Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases.
Drosophila melanogaster
GLRA2
GluClalpha
T2A-GAL4
TG4
autism spectrum disorder
functional genomics
humanization
missense variants
rare genetic diseases
undiagnosed diseases
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
15 03 2022
15 03 2022
Historique:
received:
02
02
2021
revised:
23
09
2021
accepted:
18
02
2022
entrez:
16
3
2022
pubmed:
17
3
2022
medline:
8
4
2022
Statut:
ppublish
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.
Identifiants
pubmed: 35294868
pii: S2211-1247(22)00253-4
doi: 10.1016/j.celrep.2022.110517
pmc: PMC8983390
mid: NIHMS1789669
pii:
doi:
Substances chimiques
Receptors, Glycine
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
110517Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007526
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM056929
Pays : United States
Organisme : NIMH NIH HHS
ID : F30 MH118804
Pays : United States
Organisme : NIH HHS
ID : R24 OD022005
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM069234
Pays : United States
Organisme : CIHR
ID : MFE-164712
Pays : Canada
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD083092
Pays : United States
Organisme : NINDS NIH HHS
ID : F32 NS110174
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103555
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories.
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