Key Points
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Children with 22q11.2 deletion syndrome (22q11.2DS) show substantial impairments in several areas of attention. Spatial aspects of attention are likely to contribute to numerical impairments, and executive attention or cognitive control impairments may have a role in later psychosis.
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Most but not all children with 22q11.2DS develop borderline to low average intellectual functioning abilities, with strengths tending to be in verbal domains and weaknesses in non-verbal domains.
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Neural abnormalities seem to occur more in the midline of the brain and in subcortical as well as cortical regions.
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Up to one-third of all individuals carrying the 22q11.2 deletion develop schizophrenia or schizoaffective disorder as defined strictly in the Diagnostic and Statistical Manual of Mental Disorders, although the risk factors that are predictive of the development of psychosis remain unclear and continue to be the focus of active investigation. 22q11.2 deletions account for up to 1–2% of schizophrenia cases and represent the only confirmed recurrent structural mutation responsible for introducing sporadic cases of schizophrenia to the population.
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Work on genetically engineered animal models of 22q11.2DS has uncovered behavioural and cognitive alterations, as well as a number of affected neural processes (such as compromised dendritogenesis, synaptogenesis, neurogenesis and long-range connectivity) and molecular pathways (including abnormal brain microRNA biogenesis, palmitoylation of proteins and dopaminergic activity) that all have important roles in the observed cognitive and behavioural dysfunction.
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Human genetic and animal model studies suggest that the combined effect of the imbalance of several genes in the 22q11.2 deletion determines the overall phenotype.
Abstract
Recent studies are beginning to paint a clear and consistent picture of the impairments in psychological and cognitive competencies that are associated with microdeletions in chromosome 22q11.2. These studies have highlighted a strong link between this genetic lesion and schizophrenia. Parallel studies in humans and animal models are starting to uncover the complex genetic and neural substrates altered by the microdeletion. In addition to offering a deeper understanding of the effects of this genetic lesion, these findings may guide analysis of other copy-number variants associated with cognitive dysfunction and psychiatric disorders.
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Acknowledgements
The authors wish to acknowledge grant support for their work from the US National Institutes of Health (grant R01MH67068 to M.K. and J.A.G. and grant R01HD42974 to T.J.S.). J.A.G. also gratefully acknowledges support from the Simons Foundation and M.K. from the McKnight and March of Dimes Foundations. The authors wish to thank A. Arguello for help with creating figures 2,3 and 4, B. Xu for help with Supplementary information S1 (table) and Supplementary information S3 (figure) and S. Srivastava for help with box 3 and figure 1. The authors also thank A. Arguello, L. Drew, B. Xu and other members of their laboratories for comments and critical feedback.
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Supplementary information
Supplementary information S1 (table)
RefSeq genes located in the most common 3-Mb 22q11.2 microdeletiona (PDF 86 kb)
Supplementary information S2 (table)
DTI results from children with 22q11.2DS (PDF 84 kb)
Supplementary information S3 (figure)
miRNA dysregulation and altered gene expression in 22q11.2 animal models. (PDF 397 kb)
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Glossary
- Microdeletion
-
A submicroscopic loss of a segment of DNA of varying size, typically several kilobases long.
- Breakpoint
-
A specific site of chromosomal breakage associated with a chromosomal abnormality.
- Full scale IQ
-
A standardized composite measure of global intellectual functioning generated from scores in specific domains, such as verbal, perceptual, memory and speeded functions. Typically the median age-adjusted score is 100 ± 15 points.
- Attention
-
A cognitive process that is mainly thought to be involved in selectively processing or focusing on one aspect of the environment at the expense of others. Several types of attention are thought to exist, including focused, sustained and divided attention, each of which seems to depend on different cognitive, neural and neurotransmitter systems.
- Executive function
-
Also referred to as 'cognitive control', this is a broad category of cognitive functions that are generally associated in typical humans with the prefrontal cortex. Executive functions are thought to modulate or control the use of other cognitive resources and include planning, problem solving, error monitoring, decision making and the use of working memory.
- Prepulse inhibition
-
A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a prepulse) before being presented with the startling stimulus. Deficits in prepulse inhibition have been observed in patients with schizophrenia as well as in patients with other psychiatric and neurological disorders.
- Mismatch negativity
-
A component of the electro-encephalographic (EEG) brain response that is typically generated 150–250 ms after an unusual stimulus is detected in a sequence of similar stimuli.
- Diffusion tensor imaging
-
An MRI imaging technique that takes advantage of the restricted diffusion of water through myelinated nerve fibres in the brain to map the anatomical connectivity among brain areas.
- Genetic modifiers
-
Genetic variation in (cis) or outside (trans) a gene or genetic locus that alters the phenotypic expression of the gene.
- Oligogenic
-
A phenotypic trait produced by two or more (but only a few) genes working together.
- Next-generation sequencing
-
High-throughput parallel sequencing of several megabases of DNA.
- Haploinsufficiency
-
The situation in which one copy of a gene is incapable of providing sufficient protein production to ensure normal function.
- Endophenotype
-
A state-independent biomarker or cognitive marker of an illness (present whether or not the illness is active) that is heritable and present in unaffected relatives of subjects that have the illness.
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Karayiorgou, M., Simon, T. & Gogos, J. 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat Rev Neurosci 11, 402–416 (2010). https://doi.org/10.1038/nrn2841
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DOI: https://doi.org/10.1038/nrn2841
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