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Mol Psychiatry. 2017 Apr;22(4):625-633. doi: 10.1038/mp.2016.61. Epub 2016 May 10.

CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.

Author information

1
Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France.
2
CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, Paris, France.
3
Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
4
Imagopole, Citech, Institut Pasteur, Paris, France.
5
Institut Pasteur, Unité de Microbiologie Structurale, Paris, France.
6
CNRS UMR 3528, Paris, France.
7
INRA, Unité MaIAGE, UR1404, Jouy-en-Josas, France.
8
Assistance Publique-Hôpitaux de Paris, Child and Adolescent Psychiatry Department, Robert Debré Hospital, Paris, France.
9
Centre for Applied Genomics, Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, Canada.
10
Centre National de Génotypage, Evry, France.
11
Eukaryote Genotyping Platform, Genopole, Institut Pasteur, Paris, France.
12
Assistance Publique-Hôpitaux de Paris, ENT and Head and Neck Surgery Department, Robert Debré Hospital, Paris-VII University, Paris, France.
13
Département de Génétique, CHU Dijon et Université de Bourgogne, Dijon, France.
14
Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Japan.
15
Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
16
Department of Clinical Sciences in Lund, Lund University, Lund, Sweden.
17
Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
18
INSERM U955, Psychiatrie Translationnelle, Créteil, France.
19
Université Paris Est, Faculté de Médecine, Créteil, France.
20
Assistance Publique-Hôpitaux de Paris, DHU Pe-PSY, H. Mondor Hospital, Department of Psychiatry, Créteil, France.
21
FondaMental Foundation, Créteil, France.
22
McLaughlin Centre, Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

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 CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was 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.

PMID:
27166760
PMCID:
PMC5378808
DOI:
10.1038/mp.2016.61
[Indexed for MEDLINE]
Free PMC Article

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