Published in
Cell Press, American Journal of Human Genetics, 5(94), p. 677-694, 2014
DOI: 10.1016/j.ajhg.2014.03.018
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Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders
,
Lambertus Klei,
Bhooma Thiruvahindrapuram,
Xiao Xu,
Robert Ziman,
Zhuozhi Wang,
Jacob A. S. Vorstman,
Ann Thompson,
Regina Regan,
Marion Pilorge,
Giovanna Pellecchia
and other authors.
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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 × 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 × 10(-15), ∼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.