title: Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals.
abstract: A large-scale sequencing screen of X-linked synaptic genes in individuals with autism spectrum disorder (ASD) or schizophrenia (SCZ), two common neurodevelopmental disorders, identified many variants most of which have no easily predictable effect on gene function. In this report, we evaluated the impact of these rare missense and silent variants on gene splicing. For this purpose, we used complementary in silico analyses, in vitro minigene-based assays and RNA prepared from lymphoblastoid cells derived from patients with these mutations. Our goal was to identify the variants which might either create or disrupt an acceptor splice site, a donor splice site or an exonic splicing enhancer, thus leading to aberrant splicing that could be involved in the pathogenesis of ASD or SCZ. We identified truncating mutations in distinct X-linked gamma-aminobutyric acid A (GABAA) receptor subunit-encoding genes, GABRQ and GABRA3, in two different families. Furthermore, missense and silent variants in nuclear RNA export factor 5 and histone deacetylase 6 were shown to partially disrupt the protein. While genes from the GABAergic pathway have previously been thought to be involved in the pathophysiology of ASD, this is the first report of ASD patients with truncating mutations in GABA receptors genes.
authors.affiliation: Department of Medicine, Centre of Excellence in Neuroscience of Université de Montréal, CRCHUM Notre-Dame Hospital, Montreal, Quebec, Canada.
authors.forename: Amélie
authors.initials: A
authors.lastname: Piton
authors.forename: Loubna
authors.initials: L
authors.lastname: Jouan
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dobrzeniecka
authors.forename: Karine
authors.initials: K
authors.lastname: Lachapelle
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D003198:Computer Simulation; D050172:Genes, X-Linked; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics*; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology
chemical_list: C546257:GABRA3 protein, human; C561870:GABRQ protein, human; D022821:RNA Splice Sites; D011963:Receptors, GABA-A