Contributors: Génétique Humaine et Fonctions Cognitives; Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS); Department of Pharmacy and Biotechnology; Alma Mater Studiorum Università di Bologna = University of Bologna (UNIBO); Medical Genetics Laboratory; Policlinico S. Orsola-Malpighi; Neurobiologie et Psychiatrie; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM); Service de psychopathologie de l'enfant et de l'adolescent; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7); Université Paris Diderot - Paris 7 (UPD7); Institut Mondor de recherche biomédicale (IMRB); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12); Service de psychiatrie; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier; Department of Child and Adolescent Psychiatry; Göteborgs Universitet = University of Gothenburg (GU); Saint George's Hospital Medical School; Department of Medical Genetics; Department of Psychiatry and Behavioral Sciences Stanford; Stanford Medicine; Stanford University-Stanford University; Laboratory of Molecular Genetics; Helsinki University Hospital Finland (HUS); This work was supported by the Pasteur Institute, INSERM, Assistance Publique-Hôpitaux de Paris, FP6 AUTISM MOLGEN, FP6 ENI-NET, Fondation France Télécom, Fondation de France, Fondation biomédicale de la Mairie de Paris, Fondation pour la Recherche Médicale, the Swedish Science Council, Telethon-Italy (GP030227), the Academy of Finland, and Helsinki University Hospital Research Funding. The International Molecular Genetic Study of Autism Consortium thanks the UK Medical Research Council, Wellcome Trust, BIOMED 2 (CT-97-2759), EC Fifth Framework (QLG2-CT-1999-0094), Janus Korczak Foundation, Deutsche Forschungsgemeinschaft, Conseil Regional Midi-Pyrenees, Danish Medical Research Council, Sofiefonden, Beatrice Surovell Haskells Fond for Child Mental Health Research of Copenhagen, Danish Natural Science Research Council (9802210) and the US National Institutes of Health (U19 HD35482, MO1 RR06022, K05 MH01196, K02 MH01389).; Paris Autism Research International Sib-pair (PARIS) study; International Molecular Genetic Study of Autism Consortium (IMGSAC)
نبذة مختصرة : International audience ; Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (> or = 80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes.
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