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Background\ud Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population.\ud Methods\ud IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ.\ud Findings\ud We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV.\ud Interpretation\ud Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services.

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 individualswith 22q11DS and 330matched 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, 20.90 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, 20.91 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.

BackgroundWhile genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. Despite this, few studies have investigated electrophysiological activity and connectivity in this high-risk group.MethodsMagnetoencephalography (MEG) was used to investigate resting-state cortical oscillatory patterns in 34 children with 22q11.2DS and 25 controls aged 10-17 years old. Oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, IQ and neurodevelopmental symptoms.ResultsChildren with 22q11.2DS had atypical oscillatory activity and functional connectivity across multiple frequency bands. In the 22q11.2DS group, low frequency (alpha band) activity was positively associated with cognitive ability, while connectivity was negatively associated with ASD and ADHD symptoms. Frontal high frequency (gamma band) activity and connectivity were positively associated with ASD and ADHD symptoms respectively, while posterior gamma activity was negatively associated with ASD symptoms.ConclusionsThese findings highlight that haploinsufficiency at the 22q11.2 locus alters both local and long-range cortical circuitry, which could be a mechanism underlying neurodevelopmental vulnerability in this high risk group.

Objective: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.\ud \ud Methods: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing.\ud \ud Results: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits.\ud \ud Conclusions: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.

22q11.2 deletion syndrome (22q11DS)—a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22—is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6–52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen’s d’s ranging from −0.9 to −1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers. Sin financiación 15.992 JCR (2020) Q1, 10/295 Biochemistry & Molecular Biology 5.071 SJR (2020) Q1, 5/85 Cellular and Molecular Neuroscience No data IDR 2020 UEM

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.

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 (padj = 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. ispartof: Molecular Psychiatry vol:26 issue:8 pages:1-15 ispartof: location:England status: published

ObjectiveCertain copy number variants (CNVs) greatly increase risk of autism. We conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.MethodsThis international study included 547 individuals (12.3 years (SD=4.2), 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers and 45 22q11.2 duplication carriers), as well as 2027 individuals (9.1 years (SD=4.9), 86% male) with autism of heterogeneous aetiology. The Autism Diagnostic Interview-Revised (ADI-R) and IQ testing were conducted.ResultsThe four genetic variant groups differed in autism severity, autism subdomain profile as well as IQ profile. However, we found substantial variability in phenotypic outcome within individual genetic variant groups (74% to 97% of the variance depending on the trait), whereas variability between groups was low (1% to 21% depending on trait). We compared CNV carriers who met autism criteria, to individuals with heterogeneous autism, and a range of profile differences were identified. Using clinical cut-offs, we found that 54% of individuals with one of the 4 CNVs who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic traits.ConclusionMany CNV carriers do not meet full diagnostic criteria for autism, but nevertheless meet clinical cut-offs for autistic traits. Although we find profile differences between variants, there is considerable variability in clinical symptoms within the same variant.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:106 issue:1 pages:26-40 ispartof: location:United States status: published

Diffusion MRI (dMRI) is widely used to study the brain’s white matter (WM) microstructure in a range of psychiatric and neurological diseases. As the diffusion tensor model has limitations in brain regions with crossing fibers, novel diffusion MRI reconstruction models may offer more accurate measures of tissue properties, and a better understanding of the brain abnormalities in specific diseases. Here we studied a large sample of 249 participants with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition associated with high rates of developmental neuropsychiatric disorders, and 224 age-matched healthy controls (HC) (age range: 8-35 years). Participants were scanned with dMRI at eight centers worldwide. Using a meta-analytic approach, we assessed the profile of group differences in four diffusion anisotropy measures to better understand the patterns of WM microstructural abnormalities and evaluate their consistency across alternative measures. When assessed in atlas-defined regions of interest, we found statistically significant differences for all anisotropy measures, all showing a widespread but not always coinciding pattern of effects. The tensor distribution function fractional anisotropy (TDF-FA) showed largest effect sizes all in the same direction (greater anisotropy in 22q11DS than HC). Fractional anisotropy based on the tensor model (FA) showed the second largest effect sizes after TDF-FA; some regions showed higher mean values in 22q11DS, but others lower. Generalized fractional anisotropy (GFA) showed the opposite pattern to TDF-FA with most regions showing lower anisotropy in 22q11DS versus HC. Anisotropic power maps (AP) showed the lowest effect sizes also with a mixed pattern of effects across regions. These results were also consistent across skeleton projection methods, with few differences when projecting anisotropy values from voxels sampled on the FA map or projecting values from voxels sampled from each anisotropy map. This study highlights that different mathematical definitions of anisotropy may lead to different profiles of group differences, even in large, well-powered population studies. Further studies of biophysical models derived from multi-shell dMRI and histological validations may help to understand the sources of these differences. 22q11DS is a promising model to study differences among novel anisotropy/dMRI measures, as group differences are relatively large and there exist animal models suitable for histological validation.

Background Autism is a heterogeneous condition and there is growing evidence that different features are dissociable and may be underpinned by different risk factors. Several autism risk copy number variants (CNVs) have been identified. It remains unclear whether these CNVs differentially impact autism presentation. This study aimed to contrast autism symptomatology and the clinical profile of different autism risk CNVs. Methods Patients were recruited at several international sites based on genotype, not autism phenotype. This work represents the efforts of several consortia; the ECHO study, IMAGINE-ID consortium, International 22q11.2DS Brain Behaviour Consortium, 16p11.2 European Consortium and Simons VIP. Patients were all assessed using the Autism Diagnostic Interview-Revised (ADI-R) and underwent IQ testing. We focused on 16p11.2 deletion (n=96), 16p11.2 duplication (n=47), 22q11.2 deletion (n=383) and 22q11.2 duplication (n=22) carriers. Patients were aged 4–27 years. We examined autism prevalence based on ADI-R criteria, ADI-R domain scores, whether carriers with autism had additional IQ deficits and autism male-to-female ratio. Results Autism prevalence differed by syndrome (p Discussion Autism risk genetic variants have specific genotype-phenotype correlations. This indicates that autism is dissociable at the genetic level, and supports the view that different biological pathways underpin distinct symptom domains.