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

M Mercati 1, 2 G Huguet 1, 2 A Danckaert L André-Leroux 3, 4 Anna Maruani 5 Marco Bellinzoni 4 T Rolland 1, 2 L Gouder 1, 2 Mathieu Alexandre 1, 2 Julien Buratti 1, 2 Frederique Amsellem 5 M Benabou 1, 2 J Van-Gils 1, 2 Anita Beggiato 5 M Konyukh 1, 2 Jean-Pierre Bourgeois 1, 2 M J Gazzellone 6 R K C Yuen 6 S Walker 6 M Delépine 7 Anne Boland 8 Béatrice Regnault 9 M Francois 5 T van den Abbeele 5 L Mosca-Boidron 10 L Faivre 11 Y Shimoda 12 K Watanabe 12 D Bonneau 13 M Rastam 14, 15 M Leboyer 16, 17 S W Scherer 18, 6 C Gillberg 15 R Delorme 1, 2, 5 Isabelle Cloëz-Tayarani 1, 2, * Thomas Bourgeron 1, 2, 15, 17, *
* Corresponding author
1 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
2 Gènes, Synapses et Cognition
3 MaIAGE - Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas]
4 Microb. Struc. (UMR_3528 / U-Pasteur_5) - Microbiologie structurale - Structural Microbiology
5 AP-HP Hôpital universitaire Robert-Debré [Paris]
6 SickKids - The Hospital for sick children [Toronto]
7 IG - Institut de Génomique d'Evry
8 CNG - Centre National de Génotypage
9 Génotypage des Eucaryotes (Plate-Forme)
10 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
11 GAD - Génétique des Anomalies du Développement
12 Nagaoka University of Technology
13 Département de Biochimie et Génétique [Angers]
14 Lund University [Lund]
15 GU - University of Gothenburg
16 IMRB - Institut Mondor de Recherche Biomédicale
17 Fondation FondaMental [Créteil]
18 McLaughlin Centre
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 CNTN6(W923X) was transmitted by a mother to her two sons with ASD and one variant CNTN6(P770L) 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.
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M Mercati, G Huguet, A Danckaert, L André-Leroux, Anna Maruani, et al.. CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders. Molecular Psychiatry, Nature Publishing Group, 2017, 22 (4), pp.625 - 633. ⟨10.1038/mp.2016.61⟩. ⟨pasteur-01516991⟩

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