title: Social Responsiveness Scale-aided analysis of the clinical impact of copy number variations in autism.
abstract: Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient's phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders.
authors.affiliation: Department of Child and Adolescent Psychiatry, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Emma
authors.initials: E
authors.lastname: van Daalen
authors.forename: Chantal
authors.initials: C
authors.lastname: Kemner
authors.forename: Nienke E
authors.initials: NE
authors.lastname: Verbeek
authors.forename: Bert
authors.initials: B
authors.lastname: van der Zwaag
authors.forename: Trijnie
authors.initials: T
authors.lastname: Dijkhuizen
authors.forename: Patrick
authors.initials: P
authors.lastname: Rump
authors.forename: Renske
authors.initials: R
authors.lastname: Houben
authors.forename: Ruben
authors.initials: R
authors.lastname: van 't Slot
authors.forename: Maretha V
authors.initials: MV
authors.lastname: de Jonge
authors.forename: Wouter G
authors.initials: WG
authors.lastname: Staal
authors.forename: Frits A
authors.initials: FA
authors.lastname: Beemer
authors.forename: Jacob A S
authors.initials: JA
authors.lastname: Vorstman
authors.forename: J Peter H
authors.initials: JP
authors.lastname: Burbach
authors.forename: Hans Kristian Ploos
authors.initials: HK
authors.lastname: van Amstel
authors.forename: Ron
authors.initials: R
authors.lastname: Hochstenbach
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D010375:Pedigree; D010641:Phenotype; D012919:Social Behavior