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.

Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases

Trajkova S.;Pavinato L.;Brusco A.;
2022-01-01

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.
2022
38
11
110517
110532
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00253-4?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/S2211124722002534?showall=true
autism spectrum disorder; Drosophila melanogaster; functional genomics; GLRA2; GluClalpha; humanization; missense variants; rare genetic diseases; T2A-GAL4; TG4; undiagnosed diseases; Animals; Genetic Predisposition to Disease; Humans; Autism Spectrum Disorder; Autistic Disorder; Drosophila; Neurodevelopmental Disorders; Receptors, Glycine
Marcogliese P.C.; Deal S.L.; Andrews J.; Harnish J.M.; Bhavana V.H.; Graves H.K.; Jangam S.; Luo X.; Liu N.; Bei D.; Chao Y.-H.; Hull B.; Lee P.-T.; P...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1854165
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