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.
Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders
D. Pinto,Elsa Delaby,Elsa Delaby,Elsa Delaby,D. Merico,M. Barbosa,Alison K. Merikangas,L. Klei,B. Thiruvahindrapuram,Xiao Xu,R. Ziman,Zhuozhi Wang,J. Vorstman,A. Thompson,Regina Regan,Regina Regan,M. Pilorge,M. Pilorge,M. Pilorge,G. Pellecchia,A. Pagnamenta,B. Oliveira,B. Oliveira,C. Marshall,Tiago R. Magalhães,Tiago R. Magalhães,J. Lowe,J. Howe,A. Griswold,J. Gilbert,E. Duketis,B. Dombroski,M. Jonge,M. Cuccaro,Emily L. Crawford,C. Correia,C. Correia,J. Conroy,I. Conceição,I. Conceição,A. Chiocchetti,J. Casey,J. Casey,Guiqing Cai,C. Cabrol,C. Cabrol,C. Cabrol,N. Bolshakova,E. Bacchelli,R. Anney,S. Gallinger,M. Cotterchio,G. Casey,L. Zwaigenbaum,Kerstin Wittemeyer,Kirsty Wing,S. Wallace,H. Engeland,A. Tryfon,Susanne A. Thomson,L. Soorya,B. Rogé,W. Roberts,F. Poustka,S. Mouga,N. Minshew,L. A. McInnes,S. McGrew,C. Lord,M. Leboyer,A. Couteur,A. Kolevzon,P. J. González,Suma Jacob,Suma Jacob,R. Holt,Stephen J. Guter,Jonathan Green,Andrew Green,Andrew Green,C. Gillberg,B. Fernandez,F. Duque,R. Delorme,G. Dawson,Pauline Chaste,C. Café,Sean Brennan,T. Bourgeron,P. Bolton,P. Bolton,Sven Bölte,Sven Bölte,R. Bernier,G. Baird,Anthony J. Bailey,Anthony J. Bailey,E. Anagnostou,J. Almeida,E. Wijsman,V. Vieland,A. Vicente,A. Vicente,G. Schellenberg,M. Pericak-Vance,A. Paterson,J. Parr,G. Oliveira,J. Nurnberger,Anthony P. Monaco,Anthony P. Monaco,E. Maestrini,S. Klauck,H. Hakonarson,J. Haines,D. Geschwind,C. Freitag,S. Folstein,S. Ennis,S. Ennis,H. Coon,A. Battaglia,P. Szatmari,J. Sutcliffe,Joachim Hallmayer,M. Gill,E. Cook,J. Buxbaum,B. Devlin,L. Gallagher,Catalina Betancur,Catalina Betancur,Catalina Betancur,S. Scherer
Published 2014 in American Journal of Human Genetics
ABSTRACT
PUBLICATION RECORD
- Publication year
2014
- Venue
American Journal of Human Genetics
- Publication date
2014-03-25
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- asd-affected families
Families in the cohort that include at least one individual diagnosed with autism spectrum disorder.
Aliases: families with ASD
- dominant or x-linked asd and intellectual disability loci
Previously reported genomic loci linked to autism spectrum disorder or intellectual disability under dominant or X-linked inheritance.
Aliases: dominant ASD loci, X-linked ASD loci, ASD and intellectual disability loci
- female asd subjects
Female participants in the ASD cohort.
Aliases: females with ASD, female participants with ASD
- fragile x syndrome protein targets
Genes regulated by or interacting with the fragile X mental retardation protein.
Aliases: FMRP targets
- genic deletions and duplications
Copy-number changes that overlap genes and alter the number of gene copies.
Aliases: genic deletions, genic duplications
- neuronal signaling, synapse function, and chromatin regulation networks
Biological interaction networks centered on neuronal communication, synaptic processes, and chromatin control.
Aliases: neuronal signaling networks, synapse function networks, chromatin regulation networks
- pathogenic cnvs
Copy-number variants considered to have disease-causing potential because they overlap established neurodevelopmental loci.
- rare copy-number variation (cnv)
Structural genomic variation in which DNA segments are deleted or duplicated.
Aliases: CNV, copy-number variation
REFERENCES
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