Social responsiveness scale-aided analysis of the clinical impact of copy number variations in autism

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, Hans Kristian Ploos van Amstel, Ron Hochstenbach, Eva H. Brilstra, Martin Poot*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    61 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)315-323
    Number of pages9
    JournalNeurogenetics
    Volume12
    Issue number4
    DOIs
    Publication statusPublished - Nov-2011

    Keywords

    • Autism
    • Social Responsiveness Scale (SRS)
    • SNP array-based CNV profiling
    • Gene prioritization
    • Phosphoinositol signaling
    • Contactin genes
    • COMPARATIVE GENOMIC HYBRIDIZATION
    • SPECTRUM DISORDERS
    • CHROMOSOMAL REARRANGEMENTS
    • DIAGNOSTIC INTERVIEW
    • SPEECH DELAY
    • TRAITS
    • POPULATION
    • VALIDATION
    • VARIANTS
    • GENETICS

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