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From the Archives
September 2009

Disparate Diseases Due to Copycat Copy Number Variations

Arch Neurol. 2009;66(9):1158-1159. doi:10.1001/archneurol.2009.197

Archives of General Psychiatry

Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation

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

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 (606810) and DGCR6 (601279) 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.

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