TY - JOUR
T1 - Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders
AU - de Sousa Pinto, D.
AU - Delaby, E.
AU - Merico, D.
AU - Barbosa, M.R.V.
AU - Merikangas, A.
AU - Klei, L.
AU - Thiruvahindrapuram, B.
AU - Xu, X.
AU - Ziman, R.
AU - Wang, Z.
AU - Vorstman, J.A.S.
AU - de Jonge, Maretha
AU - van Engeland, H.
AU - et al, X
AU - Scherer, S.W.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - DE-NOVO MUTATIONS
KW - COPY NUMBER VARIANTS
KW - GENOME-WIDE ASSOCIATION
KW - FRAGILE-X-SYNDROME
KW - INTELLECTUAL DISABILITY
KW - STRUCTURAL VARIATION
KW - PHENOTYPE ONTOLOGY
KW - DELETIONS
KW - DUPLICATIONS
KW - RISK
U2 - 10.1016/j.ajhg.2014.03.018
DO - 10.1016/j.ajhg.2014.03.018
M3 - Article
C2 - 24768552
SN - 0002-9297
VL - 94
SP - 677
EP - 694
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -