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22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p adj  = 6.73 × 10 -6 ). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

The 22q11.2 deletion syndrome (22q11DS) is a developmental genetic syndrome associated with a 30% risk for developing schizophrenia. Lateral ventricles and subcortical structures are abnormal in this syndrome as well as in schizophrenia. Here, we investigated whether these structures are related in young adults with 22q11DS with and without prodromal symptoms (PS) for schizophrenia and whether abnormalities in volumes are associated with global functioning. MR images were acquired on a 3T scanner from 51 individuals with 22q11DS and 30 healthy controls (mean age: 21±2 years). Correlations were performed to evaluate the relationship between ventricular and subcortical volumes, with Global Assessment of Functioning (GAF) and Premorbid Adjustment Scale (PAS) in each group. Lateral ventricular volumes correlated negatively with subcortical volumes in individuals with 22q11DS. In individuals with 22q11DS with PS only, GAF correlated positively with volumes of the lateral ventricles and negatively with subcortical volumes. PAS correlated negatively with lateral ventricle volumes, and positively with volumes of subcortical structures. The results suggest a common neurodevelopmental mechanism related to the growth of these brain structures. Further, the ratio between the volumes and clinical measures could potentially be used to characterize individuals with 22q11DS and those from the general population for the risk of the development of schizophrenia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: 22q11.2 deletion syndrome (22q11DS) is a common genetic deletion syndrome associated with psychiatric disorders and developmental delays. A significant amount of 22q11DS research literature is published annually; here, we focus exclusively on longitudinal data that have been published in the past 5 years regarding psychiatric disorders and/or cognitive and social development. After a review, areas for future research consideration and clinical recommendations are presented., Methods: Articles were reviewed and organized in adherence with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for conducting systematic reviews. The literature search identified 852 studies, and 22 studies met inclusion criteria., Results: Longitudinal study findings indicate that developmental considerations for youth with 22q11DS should focus on the primacy and enduring nature of social and executive functioning deficits, attention-deficit/hyperactivity disorder, anxiety, and negative symptoms of psychosis., Conclusion: From the diathesis of physiological conditions and genetic variance, 22q11DS and its associated phenotype of persistent cognitive deficits, comorbid psychiatric disorders, and social impairments likely conspire to increase the risk for stress in adolescence. The diathesis-stress framework, along with chronic stress, increases psychosis risk in individuals with 22q11DS. The existing literature has a heavy focus on the impact of the deletion on individual skills and attributes, such as cognition, but lacks information on the impact of the environment. Future 22q11DS research should consider specific aspects of social functioning, including interactions with parenting styles and family communication, as well as high demands in educational settings, as possible risk factors for psychosis., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group., Methods: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female)., Results: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder., Conclusions: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

Background: Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with high rates of psychiatric disorders, including schizophrenia in up to 30% of individuals with the syndrome. Despite this, we know relatively little about trajectories and predictors of persistence of psychiatric disorders from middle childhood to early adulthood. Accordingly, we followed youth over four timepoints, every 3 years, to assess long-term trajectories of attention-deficit hyperactivity disorder (ADHD), anxiety, mood, and psychosis-spectrum disorders (PSDs), as well as medication usage., Methods: Eighty-seven youth with 22q11DS and 65 controls between the ages of 9 and 15 years at the first timepoint (T1; mean age 11.88 ± 2.1) were followed for 9 years (mean age of 21.22 ± 2.01 years at T4). Baseline cognitive, clinical, and familial predictors of persistence were identified for each class of psychiatric disorders., Results: Baseline age and parent-rated hyperactivity scores predicted ADHD persistence [area under curve (AUC) = 0.81]. The presence of family conflict predicted persistence of anxiety disorders (ADs) whereas parent ratings of child internalizing symptoms predicted persistence of both anxiety and mood disorders (MDs) (AUC = 0.84 and 0.83, respectively). Baseline prodromal symptoms predicted persistent and emergent PSDs (AUC = 0.83). Parent-reported use of anti-depressants/anxiolytics increased significantly from T1 to T4., Conclusions: Psychiatric, behavioral, and cognitive functioning during late childhood and early adolescence successfully predicted children with 22q11DS who were at highest risk for persistent psychiatric illness in young adulthood. These findings emphasize the critical importance of early assessments and interventions in youth with 22q11DS.

Objective: 22q11.2 deletion syndrome (DS) or velo-cardio-facial syndrome (VCFS) is a genetic condition that has been identified as the highest genetic risk factor for developing psychotic illnesses. This unique biological nature of 22q11DS provides a valuable opportunity to explore predictive biomarkers of psychosis. In this study, we examined the relationship of cortical thickness and surface area between various brain regions and prodromal symptoms of psychosis., Methods: 75 probands with 22q11DS, 32 age-matched controls and 28 siblings underwent MRIs over 2 or 3 timepoints. Longitudinal mixed model regression analyses, with age as an interaction variable, were carried out to study the differences in longitudinal trajectories of change in average cortical thickness and surface area over 6-9years. Similar analyses were carried out to examine the relationship with positive prodromal symptoms of psychosis., Results: Significant differences were noted in the inferior and superior parietal regions in both the average thickness and longitudinal change in cortical thickness with age between the probands and controls. Significant associations were also noted between regions in the frontal cortex and positive prodromal symptoms among probands. No associations were noted with cortical surface area., Conclusion: Our results indicate that individuals with 22q11DS who develop positive prodromal symptoms demonstrate differential longitudinal trajectories of cortical thickness in some regions of the frontal lobe. Our results suggest that the pruning stage associated with adolescent brain development may be disrupted., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: 22q11.2 Deletion Syndrome (22q11DS) is considered to be a promising cohort to explore biomarkers of schizophrenia risk based on a 30 % probability of developing schizophrenia in adulthood. In this study, we investigated abnormalities in the microstructure of white matter in adolescents with 22q11DS and their specificity to prodromal symptoms of schizophrenia., Methods: Diffusion Magnetic Resonance Imaging (dMRI) data were acquired from 50 subjects with 22q11DS (9 with and 41 without prodromal psychotic symptoms), and 47 matched healthy controls (mean age 18 +/-2 years). DMRI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and compared between groups using the Tract Based Spatial Statistics (TBSS) method. Additionally, correlations between dMRI measures and scores on positive symptoms were performed., Results: Reductions in MD, AD and RD (but not FA) were found in the corpus callosum (CC), left and right superior longitudinal fasciculus (SLF), and left and right corona radiata in the entire 22q11DS group. In addition, the 22q11DS subgroup with prodromal symptoms showed reductions in AD and MD, but no changes in RD when compared to the non-prodromal subgroup, in CC, right SLF, right corona radiata and right internal capsule. Finally, AD values in these tracts correlated with the scores on the psychosis subscale., Conclusion: Microstructural abnormalities in brain white matter are present in adolescent subjects with prodromal psychotic symptoms.

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder., (© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess the extent to which the trajectories of intellectual, academic achievement, executive functioning, attention, working memory, and emotion recognition tests will be predictive of psychosis in young adults with 22q11.2 deletion syndrome (22q11DS)., Methods: Eighty-two participants with 22q11DS were assessed for psychiatric disorders and neuropsychological functioning with validated instruments. Siblings and community controls were employed as comparison groups., Results: Individuals with 22q11DS differed significantly from siblings and controls in longitudinal trajectories of visual and auditory working memory as well as academic achievement. Longitudinal trajectories of cognitive set shifting, reading decoding, and emotion recognition predicted the presence of positive symptoms of psychosis in early adulthood. Cognitive set shifting improved at a slower rate for individuals with 22q11DS + psychosis than those without psychosis. Emotion recognition increased steadily in individuals without psychosis, whereas for those with psychosis, scores increased until approximately 15 years of age, at which point they began to decrease rapidly. A similar, but more subtle effect, was seen for reading decoding., Conclusions: Our data are the first to go beyond IQ assessments in assessing longitudinal neuropsychological outcomes and risk for psychosis in 22q11DS. Individuals with 22q11DS who developed psychotic symptoms improved less appreciably and continued to demonstrate difficulties with cognitive flexibility relative to individuals with 22q11DS who did not have psychotic symptoms. Individuals with 22q11DS who developed psychosis had weaker reading skills in childhood and, after an initial improvement into adolescence, these individuals with psychosis had a decline in reading skills. In 22q11DS, cognitive deficits are both (a) traits that are preexisting and raise the risk for psychosis and (b) associated with the onset of psychotic symptoms. Future research should consider the extent to which cognitive set shifting and reading decoding are related to the Verbal IQ declines observed in the 22q11DS population., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with 22q11.2DS develop schizophrenia, though little is known about the underlying mechanisms. We hypothesized that allelic variation in functional polymorphisms in seven genes unique to the deleted region would affect lobar brain volumes, which would predict risk for psychosis in youth with 22q11.2DS. Participants included 56 individuals (30 males) with 22q11.2DS. Anatomic MR images were collected and processed using Freesurfer. Participants were genotyped for 10 SNPs in the COMT, DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms of psychosis. Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. Our results suggest that RTN4R, a relatively under-studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: 22q11.2 deletion syndrome (22q11DS) is a genetic disorder that greatly increases risk of developing schizophrenia. We previously characterized cerebral surface morphology trajectories from late childhood to mid adolescence in a cohort of youth with 22q11DS. Herein, we extend the study period into early adulthood, and describe further the trajectories associated with severe psychiatric symptoms in this cohort., Methods: Participants included 76 youth with 22q11DS and 30 unaffected siblings, assessed at three timepoints, during which high resolution, anatomic magnetic resonance images were acquired. High-dimensional, nonlinear warping algorithms were applied to images in order to derive characteristics of cerebral surface morphology for each participant at each timepoint. Repeated-measures, linear regressions using a mixed model were conducted, while covarying for age and sex., Results: Alterations in cerebral surface morphology during late adolescence/early adulthood in individuals with 22q11DS were observed in the lateral frontal, orbitofrontal, temporal, parietal, occipital, and cerebellar regions. An Age x Diagnosis interaction revealed that relative to unaffected siblings, individuals with 22q11DS showed age-related surface protrusions in the prefrontal cortex (which remained stable or increased during early adulthood), and surface indentations in posterior regions (which seemed to level off during late adolescence). Symptoms of psychosis were associated with a trajectory of surface indentations in the orbitofrontal and parietal regions., Conclusions: These results advance our understanding of cerebral maturation in individuals with 22q11DS, and provide clinically relevant information about the psychiatric phenotype associated with the longitudinal trajectory of cortical surface morphology in youth with this genetic syndrome., (© 2016 Association for Child and Adolescent Mental Health.)

Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome (22q11DS), is associated with an increased risk of major psychiatric disorders, including schizophrenia. The emergence of psychotic symptoms in individuals with schizophrenia in the general population is often preceded by a premorbid period of poor or worsening social and/or academic functioning. Our current study evaluated premorbid adjustment (via the Cannon-Spoor Premorbid Adjustment Scale [PAS]) and psychotic symptoms (via the Structured Interview for Prodromal Symptoms and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) in youth with 22q11DS (N = 96), unaffected siblings (N = 40), and community controls (N = 50). The PAS scores indicated greater maladjustment during all developmental periods in individuals with 22q11DS compared to the controls. Many participants with 22q11DS had chronically poor (n = 33) or deteriorating (n = 6) PAS scores. In 22q11DS, chronically poor PAS trajectories and poor childhood and early adolescence academic domain and total PAS scores significantly increased the risk of prodromal symptoms or overt psychosis. Taking into account the catechol-O-methyltransferase (COMT) genotype, the best predictor of (prodromal) psychosis was the early adolescence academic domain score, which yielded higher sensitivity and specificity in the subgroup of youth with 22q11DS and the high-activity (valine) allele. PAS scores may help identify individuals at higher risk for psychosis.

Dysfunction of cortical circuitry involving prefrontal cortex, cingulate gyrus and mesial temporal lobe has been implicated in the pathophysiology of psychotic symptoms. 22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that comports a 25-fold increased risk of developing psychosis. Morphological changes in the neuroanatomy of this syndrome may represent a biological risk factor for the development of psychosis. The present study explored ratios between cortical volumes and the amygdala. We also explored relationships between these ratios and the eventual development of psychosis in youth with 22q11DS. A group of 73 individuals with 22q11DS, 32 community controls, and 27 unaffected siblings were followed every three years, at four timepoints. We analyzed baseline ratios between 34 bilateral FreeSurfer-generated cortical volumes and amygdala, and examined whether baseline cortical ratios predicted positive symptoms of psychosis 12 years later, at the 4th timepoint. Youth with 22q11DS demonstrated significantly smaller cortical volume-to-amygdala ratios in left anterior cingulate, occipital and parietal cortices. An increased risk of developing psychotic episodes in individuals with 22q11DS was associated with a lower cortical volume- to-amygdala ratio, suggesting that cortico-limbic circuitry may play an important role in emotional modulation and may underlie the pathophysiology of positive symptoms of psychosis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Importance: Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age., Objective: To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS., Design, Setting, and Participants: Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years)., Main Outcomes and Measures: Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test., Results: Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward., Conclusions and Relevance: In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.

Background: This study utilized diffusion tensor imaging (DTI) to analyze white matter tractography in the anterior limb of the internal capsule (ALIC), fornix, and uncinate fasciculus (UF) of individuals with 22q11.2 deletion syndrome and controls. Aberrations in these tracts have been previously associated with schizophrenia. With up to 25% of individuals with 22q11.2DS developing schizophrenia in adulthood, we hypothesized reduction in structural integrity of these tracts, including an association with prodromal symptoms of psychosis. We further predicted an association between allelic variation in a functional polymorphism of the Nogo-66 receptor gene and 22q11.2DS white matter integrity., Methods: Tractography was conducted using fiber assignment by streamline tracking algorithm in DTI Studio. Subjects were genotyped for the rs701428 SNP of the Nogo-66 receptor gene, and assessed for presence of prodromal symptoms., Results: We found significant group differences between 22q11.2DS and controls in DTI metrics for all three tracts. DTI metrics of ALIC and UF were associated with prodromal symptoms in 22q11.2DS. Further, ALIC DTI metrics were associated with allelic variation of the rs701428 SNP of the Nogo-66 receptor gene in 22q11.2DS., Conclusions: Alterations in DTI metrics suggest white matter microstructural anomalies of the ALIC, fornix, and UF in 22q11.2DS. Structural differences in ALIC appear to be associated with the Nogo-66 receptor gene, which has been linked to myelin-mediated axonal growth inhibition. Moreover, the association between psychosis symptoms and ALIC and UF metrics suggests that the Nogo-66 receptor gene may represent a susceptibility gene for psychosis through its disruption of white matter microstructure and myelin-associated axonal growth., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Up to 30% of young adults with velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) develop schizophrenia or psychosis. Identifying the neuroanatomic trajectories that increase risk for psychosis in youth with this genetic disorder is of great interest., Methods: We acquired high-resolution anatomic magnetic resonance images and measures of psychiatric function on 72 youth with VCFS, 26 unaffected siblings, and 24 age-matched community control subjects at two time points: between late childhood (mean age 11.9 years) and mid-adolescence (mean age 15.1 years)., Results: With the exception of cranial gray matter and orbitofrontal prefrontal cortex, neuroanatomic trajectories in youth with VCFS were comparable to unaffected siblings and community control subjects during this developmental window. However, in youth with VCFS, longitudinal decreases in the volumes of cranial gray and white matter, prefrontal cortex, mesial temporal lobe, and cerebellum were associated with increased combined prodromal symptoms at Time 2. In contrast, only decreases in temporal lobe gray matter volumes (p < .002) and verbal IQ (p < .002) predicted specifically to positive prodromal symptoms of psychosis at Time 2., Conclusions: These findings are in line with studies of non-VCFS individuals at risk for schizophrenia and suggest that early decrements in temporal lobe gray matter may be predictive of increased risk of prodromal psychotic symptoms in youth with VCFS., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To predict prodromal psychosis in adolescents with velocardiofacial syndrome (VCFS)., Method: A total of 70 youth with VCFS, 27 siblings of youth with VCFS, and 25 community controls were followed from childhood (mean age = 11.8 years) into mid-adolescence (mean age = 15.0 years). Psychological tests measuring intelligence, academic achievement, learning/memory, attention, and executive functioning as well as measures of parent and clinician ratings of child psychiatric functioning were completed at both time points., Results: Major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder diagnoses increased in the VCFS sample. With very low false positive rates, the best predictor of adolescent prodromal psychotic symptoms was parent ratings of childhood odd/eccentric symptoms and child performance on a measure of executive functioning, the Wisconsin Card Sorting Test., Conclusions: Similar to the non-VCFS prodromal psychosis literature, a combination of cognitive and psychiatric variables appears to predict psychosis in adolescence. A child with VCFS who screens positive is noteworthy and demands clinical attention.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

ObjectiveChromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants.MethodThe 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years.ResultsAttention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills.ConclusionsTo the authors’ knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.