Review
Genomic Copy Number Variation in Disorders of Cognitive Development

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Objective

To highlight recent discoveries in the area of genomic copy number variation in neuropsychiatric disorders including intellectual disability, autism, and schizophrenia. To emphasize new principles emerging from this area, involving the genetic architecture of disease, pathophysiology, and diagnosis.

Method

Review of studies published in PubMed including classic studies of genomic disorders and microarray and copy number studies in normal controls, intellectual disability, autism, and schizophrenia.

Results

The advent of novel microarray technology has led to a revolution in the discovery of classic and novel copy number variants (CNVs) in various disorders affecting cognitive development. Across autism and schizophrenia, global CNV burden and de novo CNV burden are associated with disease. Also, specific recurrent CNVs may be associated with several DSM conditions. Each condition is also associated with heterogeneous and individually rare CNVs.

Conclusions

CNVs play an important role in the genetic architecture of the childhood neuropsychiatric disorders discussed. This discovery appears to suggest an important role for the strict regulation of gene dosage in the neurodevelopmental roots of these conditions. Microarrays have emerged as high-yield tests in the diagnosis and molecular subtyping of the childhood-onset disorders involving cognitive development. In summary, CNV studies in disorders of cognitive development have revealed interesting and important new insights and have opened an avenue of investigation that holds great promise for neuropsychiatric disease.

Section snippets

CNVs and Advent of Microarrays

Microarray technology has been advancing at a rapid pace and has offered an opportunity to examine changes in “copy number” across the human genome. By way of background, the normal “diploid” male genome has 22 autosomes (non-sex chromosomes) and two sex chromosomes, an X and a Y. The female genome has 22 autosomes and two X chromosomes. One copy of 23 chromosomes is inherited from each parent and is thereby considered “diploid” or “copy number 2” for each chromosome (exceptions to this involve

Early CNV Studies in Neuropsychiatric Illness

Even before microarray technology arrived, a number of “genomic disorders” (characterized by stereotypical losses or gains of genomic segments) had been identified, many of which involve abnormalities of cognitive development (Table 1) and various specific “syndromic features.”6, 14 In addition to Williams syndrome and Smith-Magenis syndrome as stated above, velocardiofacial syndrome (VCFS) is due to a stereotyped deletion of 1.5 to 3 million base pairs on the long-arm of chromosome 22 (22q11.2

CNVs, Genomic Disorders, and ID

Genomic disorders are those that are associated with a known, recurrent deletion or duplication. Numerous such genomic disorders are known and these conditions are most frequently “syndromic” such that they are associated with specific medical conditions, which in the past had raised suspicion and led to FISH testing. In addition, genomic disorders are frequently associated with abnormalities in cognitive development (Table 1). Of particular interest to neuropsychiatry, many of these genomic

CNVs and ASDs

As in ID, numerous studies have presented widely heterogeneous, individually rare, cytogenetic anomalies associated with autistic symptoms.42 Given the association of 15q11-q13 duplications in particular with autism, some hypothesized early that a subset of autism was associated with additional, rare recurrent CNVs. However, testing this hypothesis awaited the advent of dense, genomewide microarray technology. Also, given the occurrence of CNVs in the normal population, testing this hypothesis

CNVs and Schizophrenia

In 2008, a series of critical studies concurrently demonstrated a strong association of numerous, individually rare CNVs with schizophrenia. Studies by Walsh et al.,50 the International Schizophrenia Consortium (ISC),51 and Stefansson et al.52 demonstrated an increase in burden of rare, large CNVs over controls. Stefansson et al. and the ISC identified overlapping recurrent CNVs, including 22q11.2 deletions, but also deletions at 1q21.1 and 15q13.3. Each of these deletions has also been

CNVs and Diagnostic Subtyping

Microarray testing has entered the clinical arena, such that clinicians are sending patient DNA for microarray testing in the setting of a new diagnosis of idiopathic ID and/or autism. It is now widely believed by clinical geneticists that the yield of this testing is high (particularly in the setting of ID and dysmorphology).74, 76 The test is also reimbursed by insurance in many centers. That said, the interpretation of these tests in a diagnostic context is not always certain and relies

Discussion

What have CNV studies taught us about the biology of psychiatric disorders? Indeed, these CNV studies may yield fundamental insights into the genetic architecture and genetic causation of psychiatric disorders. Since the adoption studies of Ingraham and Kety80 and even before, psychiatric disorders have been known to be highly heritable. However, the genetic architecture or the specific mechanism whereby a patient's DNA contributes to an expression of any given disorder has remained elusive.

References (90)

  • E.K. Bijlsma et al.

    Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals

    Eur J Med Genet

    (2009)
  • J.M. Friedman et al.

    Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation

    Am J Hum Genet

    (2006)
  • D.T. Miller et al.

    Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies

    Am J Hum Genet

    (2010)
  • D.H. Geschwind et al.

    Autism spectrum disorders: developmental disconnection syndromes

    Curr Opin Neurobiol

    (2007)
  • M. Karayiorgou et al.

    The molecular genetics of the 22q11-associated schizophrenia

    Brain Res Mol Brain Res

    (2004)
  • E.H. Cook et al.

    Copy-number variations associated with neuropsychiatric conditions

    Nature

    (2008)
  • E.M. Morrow et al.

    Identifying autism loci and genes by tracing recent shared ancestry

    Science

    (2008)
  • OMIM—Online Mendelian Inheritance in Man

  • A.J. Sharp et al.

    Structural variation of the human genome

    Annu Rev Genomics Hum Genet

    (2006)
  • D.F. Conrad et al.

    Origins and functional impact of copy number variation in the human genome

    Nature

    (2009)
  • J.L. Freeman et al.

    Copy number variation: new insights in genome diversity

    Genome Res

    (2006)
  • A.J. Iafrate et al.

    Detection of large-scale variation in the human genome

    Nat Genet

    (2004)
  • J. Sebat et al.

    Large-scale copy number polymorphism in the human genome

    Science

    (2004)
  • S.A. McCarroll et al.

    Common deletion polymorphisms in the human genome

    Nat Genet

    (2006)
  • Database of Genomic Variants

  • J.R. Lupski

    Genomic rearrangements and sporadic disease

    Nat Genet

    (2007)
  • J.R. Lupski

    Genomic rearrangements and sporadic disease

    Nat Genet

    (2007)
  • D. Gothelf et al.

    Genes, brain development and psychiatric phenotypes in velo-cardio-facial syndrome

    Dev Disabil Res Rev

    (2008)
  • A.E. Pulver et al.

    Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives

    J Nerv Ment Dis

    (1994)
  • K.C. Murphy et al.

    High rates of schizophrenia in adults with velo-cardio-facial syndrome

    Arch Gen Psychiatry

    (1999)
  • W. Yan et al.

    Chromosome 22q11.2 interstitial deletions among childhood-onset schizophrenics and “multidimensionally impaired.”

    Am J Med Genet

    (1998)
  • M. Karayiorgou et al.

    Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11

    Proc Natl Acad Sci U S A

    (1995)
  • E.A. Lindsay et al.

    Schizophrenia and chromosomal deletions within 22q11.2

    Am J Hum Genet

    (1995)
  • D.H. Ledbetter et al.

    Deletions of chromosome 15 as a cause of the Prader-Willi syndrome

    N Engl J Med

    (1981)
  • P. Baker et al.

    Brief report: duplication of chromosome 15q11-13 in two individuals with autistic disorder

    J Autism Dev Disord

    (1994)
  • E.H. Cook et al.

    Autism or atypical autism in maternally but not paternally derived proximal 15q duplication

    Am J Hum Genet

    (1997)
  • M.T. Bonati et al.

    Trisomy 15q25.2-qter in an autistic child: genotype-phenotype correlations

    Am J Med Genet A

    (2005)
  • S. Bundey et al.

    Duplication of the 15q11-13 region in a patient with autism, epilepsy and ataxia

    Dev Med Child Neurol

    (1994)
  • J. Clayton-Smith et al.

    Duplication of chromosome 15 in the region 15q11-13 in a patient with developmental delay and ataxia with similarities to Angelman syndrome

    J Med Genet

    (1993)
  • J.A. Thomas et al.

    Genetic and clinical characterization of patients with an interstitial duplication 15q11-q13, emphasizing behavioral phenotype and response to treatment

    Am J Med Genet A

    (2003)
  • U. Bellugi et al.

    I. The neurocognitive profile of Williams Syndrome: a complex pattern of strengths and weaknesses

    J Cogn Neurosci

    (2000)
  • W. Jones et al.

    II. Hypersociability in Williams Syndrome

    J Cogn Neurosci

    (2000)
  • D.J. Levitin

    Musical behavior in a neurogenetic developmental disorder: evidence from Williams Syndrome

    Ann N Y Acad Sci

    (2005)
  • N. Roeleveld et al.

    The prevalence of mental retardation: a critical review of recent literature

    Dev Med Child Neurol

    (1997)
  • National Health Interview Survey on Disability, phase 1 [computer laser optical disks]

    (1996)
  • Cited by (0)

    The author acknowledges research support from the National Institute of Mental Health (1K23MH080954-01) and the Charles H. Hood Child Health Research Foundation and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund.

    Disclosure: Dr. Morrow reports no biomedical financial interests or potential conflicts of interest.

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