The 22q11.2 deletion syndrome as a window into complex neuropsychiatric disorders over the lifespan

Abstract

Evidence is rapidly accumulating that rare, recurrent copy number variants represent large effect risk factors for neuropsychiatric disorders. 22q11.2 deletion syndrome (22q11DS) (velocardiofacial syndrome or DiGeorge syndrome) is the most common known contiguous gene deletion syndrome and is associated with diverse neuropsychiatric disorders across the life span. One of the most intriguing aspects of the syndrome is the variability in clinical and cognitive presentation: children with 22q11DS have high prevalence of autism spectrum, attention deficit, and anxiety disorders, as well as psychotic-like features, and up to 30% of adolescents and adults develop schizophrenia-like psychosis. Recently, cases of early-onset Parkinson's disease in adults have been reported, collectively suggesting a role for disrupted dopaminergic neurotransmission in the observed neuropsychiatric phenotypes. There is also some evidence that 22q11DS-associated autism spectrum disorder and schizophrenia represent two unrelated phenotypic manifestations, consistent with a neuropsychiatric pleiotropy model. This genetic lesion thus provides a unique model for the discovery of specific genomic risk and (potentially) protective factors for neuropsychiatric disease. Here, we provide an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder's heterogeneous presentation are reviewed. Because of its known genetic etiology, animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system.

Keywords: Copy number variant; dopamine; neurodevelopment; pleiotropy; schizophrenia; velocardiofacial/DiGeorge syndrome.

Figure 1. Chromosome 22q and potential sources of genetic variability

(A) Hemizygous 22q11.2 deletion (light purple) and intact chromosome (light pink). To the right, the deleted segment of Chromosome 22 is shown (dark purple). Deletion breakpoints most commonly occur within the four distinct blocks of LCRs that lie in the deletion interval (termed A, B, C, D) (yellow) and deleted genes in the 22q11.2 locus are labeled above the segment (102). The genes COMT and PRODH are highlighted with arrows to indicate specific examples of genetic variability that are discussed in this review. (B) Breakpoint variability. The deleted segment is illustrated with the two most common deletion lengths, 3Mb (green line) and 1.5Mb deletions (red line), though other atypical deletions have been reported (see Supplemental Material). Error bars denote approximate variance in the deletion breakpoints for the 1.5 and 3Mb deletion lengths. The amount of variability in the deletion breakpoints may differ as a function of deletion size (102). The disorder is defined by a deletion in the DiGeorge critical region (DGCR), i.e. the region of the chromosome located between markers D22S36 and D22S788, which flank LCRs A and B. (C) Allelic variation within the intact chromosome and epistasis. The COMT Val¹⁵⁸Met gene variant on the intact chromosome is illustrated as an example of the potential role of allelic variation, involving substitution of a methionine (Met) for valine (Val). As an example of episatasis, PRODH and COMT are illustrated to show the interactive role of the two gene products. Additional sources of variability include, but are not limited to: unmasking of autosomal recessive mutations via hemizygous deletion, parent of origin effects, and epigenetic effects.

Figure 2. Overlapping and Distinct Neuropsychiatric Phenotypes in 22q11DS

(A) As a conceptual illustration of the variability of neuropsychiatric phenotypes in 22q11DS, we include autism spectrum disorder (ASD) (18; 103), attention-deficit/hyperactivity disorder (ADHD) (5), anxiety disorders, and psychosis (5), and estimated comorbidity rates across disorders based on existing literature (8; 103). It is important to note that comorbidity rates are not frequently reported in the literature; this is a critical issue for future research. Additionally, affective dysregulation is present in a substantial proportion of 22q11DS patients, regardless of diagnosis. (B) Developmental trajectories of psychiatric disorders with 22q11DS. As shown in the figure legend, each colored line portrays the estimated prevalence of a particular psychiatric disorder in 22q11DS patients throughout the lifespan. Shaded error bars for each line are illustrated to reflect variability across studies. Each percentage point on the line reflects data from published 22q11DS studies reporting on prevalence rates of anxiety disorder (5; 104), ADHD (5), ASD (18), mood disorder (5) psychotic disorder/schizophrenia (5; 77), and psychotic symptoms (17). In cross-sectional studies, rates of mood disorder (particularly depression) appear to peak in late adolescence and then decline, whereas rates of anxiety remain high through adulthood.

Figure 3. Neuroanatomic Abnormalities in 22q11DS

A) Effect sizes for lobar gray matter reduction in children with 22q11DS relative to typically developing controls, constructed from a meta-analysis of structural MRI studies (45). This effect tends to follow a rostral-caudal gradient. Although not displayed in the figure, effect sizes from subcortical and midline structures are variable, ranging from −0.86 (hippocampus) to −0.20 (amygdala). B) Irregular dendritic branching and abnormal interneuron cortical migration found in 22q11DS murine models (reprinted with permission from Fenelon et al, 2011 (105) and Meechan et al, 2009 (9)). The Dgcr8 gene, within the 22q11.2 locus, is a key component of the microprocessor complex critical for miRNA production. As shown (left panel), Dgcr8^+/− mice show reduced width of basal dendrites of pyramidal neurons in the medial prefrontal cortex (mPFC) compared to wildtype. Although basic synaptic transmission is normal in the mPFC of Dgcr8^+/− mice, short-term synaptic plasticity is impaired, suggesting a neural substrate for cognitive impairment in 22q11DS. Right panel shows abnormal cortical migration of 22q11DS interneurons in the LgDel mouse model (9). While the frequency of calbindin-labeled interneurons did not differ between wildtype and LgDel mice, there is an abberant distribution, indicating disrupted interneuron migration, in the cortex of LgDel mice. C) Model of sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA2)-dependent mechanism of synaptic dysfunction in Dgcr8^+/− mice, described in Earls et al., 2012 (58). SERCA2 upregulation leads to elevated endoplasmic reticulum Ca2+, increasing neurotransmitter release and increased long-term potentiation (LTP) in an age-dependent manner. MicroRNAs miR-25 and miR-185 are known regulators of SERCA2 and are absent in Dgcr8^+/− mice; their restoration rescues LTP, suggesting that miRNA-dependent SERCA2 dysregulation may contribute to learning and neuropsychiatric phenotypes in 22q11DS.

Figure 4. Endophenotypes Relevant to Neuropsychiatric Disorders in 22q11DS

Levels illustrated here indicate how a known genetic etiology can inform pathophysiologic mechanisms relevant to neuropsychiatric phenotypes, using COMT Val158Met genotype as a particular example of how allelic variation in the intact chromosome may contribute to variable phenotypes. Potential sources of genetic variation are indicated in purple, intermediate sources of variability (e.g., endophenotypes) are indicated in gray, and varying phenotypic manifestations are indicated in the bottom row. The line thickness indicates the strength of associations between levels based on existing literature. Increased dopamine (DA) levels were found in patients with 22q11DS, and Met hemizygotes in particular show lower striatal binding potential as compared to Val hemizygotes (82). Studies of structural neuroanatomy have found that Met hemizygotes have smaller frontal lobe volume as compared to Val hemizygotes, which may be associated with inefficient breakdown of DA. One functional neuroimaging study found significantly increased cingulate activity during a Go/NoGo task in Met hemizygotes as compared to Val hemizygotes, implying that the Met subgroup of 22q11DS recruits additional cingulate activation for tasks that require attention and inhibition (53). Several studies have reported significant associations between cognition and COMT genotype such that Met hemizygotes shower better executive functioning (79), although not consistently (53; 81) (see Table S1 for details).