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The 22q11.2 deletion syndrome (22q11DS) is associated with a 20–25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants. Polygenic risk scores are nearing a level of differentiation required for their clinical utility in risk prediction in populations with high-risk rare pathogenic genetic variants.

To characterize the prevalence of and contributing factors to adult obesity in the most common recurrent copy-number variation (CNV), 22q11.2 deletion, given that other rare CNVs are known to have obesity phenotypes. In 207 adults with 22q11.2 deletion syndrome (22q11.2DS), we used available height and weight measurements to calculate body mass index (BMI) and recorded associated factors that could play a role in obesity. We used the maximum BMI per subject and logistic regression to test a model predicting obesity class. The prevalence of obesity (BMI ≥30) in 22q11.2DS (n = 90, 43.5%; at median age of 26.7 years) was significantly greater than for Canadian norms (odds ratio (OR) 2.30, 95% confidence interval (CI) = 1.74–3.02, P < 0.0001), even after excluding individuals with a history of antipsychotic use. The regression model was significant (P < 0.0001). Psychotropic medication use and age, but not sex or presence of intellectual disability, were associated with higher obesity level. Ten (4.8%) individuals were diagnosed with type 2 diabetes at a median age of 39.5 years; the prevalence was higher in those with obesity (P < 0.01). The results suggest that adult obesity is related to the 22q11.2 deletion. The findings expand the potential genetic causes of obesity and have important implications for management of 22q11.2DS.

22q11.2 deletion and duplication syndromes are complex genetic syndromes composed of a wide spectrum of clinical manifestations, mostly affecting cardiovascular, endocrine, neurodevelopmental, and immune functioning. 22q11.2 deletion syndrome (22q11.2 DS) is more common and widely recognized compared to the duplication counterpart. Most of the literature focuses on delineating the genetic, molecular, and clinical impact of 22q11.2 DS, and less information focuses on the 22q11.2 duplication syndrome (22q11.2 DupS). We will cover both variants in this review and shed light on the less reported atypical 22q11.2 deletions and duplications. Variants in multiple genes in the 22q11.2 region, especially the TBX1 and DGCR8 genes, have been linked to the clinical phenotypes of 22q11.2 DS and 22q11.2 DupS. Variations in genes on the non-deleted homologous chromosome in the critical 22q11.2 region can further influence phenotypes by revealing recessive diseases. This effect has been documented for several genes in this area, such as SNAP29 and GP1BB. Neural crest development is usually impacted leading to various cardiovascular defects including Tetralogy of Fallot and truncus arteriosus. It can also cause palatal defects, especially velopharyngeal deficiency, considered another hallmark of 22q11DS. Individuals may also present with hypocalcemia and thyroid dysfunction due to impaired parathyroid gland formation and thyroid dysgenesis, respectively. Immunodeficiencies result from impaired T-cell development due to thymic hypoplasia, also a consequence of abnormal neural crest development. Humoral defects are also now increasingly recognized in these individuals. Psychiatric, neurocognitive, and developmental features are common, but severity varies across affected individuals. Other systems like the genitourinary, gastrointestinal, skeletal, and hematological are also involved. Monitoring and treating all the possible clinical manifestations require a multi-disciplinary approach to effectively address the plethora of clinical findings. The complex nature of the treatment guidelines reflects the clinical heterogeneity of these genetic variations. Further research is required to continue exploring the mechanisms relating to the impact of genetic aberrations in the 22q11.2 region on various clinical parameters. This will hopefully guide future updates to the current clinical practice guidelines to continue tailoring them to the individual needs of each affected person.

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size ( n =1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

Velocardiofacial syndrome, DiGeorge syndrome, and some other clinical syndromes have in common a high frequency of hemizygous deletions of chromosome 22q11.2. This deletion syndrome is very common, affecting nearly one in 3000 children. Here, we focus on recent advances in cardiac assessment, speech, immunology, and pathophysiology of velocardiofacial syndrome. The complex medical care of patients needs a multidisciplinary approach, and every patient has his own unique clinical features that need a tailored approach. Patients with chromosome 22q11.2 deletion syndrome might have high level of functioning, but most often need interventions to improve the function of many organ systems.

Schizophrenia (SZ) is a highly heterogeneous disorder in both its symptoms and risk factors. One of the most prevalent genetic risk factors for SZ is the hemizygous microdeletion at chromosome 22q11.2 (22q11DS) that confers a 25-fold increased risk. Six of the genes directly disrupted in 22qDS encode for mitochondrial-localizing proteins. Here, we test the hypothesis that stem cell-derived neurons from subjects with the 22q11DS and SZ have mitochondrial deficits relative to typically developing controls. Human iPSCs from four lines of affected subjects and five lines of controls were differentiated into forebrain-like excitatory neurons. In the patient group, we find significant reductions of ATP levels that appear to be secondary to reduced activity in oxidative phosphorylation complexes I and IV. Protein products of mitochondrial-encoded genes are also reduced. As one of the genes deleted in the 22q11.2 region is MRPL40, a component of the mitochondrial ribosome, we generated a heterozygous mutation of MRPL40 in a healthy control iPSC line. Relative to its isogenic control, this line shows similar deficits in mitochondrial DNA-encoded proteins, ATP level, and complex I and IV activity. These results suggest that in the 22q11DS MRPL40 heterozygosity leads to reduced mitochondria ATP production secondary to altered mitochondrial protein levels. Such defects could have profound effects on neuronal function in vivo.

Using two-photon Ca 2+ imaging in hippocampal area CA1 of Df(16)A +/− mice, an animal model of 22q11.2 deletion syndrome, the authors found a reduction in spatial map stability compared to that in wild-type mice, as well as an absence of goal-directed place cell reorganization during goal-oriented spatial learning. Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca 2+ imaging in hippocampal area CA1 of wild-type and Df(16)A +/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A +/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction.

Neuropsychiatric disorders are common in 22q11.2 Deletion Syndrome (22q11DS) with about 25% of affected individuals developing schizophrenia spectrum disorders by young adulthood. Longitudinal evaluation of psychosis spectrum features and neurocognition can establish developmental trajectories and impact on functional outcome. 157 youth with 22q11DS were assessed longitudinally for psychopathology focusing on psychosis spectrum symptoms, neurocognitive performance and global functioning. We contrasted the pattern of positive and negative psychosis spectrum symptoms and neurocognitive performance differentiating those with more prominent Psychosis Spectrum symptoms (PS+) to those without prominent psychosis symptoms (PS-). We identified differences in the trajectories of psychosis symptoms and neurocognitive performance between the groups. The PS+ group showed age associated increase in symptom severity, especially negative symptoms and general nonspecific symptoms. Correspondingly, their level of functioning was worse and deteriorated more steeply than the PS- group. Neurocognitive performance was generally comparable in PS+ and PS- groups and demonstrated a similar age-related trajectory. However, worsening executive functioning distinguished the PS+ group from PS- counterparts. Notably, of the three executive function measures examined, only working memory showed a significant difference between the groups in rate of change. Finally, structural equation modeling showed that neurocognitive decline drove the clinical change. Youth with 22q11DS and more prominent psychosis features show worsening of symptoms and functional decline driven by neurocognitive decline, most related to executive functions and specifically working memory. The results underscore the importance of working memory in the developmental progression of psychosis.

A major genetic risk factor for psychosis is 22q11.2 deletion (22q11.2DS). However, robust and replicable functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis remain elusive due to small sample sizes and a focus on small single-site cohorts. Here, we identify functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis, and their links with idiopathic early psychosis, using one of the largest multi-cohort data to date. We obtained multi-cohort clinical phenotypic and task-free fMRI data from 856 participants (101 22q11.2DS, 120 idiopathic early psychosis, 101 idiopathic autism, 123 idiopathic ADHD, and 411 healthy controls) in a case-control design. A novel spatiotemporal deep neural network (stDNN)-based analysis was applied to the multi-cohort data to identify functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis. Next, stDNN was used to test the hypothesis that the functional brain signatures of 22q11.2DS-associated psychosis overlap with idiopathic early psychosis but not with autism and ADHD. stDNN-derived brain signatures distinguished 22q11.2DS from controls, and 22q11.2DS-associated psychosis with very high accuracies (86–94%) in the primary cohort and two fully independent cohorts without additional training. Robust distinguishing features of 22q11.2DS-associated psychosis emerged in the anterior insula node of the salience network and the striatum node of the dopaminergic reward pathway. These features also distinguished individuals with idiopathic early psychosis from controls, but not idiopathic autism or ADHD. Our results reveal that individuals with 22q11.2DS exhibit a highly distinct functional brain organization compared to controls. Additionally, the brain signatures of 22q11.2DS-associated psychosis overlap with those of idiopathic early psychosis in the salience network and dopaminergic reward pathway, providing substantial empirical support for the theoretical aberrant salience-based model of psychosis. Collectively, our findings, replicated across multiple independent cohorts, advance the understanding of 22q11.2DS and associated psychosis, underscoring the value of 22q11.2DS as a genetic model for probing the neurobiological underpinnings of psychosis and its progression.

The thalamus-enriched microRNA miR-338-3p is depleted in mouse models of 22q11.2 deletion syndrome and in humans with schizophrenia, leading to a late-onset dysfunction of auditory thalamocortical synaptic transmission, behavioral abnormalities and altered sensitivity to antipsychotics. Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.