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

M Mercati (1, 2) , G Huguet (1, 2) , Anne Danckaert (3) , L André-Leroux (4, 5) , Anna Maruani (6) , Marco Bellinzoni (5) , T Rolland (1, 2) , L Gouder (1, 2) , Mathieu Alexandre (1, 2) , Julien Buratti (1, 2) , Frederique Amsellem (6) , M Benabou (1, 2) , J Van-Gils (1, 2) , Anita Beggiato (6) , M Konyukh (1, 2) , Jean-Pierre Bourgeois (1, 2) , M J Gazzellone (7) , R K C Yuen (7) , S Walker (7) , M Delépine (8) , Anne Boland (9) , Béatrice Regnault (10) , M Francois (6) , T van den Abbeele (6) , L Mosca-Boidron (11) , L Faivre (12) , Y Shimoda (13) , K Watanabe (13) , Dominique Bonneau (14) , M Rastam (15, 16) , M Leboyer (17, 18) , S W Scherer (19, 7) , C Gillberg (16) , R Delorme (1, 2, 6) , Isabelle Cloëz-Tayarani (1, 2) , Thomas Bourgeron (1, 2, 16, 18)

1 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
2 CNRS - UMR3571 - Gènes, Synapses et Cognition
3 CITECH - Imagopole
4 MaIAGE - Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas]
5 Microb. Struc. (UMR_3528 / U-Pasteur_5) - Microbiologie structurale - Structural Microbiology
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 SickKids - The Hospital for sick children [Toronto]
8 IG - Institut de Génomique d'Evry
9 CNG - Centre National de Génotypage
10 Génotypage des Eucaryotes (Plate-Forme)
11 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
12 GAD - Génétique des Anomalies du Développement
13 Nagaoka University of Technology
14 Département de Biochimie et Génétique [Angers]
15 Lund University [Lund]
16 GU - University of Gothenburg
17 IMRB - Institut Mondor de Recherche Biomédicale
18 Fondation FondaMental [Créteil]
19 McLaughlin Centre

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.

Domains: Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]; Neurobiology; Life Sciences [q-bio]; Pharmaceutical sciences; Pharmacology; Life Sciences [q-bio]; Human health and pathology; Psychiatrics and mental health; Cognitive science; Neuroscience

M Mercati, G Huguet, Anne Danckaert, L André-Leroux, Anna Maruani, et al.. CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders. Molecular Psychiatry, 2017, 22 (4), pp.625 - 633. ⟨10.1038/mp.2016.61⟩. ⟨pasteur-01516991⟩