Functional impact of global rare copy number variation in autism spectrum disorders

  title={Functional impact of global rare copy number variation in autism spectrum disorders},
  author={Dalila Pinto and Alistair T. Pagnamenta and Lambertus Klei and Richard J. L. Anney and Daniele Merico and Regina Regan and Judith M. Conroy and Tiago R. Magalh{\~a}es and Catarina Correia and Brett S. Abrahams and Joana Almeida and Elena Bacchelli and Gary D Bader and Anthony J. Bailey and Gillian Baird and Agatino Battaglia and Thomas P. Berney and Nadia Bolshakova and Sven B{\"o}lte and Patrick F. Bolton and Thomas Bourgeron and Sean Brennan and Jessica A. Brian and Susan E. Bryson and Andrew R. Carson and Guillermo Casallo and Jillian P Casey and Brian HY Chung and Lynne E. Cochrane and Christina Corsello and Emily L. Crawford and Andrew Crossett and Cheryl Cytrynbaum and Geraldine Dawson and Maretha V. de Jonge and Richard Delorme and Irene Drmic and Eftichia Duketis and Frederico Duque and Annette M. Estes and Penny Farrar and Bridget A. Fernandez and Susan E B Folstein and Eric Fombonne and Christine M. Freitag and John R. Gilbert and Christopher Gillberg and Joseph T. Glessner and Jeremy Goldberg and Andrew J. Green and Jonathan Green and Stephen J. Guter and Hakon H. Hakonarson and Elizabeth A. Heron and Matthew J. Hill and Richard James Holt and Jennifer L. Howe and Gillian Hughes and Vanessa Hus and Roberta Igliozzi and Cecilia Kim and Sabine M. Klauck and Alexander Kolevzon and Olena Korvatska and Vlad Kustanovich and Clara Lajonchere and Janine A. Lamb and Magdalena Laskawiec and Marion Leboyer and Ann Le Couteur and Bennett L. Leventhal and Anath Christopher Lionel and Xiao-qing Liu and Catherine Lord and Linda J. Lotspeich and Sabata C. Lund and Elena Maestrini and William J. Mahoney and Carine Mantoulan and Christian R. Marshall and Helen McConachie and Christopher J. McDougle and Jane McGrath and William M. McMahon and Alison K. Merikangas and Ohsuke Migita and Nancy J. Minshew and Ghazala K. Mirza and Jeff Munson and Stanley F. Nelson and Carolyn Noakes and Abdul Noor and Gudrun Nygren and Guiomar Oliveira and Katerina Papanikolaou and Jeremy R Parr and Barbara Parrini and Tara A. Paton and Andrew Pickles and Marion Pilorge and Joseph Piven and Chris Paul Ponting and David J. Posey and Annemarie Poustka and Fritz Poustka and Aparna Prasad and Jiannis Ragoussis and Katy Renshaw and Jessica Rickaby and Wendy Roberts and Kathryn Roeder and Bernadette Rog{\'e} and Michael L. Rutter and Laura J. Bierut and John P. Rice and Jeff Salt and Katherine Sansom and Daisuke Sato and Ricardo Segurado and Ana Filipa Sequeira and Lili Senman and Naisha Shah and Val C. Sheffield and Latha V Soorya and In{\^e}s Sousa and Olaf Stein and Nuala H Sykes and Vera Stoppioni and Christina P Strawbridge and Raffaella Tancredi and Katherine E. Tansey and Bhooma Thiruvahindrapduram and Ann P. Thompson and Susanne A. Thomson and Ana Tryfon and John Tsiantis and Herman van Engeland and John B. Vincent and Fred R. Volkmar and Simon Wallace and Kai Wang and Zhouzhi Wang and Thomas H. Wassink and Caleb Webber and Rosanna Weksberg and Kirsty Wing and Kerstin Wittemeyer and Shawn Wood and Jing Wu and Brian L. Yaspan and Danielle Zurawiecki and Lonnie Zwaigenbaum and Joseph. D. Buxbaum and Rita M. Cantor and Edwin H. Cook and Hilary Coon and Michael L Cuccaro and Bernie Devlin and Sean Ennis and Louise Gallagher and Daniel H. Geschwind and Michael Gill and Jonathan L. Haines and Joachim Hallmayer and Judith S Miller and Anthony P. Monaco and John I. Nurnberger and Andrew D. Paterson and Margaret A. Pericak-Vance and Gerard D. Schellenberg and Peter Szatmari and Astrid Moura Vicente and Veronica J. Vieland and Ellen M. Wijsman and Stephen W. Scherer and James S. Sutcliffe and Catalina Betancur},
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable (∼90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of… 

Association of Copy Number Variations in Autism Spectrum Disorders: A Systematic Review

This review emphasizes the major CNVs reported to date in ASD and reveals that submicroscopic CNVs can have a role in ASD, and de novo CNVs seem to be a more common risk factor in sporadic compared with inherited forms of ASD.

The phenotypic manifestations of rare genic CNVs in autism spectrum disorder

This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.

[Genetic analyses for identifying molecular mechanisms in autism spectrum disorders].

The state of the art of genome analyses in ASD, the most widely used mouse models for polygenic or monogenetic forms of autism, are described and new insights gained from these analyses are discussed.

Genetic architecture in autism spectrum disorder.

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

A large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD highlights the applicability of HH mapping in complex disorders such as ASD and offers an alternative approach to the analysis of genome-wide association data.

Genetic contributions to autism spectrum disorder

This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings, and considersable increases in sample sizes needed to better understand the hundreds or thousands of common and rare genetic variants involved.

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Copy number variation in 19 Italian multiplex families with autism spectrum disorder: Importance of synaptic and neurite elongation genes

Gene Ontology enrichment analysis indicates that most potentially causal or relevant ASD genes detected in this cohort belong to nervous system‐specific categories, especially involved in neurite elongation and synaptic structure/function, which point toward the existence of genomic instability in these families, whose underlying genetic and epigenetic mechanisms deserve further scrutiny.

Large mosaic copy number variations confer autism risk

The results indicate that mCNVs contribute a previously unexplained component of ASD risk, and are experimentally validated in postmortem brain tissue from 59 additional probands.

Copy number variation characteristics in subpopulations of patients with autism spectrum disorders

  • A. BremerM. Giacobini J. Schoumans
  • Medicine, Biology
    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
  • 2011
It is concluded that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs.



Structural variation of chromosomes in autism spectrum disorder.

Strong Association of De Novo Copy Number Mutations with Autism

Findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

To pinpoint genes likely to contribute to ASD etiology, high density genotyping was performed in 912 multiplex families from the Autism Genetics Resource Exchange collection and contrasted results to those obtained for 1,488 healthy controls.

Rare chromosomal deletions and duplications increase risk of schizophrenia

A genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls provides strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.

Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Linkage and copy number variation analyses implicate chromosome 11p12–p13 and neurexins, respectively, among other candidate loci, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Autism as a paradigmatic complex genetic disorder.

It is essential that the restricted interests of patients with autism not be reflected in overly restrictive genetic approaches if the authors are to better understand the genetics of autism in the most expeditious and thorough manner.

Association between microdeletion and microduplication at 16p11.2 and autism.

A novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases are identified.

Recurrent 16p11.2 microdeletions in autism.

This work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date.


A linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms in a common set of 1,031 multiplex autism families, implicating SEMA5A as an autism susceptibility gene.

Copy-number variation in control population cohorts.

An example of how to discover new CNVs from existing genotype data from large-scale genetic epidemiological studies is provided and the need to expand surveys of CNV in different population-based cohorts and to apply the information to studies of human variation and disease is discussed.