HHS F32 NS110174
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.
Indexed as
Autism Spectrum DisorderAutistic DisorderDrosophilaNeurodevelopmental DisordersReceptors, GlycineAnimalsGenetic Predisposition to DiseaseHumansReceptors, Glycineautism spectrum disorderDrosophila melanogasterfunctional genomicsGLRA2GluClalphahumanizationmissense variantsrare genetic diseasesT2A-GAL4TG4undiagnosed diseases
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