Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
Case-control study.


METHODS
Academic research.


METHODS
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.


METHODS
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.
Guilmatre
Audrey
A
Institut National de la Santé et de la Recherche Médicale, Unité 614, Institut Hospitalo-Universitaire de Recherche Biomédicale, 76000 Rouen, France.
Dubourg
Christèle
C
Mosca
Anne-Laure
AL
Legallic
Solenn
S
Goldenberg
Alice
A
Drouin-Garraud
Valérie
V
Layet
Valérie
V
Rosier
Antoine
A
Briault
Sylvain
S
Bonnet-Brilhault
Frédérique
F
Laumonnier
Frédéric
F
Odent
Sylvie
S
Le Vacon
Gael
G
Joly-Helas
Géraldine
G
David
Véronique
V
Bendavid
Claude
C
Pinoit
Jean-Michel
JM
Henry
Céline
C
Impallomeni
Caterina
C
Germano
Eva
E
Tortorella
Gaetano
G
Di Rosa
Gabriella
G
Barthelemy
Catherine
C
Andres
Christian
C
Faivre
Laurence
L
Frébourg
Thierry
T
Saugier Veber
Pascale
P
Campion
Dominique
D
D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000706:statistics & numerical data; D055028:Comparative Genomic Hybridization / Q000706:statistics & numerical data; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000706:statistics & numerical data; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D055495:Neurogenesis; D020411:Oligonucleotide Array Sequence Analysis; D011392:Proline / Q000097:blood; D011618:Psychotic Disorders / Q000175:diagnosis / Q000235:genetics; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*
D011392:Proline