Journal of the American Academy of Child & Adolescent Psychiatry
ReviewGenomic Copy Number Variation in Disorders of Cognitive Development
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.
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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.