title: Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach.
abstract: The hypothetical 'AXAS' gene network model that profiles functional patterns of heterogeneous DNA variants overrepresented in autism spectrum disorder (ASD), X-linked intellectual disability, attention deficit and hyperactivity disorder and schizophrenia was used in this current study to analyze whole exome sequencing data from an Australian ASD cohort. An optimized DNA variant filtering pipeline was used to identify loss-of-function DNA variations. Inherited variants from parents with a broader autism phenotype and de novo variants were found to be significantly associated with ASD. Gene ontology analysis revealed that putative rare causal variants cluster in key neurobiological processes and are overrepresented in functions involving neuronal development, signal transduction and synapse development including the neurexin trans-synaptic complex. We also show how a complex gene network model can be used to fine map combinations of inherited and de novo variations in families with ASD that converge in the L1CAM pathway. Our results provide an important step forward in the molecular characterization of ASD with potential for developing a tool to analyze the pathogenesis of individual affected families.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: J Y
authors.initials: JY
authors.lastname: An
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: A S
authors.initials: AS
authors.lastname: Cristino
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Edson
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: School of Pathology and Laboratory Medicine, Perth, WA, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Ravine
authors.affiliation: State Child Development Centre, Child and Adolescent Health Service, Princess Margaret Hospital for Children, Perth, WA, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Wray
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: V M
authors.initials: VM
authors.lastname: Marshall
authors.affiliation: Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Subiaco, WA, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Hunt
authors.affiliation: 1] Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Subiaco, WA, Australia [2] Cooperative Research Centre for Living with Autism Spectrum Disorders (Autism CRC), Brisbane, QLD, Australia.
authors.forename: A J O
authors.initials: AJ
authors.lastname: Whitehouse
authors.affiliation: 1] Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia [2] Cooperative Research Centre for Living with Autism Spectrum Disorders (Autism CRC), Brisbane, QLD, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Claudianos
mesh_terms: D000328:Adult; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics; D010641:Phenotype; D012042:Registries
chemical_list: D039842:Neural Cell Adhesion Molecule L1