title: CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.
abstract: Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923Xwas transmitted by a mother to her two sons with ASD and one variant CNTN6P770Lwas found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Mercati
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: G
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authors.lastname: Huguet
authors.affiliation: Imagopole, Citech, Institut Pasteur, Paris, France.
authors.forename: A
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authors.lastname: Danckaert
authors.affiliation: Institut Pasteur, Unité de Microbiologie Structurale, Paris, France.|CNRS UMR 3528, Paris, France.|INRA, Unité MaIAGE, UR1404, Jouy-en-Josas, France.
authors.forename: G
authors.initials: G
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authors.affiliation: Assistance Publique-Hôpitaux de Paris, Child and Adolescent Psychiatry Department, Robert Debré Hospital, Paris, France.
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authors.affiliation: Institut Pasteur, Unité de Microbiologie Structurale, Paris, France.|CNRS UMR 3528, Paris, France.
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authors.lastname: Bellinzoni
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Rolland
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: L
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authors.lastname: Gouder
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: A
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authors.lastname: Mathieu
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: J
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authors.affiliation: Assistance Publique-Hôpitaux de Paris, Child and Adolescent Psychiatry Department, Robert Debré Hospital, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Amsellem
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: M
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authors.lastname: Benabou
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: J
authors.initials: J
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authors.affiliation: Assistance Publique-Hôpitaux de Paris, Child and Adolescent Psychiatry Department, Robert Debré Hospital, Paris, France.
authors.forename: A
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authors.lastname: Beggiato
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: M
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authors.lastname: Konyukh
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Bourgeois
authors.affiliation: Centre for Applied Genomics, Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Gazzellone
authors.affiliation: Centre for Applied Genomics, Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: R K C
authors.initials: RK
authors.lastname: Yuen
authors.affiliation: Centre for Applied Genomics, Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Walker
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: M
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authors.lastname: Delépine
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: A
authors.initials: A
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authors.affiliation: Eukaryote Genotyping Platform, Genopole, Institut Pasteur, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Régnault
authors.affiliation: Assistance Publique-Hôpitaux de Paris, ENT and Head and Neck Surgery Department, Robert Debré Hospital, Paris-VII University, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Francois
authors.affiliation: Assistance Publique-Hôpitaux de Paris, ENT and Head and Neck Surgery Department, Robert Debré Hospital, Paris-VII University, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Van Den Abbeele
authors.affiliation: Département de Génétique, CHU Dijon et Université de Bourgogne, Dijon, France.
authors.forename: A L
authors.initials: AL
authors.lastname: Mosca-Boidron
authors.affiliation: Département de Génétique, CHU Dijon et Université de Bourgogne, Dijon, France.
authors.forename: L
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Japan.
authors.forename: Y
authors.identifier: 0000-0001-9230-6784
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
authors.forename: D
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: Department of Clinical Sciences in Lund, Lund University, Lund, Sweden.|Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Rastam
authors.affiliation: INSERM U955, Psychiatrie Translationnelle, Créteil, France.|Université Paris Est, Faculté de Médecine, Créteil, France.|Assistance Publique-Hôpitaux de Paris, DHU Pe-PSY, H. Mondor Hospital, Department of Psychiatry, Créteil, France.|FondaMental Foundation, Créteil, France.
authors.forename: M
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authors.lastname: Leboyer
authors.affiliation: Centre for Applied Genomics, Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada.|McLaughlin Centre, Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: S W
authors.initials: SW
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authors.affiliation: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
authors.forename: C
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authors.lastname: Gillberg
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.|Assistance Publique-Hôpitaux de Paris, Child and Adolescent Psychiatry Department, Robert Debré Hospital, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Delorme
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Cloëz-Tayarani
authors.affiliation: Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.|Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.|FondaMental Foundation, Créteil, France.
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mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D001307:Auditory Perception / Q000235:genetics*; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism; D002648:Child; D058966:Contactins / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: C000595918:CNTN5 protein, human; C111104:CNTN6 protein, human; D058966:Contactins