La génétique de l’autisme

Genetics of autism: from genome scans to candidate genes

¹ Laboratoire de génétique humaine et fonctions cognitives, Université Paris 7, Inserm EPI21, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France
² Inserm U.513, Neurobiologie et Psychiatrie, Faculté de Médecine, 8, rue du Général Sarrail, 94010 Créteil Cedex, France
³ Inserm U.513, Service de Psychiatrie Adulte, Hôpitaux Albert Chenevier et Henri Mondor, Assistance Publique-Hôpitaux de Paris, 40, rue de Mesly, 94000 Créteil, France

^* sjamain@pasteur.fr

Résumé

Soixante ans après sa caractérisation par Léo Kanner puis par Hans Asperger, les causes majeures du syndrome autistique restent toujours inconnues. Bien qu’un quart des cas d’autisme soit associé à des affections connues, les trois quarts restants demeurent idiopathiques.Cependant, les études sur les couples de jumeaux, réalisées durant les années 1970-1980, ont permis de déceler une forte influence géné-tique dans l’apparition de ce syndrome. En outre, le développement de nouvelles techniques d’analyse génétique, les nombreuses analyses de gènes candidats et l’amélioration de la définition du diagnostic ont permis au fil du temps de diri-ger les recherches sur plusieurs régions du génome comme les bras longs des chromosomes 2, 6, 7 et 15 ou les chromosomes sexuels. Cet article a donc pour but de retracer les dernières avancées dans la recherche de la prédisposition génétique au syndrome autistique.

Abstract

The autistic disorder was firstly described by Leo Kanner sixty years ago. This complex developmental disability is characterized by social and communicative impairments and repetitive and stereotyped behaviours and interests. The prevalence of autism in the general population is about 1 in 1,000, with four males affected for one female. In approximately 15% of the cases, autism is associated with known genetic disorders, such as fragileX syndrome, tuberous sclerosis or Rett syndrome. Nevertheless, a recognised medical etiology can only be identified in a minority of cases. A higher recurrence risk in families with autistic subjects (45 times greater than the prevalence in the general population) and higher concordance for autism among monozygotic (60-90%) than dizygotic (0-10%) twins argue for a genetic predisposition to idiopathic autism. The past decade has been marked by an increased interest in the genetic basis of autism, with a series of multiple independent whole genome scans and chromosomal abnormalities studies. These analyses have pointed out several candidate regions on chromosomes 2q, 7q, 6q, 15q and sex chromosomes. These regions possess candidate genes that have been screened for mutations or association with autism. However, a clear involvement of a major susceptibility gene (or genes) in autism remains far from clear. The results from linkage studies and the clear drop in the concordance rates between monozygotic and dizygotic twins suggests that the genetic aetiology of autism is certainly heterogeneous (different genes in different families) and polygenic (more than one affected gene per individual). The almost finished sequence of the human genome and the generation of haplotype maps will shed light on the inter-individual genetic variability and will certainly increase the power and reliability of association studies for complex traits, such as autism.