Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism
Stéphane Jamain,1 Hélène Quach,1 Catalina Betancur,2 Maria Råstam,3 Catherine Colineaux,4,2 I Carina Gillberg,3 Henrik Söderström,3 Bruno Giros,2 Marion Leboyer,2,5 Christopher Gillberg,3,6 Thomas Bourgeron,1* and Paris Autism Research International Sibpair (PARIS) Study
1Laboratoire d'immunogénétique humaine Institut Pasteur de Paris, INSERM : EPI21, Université Denis Diderot - Paris VII, 25 rue du Docteur Roux
75724 Paris Cedex 15,FR
2Neurobiologie et Psychiatrie INSERM : U513, Université Paris XII Val de Marne, Faculte de Medecine PARIS XII
8, Rue du General Sarrail
94010 CRETEIL CEDEX,FR
3Department of Child and Adolescent Psychiatry Goteborg University, Goteborg,SE
4Service de psychopathologie de l'enfant et de l'adolescent AP-HP, Hôpital Robert Debré, Université Denis Diderot - Paris VII, 48, Bd Sérurier
5Département de Psychiatrie AP-HP, Hôpital Albert Chenevier, 40 rue de Mesly
6Department of Psychiatry Saint George's Hospital Medical School, London,GB
Many studies have supported a genetic aetiology for autism. Here we report mutations in two X-linked genes, neuroligins NLGN3 and NLGN4, in siblings with autism spectrum disorders. These mutations affect cell adhesion molecules localised at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
Autism is characterised by impairments in reciprocal social interaction and communication as well as restricted and stereotyped patterns of interests and activities1. Asperger syndrome (AS) refers to subjects with higher cognitive abilities and more normal language function2. The recurrence risk of autism in sib-ships is approximately 45 times greater than in the general population and twin studies have documented a higher concordance rate in monozygotic (60%–91%) than in dizygotic twins (0%–6%)3. The male-to-female ratio is 4:1 in autism and 8:1 in AS. Male predisposition t o autistic disorder remains unexplained, although abnormalities of the sex chromosomes are frequently associated with autistic spectrum disorders4. At least two loci for a predisposition t o autism have been suggested on the X chromosome. At Xp22.3, de novo chromosomal deletions have been observed in three autistic females5 and a second locus at Xq13-21 is supported by two independent genome scans, showing increased allele sharing around markers DXS7132 (52 cM) and DXS6789 (62 cM) in affected sib-pair (ASP) analyses6,7.