ReviewThe 22q11.2 Deletion Syndrome as a Window into Complex Neuropsychiatric Disorders Over the Lifespan
Section snippets
The Neuropsychiatric Phenotype of 22q11DS
The most specific neuropsychiatric phenotype associated with 22q11DS is schizophrenia, as this is the only psychiatric condition that appears to be found at much higher frequency among 22q11.2 microdeletion carriers relative to other neurogenetic and developmental disorders associated with intellectual disability 5, 6. Nevertheless, one third to one half of children with the deletion are diagnosed with attention-deficit/hyperactivity disorder (ADHD), anxiety disorders (most commonly specific
Developmental Trajectories of Neuropsychiatric Phenotypes
Although attention deficits (dimensionally assessed) characterize the vast majority of children with 22q11DS, clinical diagnoses of ADHD are not particularly stable over time (14). Nevertheless, a 4-year longitudinal study (16) recently found that persistence of ADHD into adolescence in 22q11DS is predicted by childhood variables previously documented in the non-22q11DS ADHD literature, including higher rates of familial ADHD and history of childhood depression. These findings suggest that
Sources of Genetic Variability
An initial approach to characterizing genetic variability in 22q11DS was to investigate the effect of the two most common deletion lengths, 1.5 Mb and 3 Mb, on clinical phenotypes. Early studies did not find evidence for effects of deletion size on severity of syndromic features 27, 28, and it has been argued that the 1.5 Mb region contains all of the key genes responsible for the development of the syndrome and associated psychiatric risk 28, 29. However, more recent studies using
Endophenotypes in Mice and Men
Analysis of quantitative traits that lie intermediate between these levels of analysis, such as changes in molecular and cellular properties, brain structure and function, and cognition, may better elucidate the pathophysiologic mechanisms linking structural genetic variation to distal psychiatric phenotypes. Such deep phenotyping approaches in the context of a known genetic model such as 22q11DS allow us to map a relatively homogeneous biological pathway to the development of complex
Biological Mechanisms of Psychotic Symptom Development
Studies in idiopathic schizophrenia have demonstrated a decline in cognitive abilities and other changes in behavior, as well as changes in brain morphology, which precede the onset of overt psychotic symptomology 91, 92, 93, and thus may have utility as predictive biomarkers. Importantly, individuals with 22q11DS and schizophrenia do not differ from patients with idiopathic schizophrenia in terms of core clinical symptoms, including age at onset and course of illness (94), but may differ with
Moving Forward
Collectively, animal studies and candidate gene studies in humans implicate more than one gene within the 22q11.2 locus in the associated neurobehavioral phenotypes, suggesting an oligogenic basis. Evidence for the relevance of some of these genes to neuropsychiatric disorders in non-22q11DS individuals (Table S1 in Supplement 1) suggests that common variants within the 22q11.2 locus may contribute to broader disease risk.
Novel methods in functional genomics and systems biology can shed light
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