Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Journal article

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.

Authors: Pinto, D; Delaby, E; Merico, D; Barbosa, M; Merikangas, A

• Publication status: Published
• Journal: American journal of human genetics
• Volume: 94
• Issue: 5
• Pages: 677-694
• Publication date: 2014-05-01
• DOI: 10.1016/j.ajhg.2014.03.018
• EISSN: 1537-6605
• ISSN: 0002-9297
• Language: English
• Keywords: Gene Regulatory Networks; Humans; Metabolic Networks and Pathways; Child; Sequence Deletion; Multigene Family; DNA Copy Number Variations; Female; Male; Pedigree; Child Development Disorders, Pervasive