Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

D. de Sousa Pinto, E. Delaby, D. Merico, M.R.V. Barbosa, A. Merikangas, L. Klei, B. Thiruvahindrapuram, X. Xu, R. Ziman, Z. Wang, J.A.S. Vorstman, Maretha de Jonge, H. van Engeland, X et al, S.W. Scherer

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 x 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 x 10(-15), similar to 3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Original languageEnglish
Pages (from-to)677-694
Number of pages18
JournalAmerican Journal of Human Genetics
Volume94
Issue number5
DOIs
Publication statusPublished - 2014

Keywords

  • DE-NOVO MUTATIONS
  • COPY NUMBER VARIANTS
  • GENOME-WIDE ASSOCIATION
  • FRAGILE-X-SYNDROME
  • INTELLECTUAL DISABILITY
  • STRUCTURAL VARIATION
  • PHENOTYPE ONTOLOGY
  • DELETIONS
  • DUPLICATIONS
  • RISK

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