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Audrey Guilmatre, PhD; Christèle Dubourg, PhD; Anne-Laure Mosca, MD; Solenn Legallic, BSc; Alice Goldenberg, MD; Valérie Drouin-Garraud, MD; Valérie Layet, MD; Antoine Rosier, MD; Sylvain Briault, MD; Frédérique Bonnet-Brilhault, MD, PhD; Frédéric Laumonnier, PhD; Sylvie Odent, MD, PhD; Gael Le Vacon, MD; Géraldine Joly-Helas, MD; Véronique David, MD; Claude Bendavid, MD; Jean-Michel Pinoit, MD; Céline Henry, MD; Caterina Impallomeni, MD; Eva Germano, MD; Gaetano Tortorella, MD; Gabriella Di Rosa, MD; Catherine Barthelemy, MD; Christian Andres, MD; Laurence Faivre, MD, PhD; Thierry Frébourg, MD, PhD; Pascale Saugier Veber, PhD; Dominique Campion, MD, PhD

Arch Gen Psychiatry. 2009;66(9):947-956.

Context  Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia.

Objectives  To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category.

Design  Case-control study.

Setting  Academic research.

Participants  We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls.

Main Outcome Measures  Collective and individual frequencies of the analyzed CNVs in cases compared with controls.

Results  Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes.

Conclusions  Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.

Author Affiliations: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 614, Institut Hospitalo-Universitaire de Recherche Biomédicale (Drs Guilmatre, Mosca, Frébourg, Saugier Veber, and Campion and Ms Legallic), Department of Research, Centre Hospitalier de Saint Etienne du Rouvray (Drs Le Vacon and Campion), and Department of Genetics, University Hospital (Drs Goldenberg, Drouin-Garraud, Joly-Helas, Frébourg, and Saugier Veber), Rouen, Unité Mixte de Recherche 6061, Centre National de Recherche Scientifique, University of Rennes I (Drs Dubourg, David, and Bendavid), and Department of Genetics, University Hospital (Dr Odent), Rennes, Department of Genetics, Groupe Hospitalier du Havre, Le Havre (Dr Layet), Centre de Ressources Autisme de Haute Normandie, Saint Etienne du Rouvray (Dr Rosier), Department of Genetics, University Hospital, and Unité Mixte de Recherche 930 Centre National de Recherche Scientifique, Orléans (Dr Briault), INSERM Unité 930, University Hospital Bretonneau, University François-Rabelais (Drs Bonnet-Brilhault, Laumonnier, and Barthelemy), and INSERM Unité 619 (Dr Andres), Tours, and Department of Genetics (Drs Mosca and Faivre) and Centre de Ressources Autisme de Bourgogne, Childrens Hospital (Drs Pinoit and Henry), University Hospital, Dijon, France; and Department of Medical and Surgical Pediatrics, University Hospital, Messina, Italy (Drs Impallomeni, Germano, Tortorella, and Di Rosa).

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