• Emma van Daalen, Chantal Kemner, Nienke E Verbeek, Bert van der Zwaag, Trijnie Dijkhuizen, Patrick Rump, Renske Houben, Ruben van 't Slot, Maretha V de Jonge, Wouter G Staal, Frits A Beemer, Jacob A S Vorstman, J Peter H Burbach, van Amstel Hans Kristian Ploos HK, Ron Hochstenbach, Eva H Brilstra, and Martin Poot.
• Department of Child and Adolescent Psychiatry, University Medical Centre, Utrecht, The Netherlands.
• Neurogenetics. 2011 Nov 1; 12 (4): 315-23.

AbstractRecent 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.

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