title: GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability.
abstract: Phenotypic and genetic heterogeneity is predominant in autism spectrum disorders (ASD), for which the molecular and pathophysiological bases are still unclear. Significant comorbidity and genetic overlap between ASD and other neurodevelopmental disorders are also well established. However, little is understood regarding the frequent observation of a wide phenotypic spectrum associated with deleterious mutations affecting a single gene even within multiplex families. We performed a clinical, neurophysiological (in vivo electroencephalography-auditory-evoked related potentials) and genetic (whole-exome sequencing) follow-up analysis of two families with known deleterious NLGN4X gene mutations (either truncating or overexpressing) present in individuals with ASD and/or with intellectual disability (ID). Complete phenotypic evaluation of the pedigrees in the ASD individuals showed common specific autistic behavioural features and neurophysiological patterns (abnormal MisMatch Negativity in response to auditory change) that were absent in healthy parents as well as in family members with isolated ID. Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting either the GLRB or the ANK3 genes encoding NLGN4X interacting proteins expressed in inhibitory or in excitatory synapses, respectively. The GRLB and ANK3 mutations were absent in relatives with ID as well as in control databases. In summary, our findings provide evidence of a double-hit genetic model focused on excitatory/inhibitory synapses in ASD, that is not found in isolated ID, associated with an atypical in vivo neurophysiological pattern linked to predictive coding.
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.|Centre Hospitalier Régional Universitaire, Centre Universitaire de pédopsychiatrie, Tours, France.
authors.forename: F
authors.initials: F
authors.lastname: Bonnet-Brilhault
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.
authors.forename: S
authors.identifier: http://orcid.org/0000-0003-4156-5959
authors.initials: S
authors.lastname: Alirol
authors.affiliation: Centre Hospitalier Régional Universitaire, Centre Universitaire de pédopsychiatrie, Tours, France.|Université Paris Descartes, Sorbonne Paris Cité, Institut de Psychologie, Laboratoire de Psychopathologie et Processus de Santé (EA 4057), Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Blanc
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.
authors.forename: S
authors.initials: S
authors.lastname: Bazaud
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.
authors.forename: S
authors.initials: S
authors.lastname: Marouillat
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.
authors.forename: R-A
authors.initials: RA
authors.lastname: Thépault
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.|Centre Hospitalier Régional Universitaire, Service de Biochimie et de Biologie moléculaire, Tours, France.
authors.forename: C R
authors.initials: CR
authors.lastname: Andres
authors.affiliation: Centre Hospitalier Universitaire, Centre Expert Autisme, Limoges, France.|Universite de Bretagne occidentale, Laboratoire de neuroscience, Brest, France.
authors.forename: É
authors.initials: É
authors.lastname: Lemonnier
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.|Centre Hospitalier Régional Universitaire, Centre Universitaire de pédopsychiatrie, Tours, France.
authors.forename: C
authors.initials: C
authors.lastname: Barthélémy
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.|Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France.
authors.forename: M
authors.initials: M
authors.lastname: Raynaud
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.|Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France.
authors.forename: A
authors.initials: A
authors.lastname: Toutain
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.
authors.forename: M
authors.initials: M
authors.lastname: Gomot
authors.affiliation: INSERM, U930, Tours, France.|Université François-Rabelais, UMR « Imaging and Brain », Tours, France.|Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France.
authors.forename: F
authors.initials: F
authors.lastname: Laumonnier
mesh_terms: D000161:Acoustic Stimulation; D001321:Autistic Disorder / Q000150:complications* / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002675:Child, Preschool; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory / Q000235:genetics / Q000502:physiology*; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D023281:Genomics; D018698:Glutamic Acid; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology*; D008297:Male; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics; D005680:gamma-Aminobutyric Acid
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C430845:NLGN4X protein, human; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid