Duncan NRI Faculty and Staff Publications
Publication Date
3-15-2022
Journal
Cell Reports
DOI
10.1016/j.celrep.2022.110517
PMID
35294868
PMCID
PMC8983390
PubMedCentral® Posted Date
4-6-2022
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Autism Spectrum Disorder, Autistic Disorder, Drosophila, Genetic Predisposition to Disease, Humans, Neurodevelopmental Disorders, Receptors, Glycine
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.
Graphical Abstract
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Genetic Phenomena Commons, Medical Genetics Commons, Neurology Commons, Neurosciences Commons