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

Mercati, O. et al. (2017) CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders. Molecular Psychiatry, 22(4), pp. 625-633. (doi: 10.1038/mp.2016.61) (PMID:27166760) (PMCID:PMC5378808)

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.

• Item Type: Articles
• Additional Information: This work was funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, Centre National de la Recherche Scientifique, University Paris Diderot, Agence Nationale de la Recherche (ANR-08-MNPS-037-01- SynGen), the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, the Fondamental Foundation, the GenMed Labex and the BioPsy labex. O Mercati was supported by an undergraduate fellowship from the Neuropole de Recherche Francilien (NeRF) and the Orange Foundation. The research leading to these results has also received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gillberg, Professor Christopher
• Authors: Mercati, O., Huguet, G., Danckaert, A., André-Leroux, G., Maruani, A., Bellinzoni, M., Rolland, T., Gouder, L., Mathieu, A., Buratti, J., Amsellem, F., Benabou, M., Van-Gils, J., Beggiato, A., Konyukh, M., Bourgeois, J.-P., Gazzellone, M.J., Yuen, R.K.C., Walker, S., Delépine, M., Boland, A., Régnault, B., Francois, M., Van Den Abbeele, T., Mosca-Boidron, A.L., Faivre, L., Shimoda, Y., Watanabe, K., Bonneau, D., Rastam, M., Leboyer, M., Scherer, S.W., Gillberg, C., Delorme, R., Cloëz-Tayarani, I., and Bourgeron, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Molecular Psychiatry
• Publisher: Springer Nature
• ISSN: 1359-4184
• ISSN (Online): 1476-5578
• Published Online: 10 May 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Molecular Psychiatry 22(4):625-633
• Publisher Policy: Reproduced under a creative commons licence