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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.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Background: The 22q11.2 deletion syndrome (22q11DS) is associated with a variety of neuropsychiatric outcomes that vary across deletion carriers. We adopted a dimensional approach to provide a comprehensive overview of neuropsychiatric symptom expression in adolescents with 22q11DS and further our understanding of the observed phenotypical heterogeneity., Methods: Participants were 208 adolescents with 22q11DS between 10 and 19 years old. Semi-structured clinical interviews and IQ tests were used to quantify symptom expression on multiple symptom dimensions, some reflecting DSM-IV diagnostic domains. We investigated symptom expression in those with and without a formal DSM-IV classification and examined between and within symptom dimensions. We used correlation analyses to explore associations between different symptom dimensions., Results: We demonstrated inter-individual differences in symptom expression, both between and within neuropsychiatric symptom dimensions. On most symptom dimensions, more than 50% of adolescents expressed at least one clinically relevant symptom. In addition, a significant proportion of youth without a formal DSM-IV diagnosis reported clinically relevant symptoms (e.g. >85% of those without an ADHD diagnosis reported ADHD symptoms). The exploratory correlation analysis indicated mostly positive correlations between symptom dimensions., Conclusions: The finding that most adolescents with 22q11DS express neuropsychiatric symptoms, even in the absence of a DSM-IV classification, has substantial ramifications for guiding adequate support. Findings may spur further research into the dimensional structure of neuropsychiatric symptoms in 22q11DS and aid in uncovering mechanisms that contribute to symptom expression. Ultimately, this provides leads to improve clinical care for 22q11DS and to understand phenotypical variation in other high-risk genetic variants., (© 2024 The Author(s). Journal of Intellectual Disability Research published by MENCAP and John Wiley & Sons Ltd.)

Introduction: Adolescent idiopathic scoliosis (AIS) and schizophrenia (SCZ) are two distinct conditions with poorly understood aetiologies that both emerge in otherwise healthy young adolescents. One rare genetic condition associated with both phenotypic outcomes is the 22q11.2 deletion (22q11DS). This microdeletion, encompassing 47 genes, occurs in approximately 1 in 2,148 live births and confers a 20-fold higher risk for both AIS and schizophrenia compared to the general population. In the general population (non-22q11DS carriers), AIS and SCZ have also been reported to be related and genetic studies suggest the involvement of genetic variants implicated in the central nervous functioning. In this study, our objective was to further investigate genetic overlaps between these conditions in the general population. Specifically, we aimed to explore the role of genes within the 22q11.2 region, not only in terms of common variants but also their potential impact on gene networks and biopathways., Methods: We used summary statistics from three genome-wide association studies (GWAS): two focused on AIS (n = 11,210), and one on schizophrenia (n = 36,989). To explore potential overlaps between the two conditions, we conducted a comparative analysis on the significance-based ranked single nucleotide polymorphisms (SNPs) that are associated with both AIS and SCZ. Next, we employed in silico analyses to assess gene-networks enrichment for the most significant SNPs and investigate the contribution of genes within the 22q11.2 region. Post-hoc analysis was conducted to explore the biological pathways correlated with SNPs significantly associated with both AIS and SCZ., Results: The in silico analyses revealed a significant (adjusted-p < 0.05) genetic overlap between SCZ and both AIS cohorts. The top 3% of the most significant SNPs associated with both conditions exhibited a distinct enrichment cluster which is unlikely to be a result of chance (p < 3e-04). The gene-networks analyses showed a significant overlap of 26-41% with the ones involving genes in the 22q11DS region. However, there was no overlap between SNPs in this region and the most significant SNPs identified in the GWAS., Conclusion: This study revealed compelling evidence that beyond the shared association with 22q11DS as a rare genetic variant, AIS and SCZ exhibit common genetic risk variants and an overlap of important genes. The gene networks enriched by the most significant SNPs for both conditions also intersect with the ones involving genes in the 22q11DS region. However, SNPs within this region were not overrepresented among the most significant SNPs from GWAS for both conditions. Notably, gene networks linked to the risk for both conditions suggest an involvement of biopathways related to cellular signaling and neuronal development., (© 2024. The Author(s).)

Aim: A first episode of psychosis (FEP) is a stressful, often life-changing experience. Scarce information is available about personal preferences regarding their care needs during and after a FEP. Whereas a more thorough understanding of these preferences is essential to aid shared decision-making during treatment and improve treatment satisfaction., Methods: Face-to-face interviews with participants in remission of a FEP were set up, addressing personal preferences and needs for care during and after a FEP. The interviews were conducted by a female and a male researcher, the latter being an expert with lived experience., Results: Twenty individuals in remission of a FEP were interviewed, of which 16 had been hospitalized. The distinguished themes based on personal preferences were tranquillity, peace and quietness, information, being understood, support from significant others, and practical guidance in rebuilding one's life. Our findings revealed that the need for information and the need to be heard were often not sufficiently met. For 16/20 participants, the tranquillity of inpatient treatment of the FEP was predominantly perceived as a welcome safe haven. The presence and support of family and close friends were mentioned as an important factor in the process of achieving remission., Conclusions: The current exploratory study showed that patients were able to indicate their personal needs. Important findings are the need for information and the need to be heard. Interestingly, hospitalization was mostly seen as an opportunity to achieve tranquillity. More lived experience expertise is needed to elucidate the needs of individuals in the early phase of a FEP to aid people who are recovering from their first psychosis in rebuilding their lives again., (© 2023 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and "behavioural issues", or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era., (© 2024. The Author(s).)

We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health and cognition in a community sample of 7100 unrelated children and youth of European or East Asian ancestry (Spit for Science). Clinically significant or susceptibility CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of attention-deficit/hyperactivity disorder (ADHD) traits (P = 5.0 × 10-3), longer response inhibition (a cognitive deficit found in several mental health and neurodevelopmental disorders; P = 1.0 × 10-2) and increased prevalence of mental health diagnoses (P = 1.9 × 10-6, odds ratio: 3.09), specifically ADHD, autism spectrum disorder anxiety and learning problems/learning disorder (P's < 0.01). There was an increased burden of rare deletions in gene-sets related to brain function or expression in brain associated with more ADHD traits. With the current mental health crisis, our data established a baseline for delineating genetic contributors in pediatric-onset conditions., (© The Author(s) 2023. Published by Oxford University Press.)

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD., (© 2023. The Author(s).)

Background: Executive functioning (EF) is an umbrella term for various cognitive functions that play a role in monitoring and planning to effectuate goal-directed behavior. The 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome, is associated with a multitude of both somatic and cognitive symptoms, including EF impairments in school-age and adolescence. However, results vary across different EF domains and studies with preschool children are scarce. As EF is critically associated with later psychopathology and adaptive functioning, our first aim was to study EF in preschool children with 22q11DS. Our second aim was to explore the effect of a congenital heart defects (CHD) on EF abilities, as CHD are common in 22q11DS and have been implicated in EF impairment in individuals with CHD without a syndromic origin., Methods: All children with 22q11DS (n = 44) and typically developing (TD) children (n = 81) were 3.0 to 6.5 years old and participated in a larger prospective study. We administered tasks measuring visual selective attention, visual working memory, and a task gauging broad EF abilities. The presence of CHD was determined by a pediatric cardiologist based on medical records., Results: Analyses showed that children with 22q11DS were outperformed by TD peers on the selective attention task and the working memory task. As many children were unable to complete the broad EF task, we did not run statistical analyses, but provide a qualitative description of the results. There were no differences in EF abilities between children with 22q11DS with and without CHDs., Conclusion: To our knowledge, this is the first study measuring EF in a relatively large sample of young children with 22q11DS. Our results show that EF impairments are already present in early childhood in children with 22q11DS. In line with previous studies with older children with 22q11DS, CHDs do not appear to have an effect on EF performance. These findings might have important implications for early intervention and support the improvement of prognostic accuracy., (© 2023. The Author(s).)

22q11.2 deletion is one of the strongest known genetic risk factors for schizophrenia. Recent whole-genome sequencing of schizophrenia cases and controls with this deletion provided an unprecedented opportunity to identify risk modifying genetic variants and investigate their contribution to the pathogenesis of schizophrenia in 22q11.2 deletion syndrome. Here, we apply a novel analytic framework that integrates gene network and phenotype data to investigate the aggregate effects of rare coding variants and identified modifier genes in this etiologically homogenous cohort (223 schizophrenia cases and 233 controls of European descent). Our analyses revealed significant additive genetic components of rare nonsynonymous variants in 110 modifier genes (adjusted P = 9.4E-04) that overall accounted for 4.6% of the variance in schizophrenia status in this cohort, of which 4.0% was independent of the common polygenic risk for schizophrenia. The modifier genes affected by rare coding variants were enriched with genes involved in synaptic function and developmental disorders. Spatiotemporal transcriptomic analyses identified an enrichment of coexpression between modifier and 22q11.2 genes in cortical brain regions from late infancy to young adulthood. Corresponding gene coexpression modules are enriched with brain-specific protein-protein interactions of SLC25A1, COMT, and PI4KA in the 22q11.2 deletion region. Overall, our study highlights the contribution of rare coding variants to the SCZ risk. They not only complement common variants in disease genetics but also pinpoint brain regions and developmental stages critical to the etiology of syndromic schizophrenia., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics., (© 2022. The Author(s).)

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic., Competing Interests: Declaration of interests E. Anagnostou has received consultation fees from Roche, Quadrant, and Oron; grant funding from Roche; in-kind supports from AMO Pharma and CRR; editorial honoraria from Wiley; and book royalties from APPI and Springer. She co-holds a patent for the device Anxiety Meter (patent # US20160000365A1). S.W.S. is on the Scientific Advisory Committee of Population Bio and serves as a Highly Cited Academic Advisor for King Abdulaziz University, and intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Genotype-first and within-family studies can elucidate factors that contribute to psychiatric illness. Combining these approaches, we investigated the patterns of influence of parental scores, a high-impact variant, and schizophrenia on dimensional neurobehavioral phenotypes implicated in major psychiatric disorders., Methods: We quantitatively assessed cognitive (FSIQ, VIQ, PIQ), social, and motor functioning in 82 adult individuals with a de novo 22q11.2 deletion (22 with schizophrenia), and 148 of their unaffected parents. We calculated within-family correlations and effect sizes of the 22q11.2 deletion and schizophrenia, and used linear regressions to assess contributions to neurobehavioral measures., Results: Proband-parent intra-class correlations (ICC) were significant for cognitive measures (e.g. FSIQ ICC = 0.549, p < 0.0001), but not for social or motor measures. Compared to biparental scores, the 22q11.2 deletion conferred significant impairments for all phenotypes assessed (effect sizes -1.39 to -2.07 s.d.), strongest for PIQ. There were further decrements in those with schizophrenia. Regression models explained up to 37.7% of the variance in IQ and indicated that for proband IQ, parental IQ had larger effects than schizophrenia., Conclusions: This study, for the first time, disentangles the impact of a high-impact variant from the modifying effects of parental scores and schizophrenia on relevant neurobehavioral phenotypes. The robust proband-parent correlations for cognitive measures, independent of the impact of the 22q11.2 deletion and of schizophrenia, suggest that, for certain phenotypes, shared genetic variation plays a significant role in expression. Molecular genetic and predictor studies are needed to elucidate shared factors and their contribution to psychiatric illness in this and other high-risk groups.

Purpose: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not., Methods: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship., Results: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants., Conclusion: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs., Competing Interests: Conflict of Interest A.Br. is a shareholder of and employed by Natera. A.Br. has also been an employee of Invitae and Quest Diagnostics commercial laboratories. A.R.C. and K.B. are shareholders of and employed by Illumina, Inc. A.Be. is a shareholder of and is employed by Invitae. B.B. has received research support from Biomarin Pharmaceuticals Inc. He is currently employed by and is a shareholder of Alnylam Pharmaceuticals, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: In people with cognitive impairment, loss of social interactions has a major impact on well-being. Therefore, patients would benefit from early detection of symptoms of social withdrawal. Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone apps, which measure social behavior passively and objectively., Objective: This study uses the remote monitoring smartphone app Behapp to assess social behavior, and aims to investigate (1) the association between social behavior, demographic characteristics, and neuropsychiatric symptoms in cognitively normal (CN) older adults, and (2) if social behavior is altered in cognitively impaired (CI) participants. In addition, we explored in a subset of individuals the association between Behapp outcomes and neuropsychiatric symptoms., Methods: CN, subjective cognitive decline (SCD), and CI older adults installed the Behapp app on their own Android smartphone for 7 to 42 days. CI participants had a clinical diagnosis of mild cognitive impairment (MCI) or Alzheimer-type dementia. The app continuously measured communication events, app use and location. Neuropsychiatric Inventory (NPI) total scores were available for 20 SCD and 22 CI participants. Linear models were used to assess group differences on Behapp outcomes and to assess the association of Behapp outcomes with the NPI., Results: We included CN (n=209), SCD (n=55) and CI (n=22) participants. Older cognitively normal participants called less frequently and made less use of apps (P<.05). No sex effects were found. Compared to the CN and SCD groups, CI individuals called less unique contacts (β=-0.7 [SE 0.29], P=.049) and contacted the same contacts relatively more often (β=0.8 [SE 0.25], P=.004). They also made less use of apps (β=-0.83 [SE 0.25], P=.004). Higher total NPI scores were associated with further traveling (β=0.042 [SE 0.015], P=.03)., Conclusions: CI individuals show reduced social activity, especially those activities that are related to repeated and unique behavior, as measured by the smartphone app Behapp. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with Behapp. This research shows that the Behapp app is able to objectively and passively measure altered social behavior in a cognitively impaired population., (©Marijn Muurling, Lianne M Reus, Casper de Boer, Sterre C Wessels, Raj R Jagesar, Jacob A S Vorstman, Martien J H Kas, Pieter Jelle Visser. Originally published in JMIR Aging (https://aging.jmir.org), 20.05.2022.)

Background: Genomic loci where recurrent pathogenic copy number variants are associated with psychiatric phenotypes in the population may also be sensitive to the collective impact of multiple functional low-frequency single nucleotide variants (SNVs)., Methods: We examined the cumulative impact of low-frequency, functional SNVs within the 22q11.2 region on schizophrenia risk in a discovery cohort and an independent replication cohort (N = 1933 and N = 11,128, respectively), as well as the impact on educational attainment (EA) in a third, independent, general population cohort (N = 2081). In the discovery and EA cohorts, SNVs were identified using genotyping arrays; in the replication cohort, whole-exome sequencing was available. For verification, we compared the regional SNV count for schizophrenia cases in the discovery cohort with a normative count distribution derived from a large population dataset (N = 26,500) using bootstrap procedures., Results: In both schizophrenia cohorts, an increased regional SNV burden (≥4 low-frequency SNVs) in the 22q11.2 region was associated with schizophrenia (discovery cohort: odds ratio = 7.48, p = .039; replication cohort: odds ratio = 1.92, p = .004). In the EA cohort, an increased regional SNV burden at 22q11.2 was associated with decreased EA (odds ratio = 4.65, p = .049). Comparing the SNV count for schizophrenia cases with a normative distribution confirmed the unique nature of the distribution for schizophrenia cases (p = .002)., Conclusions: In the general population, an increased burden of low-frequency, functional SNVs in the 22q11.2 region is associated with schizophrenia risk and a decrease in EA. These findings suggest that in addition to structural variation, a cumulative regional burden of low-frequency, functional SNVs in the 22q11.2 region can also have a relevant phenotypic impact., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with increased risk of neurodevelopmental phenotypes including autism spectrum disorders (ASD) and intellectual impairment. The typically deleted region in 22q11.2DS contains multiple genes with the potential of altering metabolism. Deficits in metabolic processes during early brain development may help explain the increased prevalence of neurodevelopmental phenotypes seen in 22q11.2DS. However, relatively little is known about the metabolic impact of the 22q11.2 deletion, while such insight may lead to increased understanding of the etiology. We performed untargeted metabolic analysis in a large sample of dried blood spots derived from 49 22q11.2DS patients and 87 controls, to identify a metabolic signature for 22q11.2DS. We also examined trait-specific metabolomic patterns within 22q11.2DS patients, focusing on intelligence (intelligence quotient, IQ) and ASD. We used the Boruta algorithm to select metabolites distinguishing patients from controls, patients with ASD from patients without, and patients with an IQ score in the lowest range from patients with an IQ score in the highest range. The relevance of the selected metabolites was visualized with principal component score plots, after which random forest analysis and logistic regression were used to measure predictive performance of the selected metabolites. Analysis yielded a distinct metabolic signature for 22q11.2DS as compared to controls, and trait-specific (IQ and ASD) metabolomic patterns within 22q11.2DS patients. The metabolic characteristics of 22q11.2DS provide insights in biological mechanisms underlying the neurodevelopmental phenotype and may ultimately aid in identifying novel therapeutic targets for patients with developmental disorders., (© 2022. The Author(s).)

Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition, and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes to Mental Health Network (G2MH) is a newly funded National Institute of Mental Health initiative that will collect, share, and analyze large-scale data sets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. The authors present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions and discuss strategies that will be pursued within the G2MH network, as well as how expected results can be translated into clinical practice to improve patient outcomes.

Background: In recent years, technological advances have led to the identification of numerous genetic variations that are associated with psychiatric symptoms. Establishing a genetic cause may provide patients and family members with an explanation for the problems and in specific cases allows targeted treatment of psychiatric and somatic (co)morbidity. At present, patients with psychiatric disorders are rarely referred for genetic testing., Aim: To provide an overview of literature and (inter)national guidelines in the field of genetic testing for patients with psychiatric disorder, and to present guidance on indications for genetic testing in clinical practice., Method: A systematic search was conducted in PubMed and Embase focusing on articles with recommendations on genetic testing in psychiatric disorders. In addition, national and international guidelines on genetic testing in psychiatry were studied. The main findings were summarized in an infographic., Results: Based on the current literature and (inter)national guidelines, patients with (comorbid) intellectual disability should always be referred to a clinical geneticist. Psychiatrists should consider genetic testing in patients with other psychiatric disorders if there are &lsquo;red flags&rsquo; such as a positive family history, congenital abnormalities, developmental delay, dysmorphic features, movement disorders or cognitive decline. Psychiatrists may request genetic testing themselves or refer patients to clinical geneticists., Conclusion: Psychiatric disorders may be underpinned by a genetic anomaly, particularly in patients presenting with psychiatric as well as somatic symptomatology. Psychiatrists should recognize symptoms and warning signs indicative of an underlying genetic abnormality, and know when to refer their patients for genetic testing.

Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants" a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants., (© 2021 New York Academy of Sciences.)

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.)

Hyperprolinemia Type I and II are genetic metabolic disorders caused by disrupted proline degradation. It has been suggested that hyperprolinemia is associated with increased risk of developmental and mental disorders but detailed information on the psychiatric phenotype in hyperprolinemic patients is limited. Following PRISMA guidelines, we carried out a systematic review to clarify psychiatric phenotypes in patients with hyperprolinemia. We screened 1753 studies and included 35 for analysis, including 20 case reports and 15 case-control and cohort studies. From these studies, a common psychiatric phenotype is observed with a high prevalence of developmental delay, intellectual disability, autism spectrum disorders, and psychosis spectrum disorders. In most cases, a genetic cause of hyperprolinemia was known, these included mutations in the PRODH and ALDH4A1 genes and deletions of chromosome 22q11.2. No evidence for a biochemical phenotype-clinical phenotype correlation was found; that is, no association between higher proline levels and specific psychiatric phenotypes was observed. This suggests that genomic and environmental factors are likely to contribute to clinical outcomes. More studies are needed to clarify whether hyperprolinemia is a primary causal factor underlying the increased risk of developing psychiatric disorders seen in patients with hyperprolinemia, or whether hyperprolinemia and psychiatric disorders are both consequences of a shared underlying mechanism., (© 2021 Wiley Periodicals LLC.)

Purpose of Review: The 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for schizophrenia. Compared to other rare structural pathogenic genetic variants, 22q11DS is relatively common and one of the most extensively studied. This review provides a state-of-the-art overview of current insights regarding associated neurodevelopmental phenotypes and potential implications for 22q11DS and beyond., Recent Findings: We will first discuss recent findings with respect to neurodevelopmental phenotypic expression associated with 22q11DS, including psychotic disorders, intellectual functioning, autism spectrum disorders, as well as their interactions. Second, we will address considerations that are important in interpreting these data and propose potential implications for both the clinical care for and the empirical study of individuals with 22q11DS. Third, we will highlight variable penetrance and pleiotropy with respect to neurodevelopmental phenotypes in 22q11DS. We will discuss how these phenomena are consistently observed in the context of virtually all rare pathogenic variants and that they pose substantial challenges from both a clinical and a research perspective. We outline how 22q11DS could be viewed as a genetic model for studying neurodevelopmental phenotypes. In addition, we propose that 22q11DS research can help elucidate mechanisms underlying variable expression and pleiotropy of neurodevelopmental phenotypes, insights that are likely relevant for 22q11DS and beyond, including for individuals with other rare pathogenic genetic variants and for individuals with idiopathic neurodevelopmental conditions.

The COVID-19 pandemic has led to unprecedented societal changes limiting us in our mobility and our ability to connect with others in person. These unusual but widespread changes provide a unique opportunity for studies using digital phenotyping tools. Digital phenotyping tools, such as mobile passive monitoring platforms (MPM), provide a new perspective on human behavior and hold promise to improve human behavioral research. However, there is currently little evidence that these tools can reliably detect changes in behavior. Considering the Considering the COVID-19 pandemic as a high impact common environmental factor we studied potential impact on behavior of participants using our mobile passive monitoring platform BEHAPP that was ambulatory tracking them during the COVID-19 pandemic. We pooled data from three MPM studies involving Schizophrenia (SZ), Major Depressive Disorder (MDD) and Bipolar Disorder (BD) patients (N = 12). We compared the data collected on weekdays during three weeks prior and three weeks subsequent to the start of the quarantine. We hypothesized an increase in communication and a decrease in mobility. We observed a significant increase in the total time spent on communication applications (median 179 and 243 min per week respectively, p = 0.005), and a significant decrease in the number of unique places visited (median 6 and 3 visits per week respectively, p = 0.007), while the total time spent at home did not change significantly (median 64 and 77 h per week, respectively, p = 0.594). The data provides a proof of principle that digital phenotyping tools can identify changes in human behavior incited by a common external environmental factor., Competing Interests: Conflict of Interest Authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

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.

Background: 22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with an increased risk of psychiatric disorders. Vulnerability for psychopathology has been related to an increased reactivity to stress. Here, we examined affective states, perceived stress, affective and psychotic reactivity to various sources of environmental stress using the experience sampling method (ESM), a structured diary technique allowing repeated assessments in the context of daily life., Methods: Adults with 22q11DS (n = 31; age, 34.1 years) and matched healthy controls (HCs; n = 24; age, 39.9 years) were included. ESM was used to assess affective states, perceived stress, and stress reactivity. Data were analyzed using multilevel regression models., Results: Adults with 22q11DS displayed overall higher levels of negative affect but comparable levels of positive affect compared to HCs. Higher levels of perceived stress were reported by individuals with 22q11DS. Comparable affective and psychotic reactivity in relation to all types of environmental stress was observed between the two groups., Conclusion: The results point toward higher levels of negative affect and differences in the perception of daily hassles in 22q11DS but no difference in affective or psychotic reactivity to stress. This study contributes to the growing literature regarding the impact of stress on the development of psychopathology in the 22q11DS population.

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.

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

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., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of >1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal 'allelic' homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: 22q11.2 deletion syndrome (22q11DS), one of the most common recurrent copy number variant disorders, is associated with dopaminergic abnormalities and increased risk for psychotic disorders., Aims: Given the elevated prevalence of substance use and dopaminergic abnormalities in non-deleted patients with psychosis, we investigated the prevalence of substance use in 22q11DS, compared with that in non-deleted patients with psychosis and matched healthy controls., Method: This cross-sectional study involved 434 patients with 22q11DS, 265 non-deleted patients with psychosis and 134 healthy controls. Psychiatric diagnosis, full-scale IQ and COMT Val158Met genotype were determined in the 22q11DS group. Substance use data were collected according to the Composite International Diagnostic Interview., Results: The prevalence of total substance use (36.9%) and substance use disorders (1.2%), and weekly amounts of alcohol and nicotine use, in patients with 22q11DS was significantly lower than in non-deleted patients with psychosis or controls. Compared with patients with 22q11DS, healthy controls were 20 times more likely to use substances in general (P < 0.001); results were also significant for alcohol and nicotine use separately. Within the 22q11DS group, there was no relationship between the prevalence of substance use and psychosis or COMT genotype. Male patients with 22q11DS were more likely to use substances than female patients with 22q11DS., Conclusions: The results suggest that patients with 22q11DS are at decreased risk for substance use and substance use disorders despite the increased risk of psychotic disorders. Further research into neurobiological and environmental factors involved in substance use in 22q11DS is necessary to elucidate the mechanisms involved., Declaration of Interest: None.

22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson's disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders. 1 Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised. 2 Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain. 3-5 Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype. 3,5 In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1 , SEH1L , LDLRAD4 , GNAL , GNG13 , MKRN1 , DCTN2, KNDC1 , PCMTD2 , KIF5A , SYNM , and long non-coding RNAs: AK127244 and PTCHD1-AS . We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants., Competing Interests: Competing interestsS.W.S. serves on the Scientific Advisory Committees of Population Bio and Deep Genomics; intellectual property originating from his research and held at the Hospital for Sick Children is licensed to Lineagen, and separately Athena Diagnostics. D.M. is a full-time employee of Deep Genomics and is entitled to a stock option. R.J.S., P.D.A., and J.C. consult for Highland Therapeutics. Intellectual property from ADHD research at the Hospital for Sick Children is licensed to Ehave and the National Research Council of Canada. Other authors declare no competing interests for the data and interpretation presented in this study. R.J.S., P.D.A., and J.C. consults for Highland Therapeutics. Intellectual property from their research at the Hospital for Sick Children is licensed to Ehave and the National Research Council. D.M. is a full-time employee of Deep Genomics and is entitled to stock options. S.W.S. is on the Scientific Advisory Committees of Population Bio and Deep Genomics; intellectual property from his research held at the Hospital for Sick Children is licensed to Athena Diagnostics, and separately to Lineagen. These relationships did not influence data interpretation or presentation during this study, but are disclosed for potential future consideration., (© The Author(s) 2019.)

Adolescent idiopathic scoliosis (AIS), defined as a lateral deviation of the spine of at least ten degrees, is a classic enigma in orthopaedics and affects 1-4% of the general population. Despite (over) a century of intensive research, the etiology is still largely unknown. One of the major problems in all existing AIS research is the fact that most patients come to medical attention after onset of the curve. Therefore, it is impossible to know whether current investigated parameters are causative, or an effect of the scoliosis. Moreover, up until now there is no known animal model that captures the core features of AIS. In order to identify causal pathways leading to AIS we propose another approach, which has been of great value in other medical disciplines: To use a subset of the population, with a higher risk for a certain disease as a "model" for the general population. Such a "model" may allow the identification of causative mechanisms that might be applicable to the general population. The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome and occurs in ∼1:3000-6000 children and 1:1000 pregnancies. Nearly half of the population of patients with 22q11.2DS develop a scoliosis that in most cases resembles AIS as far as age at onset and curve pattern. We postulate that within 22q11.2DS certain causal pathways leading to scoliosis can be identified and that these are applicable to the general population., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Identifying factors that influence the functional outcome is an important goal in schizophrenia research. The 22q11.2 deletion syndrome (22q11DS) is a unique genetic model with high risk (20-25%) for schizophrenia. This study aimed to identify potentially targetable domains of neurocognitive functioning associated with functional outcome in adults with 22q11DS., Methods: We used comprehensive neurocognitive test data available for 99 adults with 22q11DS (n = 43 with schizophrenia) and principal component analysis to derive four domains of neurocognition (Verbal Memory, Visual and Logical Memory, Motor Performance, and Executive Performance). We then investigated the association of these neurocognitive domains with adaptive functioning using Vineland Adaptive Behavior Scales data and a linear regression model that accounted for the effects of schizophrenia status and overall intellectual level., Results: The regression model explained 46.8% of the variance in functional outcome (p &lt; 0.0001). Executive Performance was significantly associated with functional outcome (p = 0.048). Age and schizophrenia were also significant factors. The effects of Executive Performance on functioning did not significantly differ between those with and without psychotic illness., Conclusion: The findings provide the impetus for further studies to examine the potential of directed (early) interventions targeting Executive Performance to improve long-term adaptive functional outcome in individuals with, or at high risk for, schizophrenia. Moreover, the neurocognitive test profiles may benefit caregivers and clinicians by providing insight into the relative strengths and weaknesses of individuals with 22q11DS, with and without psychotic illness.

Background: Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs., Methods: We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases., Results: We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs., Conclusions: Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.

Individuals with 22q11.2 Deletion Syndrome (22q11.2DS) are at substantially heightened risk for psychosis. Thus, prevention and early intervention strategies that target the antecedents of psychosis in this high-risk group are a clinical priority. Attention Deficit Hyperactivity Disorder (ADHD) is one the most prevalent psychiatric disorders in children with 22q11.2DS, particularly the inattentive subtype. The aim of this study was to test the hypothesis that ADHD inattention symptoms predict later psychotic symptoms and/or psychotic disorder in those with 22q11.2DS. 250 children and adolescents with 22q11.2DS without psychotic symptoms at baseline took part in a longitudinal study. Assessments were performed using well-validated structured diagnostic instruments at two time points (T1 (mean age = 11.2, SD = 3.1) and T2 (mean age = 14.3, SD = 3.6)). Inattention symptoms at T1 were associated with development of psychotic symptoms at T2 (OR:1.2, p = 0.01) but weak associations were found with development of psychotic disorder (OR:1.2, p = 0.15). ADHD diagnosis at T1 was strongly associated with development of psychotic symptoms at T2 (OR:4.5, p < 0.001) and psychotic disorder (OR:5.9, p = 0.02). Our findings that inattention symptoms and the diagnosis of ADHD are associated with subsequent psychotic outcomes in 22q11.2DS have important clinical implications. Future studies examining the effects of stimulant and other ADHD treatments on individuals with 22q11.2DS are warranted., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The purpose of this article is to provide an overview of current insights into the neurodevelopmental and psychiatric manifestations of 22q11.2 deletion syndrome (22q11DS) in children and adolescents. The pediatric neuropsychiatric expression of 22q11DS is characterized by high variability, both interindividual and intraindividual (different expressions over the lifespan). Besides varying levels of intellectual disability, the prevalence of autism spectrum disorders, attention deficit disorders, anxiety disorders, and psychotic disorders in young individuals with 22q11DS is significantly higher than in the general population, or in individuals with idiopathic intellectual disability. Possible explanations for this observed phenotypic variability will be discussed, including genetic pleiotropy, gene-environment interactions, the age-dependency of phenotypes, but also the impact of assessment and ascertainment bias as well as the limitations of our current diagnostic classification system. The implications inferred by these observations aforementioned bear direct relevance to both scientists and clinicians. Observations regarding the neuropsychiatric manifestations in individuals with 22q11DS exemplify the need for a dimensional approach to neuropsychiatric assessment, in addition to our current categorical diagnostic classification system. The potential usefulness of 22q11DS as a genetic model to study the early phases of schizophrenia as well as the phenomenon of neuropsychiatric pleiotropy observed in many CNV's will be delineated. From a clinical perspective, the importance of regular neuropsychiatric evaluations with attention to symptoms not always captured in diagnostic categories and of maintaining equilibrium between individual difficulties and competencies and environmental demands will be discussed., (© 2018 Wiley Periodicals, Inc.)

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort., (© 2018 Wiley Periodicals, Inc.)

The co-occurrence of a copy number variant (CNV) and a functional variant on the other allele may be a relevant genetic mechanism in schizophrenia. We hypothesized that the cumulative burden of such double hits-in particular those composed of a deletion and a coding single-nucleotide variation (SNV)-is increased in patients with schizophrenia. We combined CNV data with coding variants data in 795 patients with schizophrenia and 474 controls. To limit false CNV-detection, only CNVs called by two algorithms were included. CNV-affected genes were subsequently examined for coding SNVs, which we termed "CNV-SNVs." Correcting for total queried sequence, we assessed the CNV-SNV-burden and the combined predicted deleterious effect. We estimated P-values by permutation of the phenotype. We detected 105 CNV-SNVs; 67 in duplicated and 38 in deleted genic sequence. Although the difference in CNV-SNVs rates was not significant, the combined deleteriousness inferred by CNV-SNVs in deleted sequence was almost 4-fold higher in cases compared with controls (nominal P = 0.009). This effect may be driven by a higher number of CNV-SNVs and/or by a higher degree of predicted deleteriousness of CNV-SNVs. No such effect was observed for duplications. We provide early evidence that deletions co-occurring with a functional variant may be relevant, albeit of modest impact, for the genetic etiology of schizophrenia. Large-scale consortium studies are required to validate our findings. Sequence-based analyses would provide the best resolution for detection of CNVs as well as coding variants genome-wide., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Decline in cognitive functioning precedes the first psychotic episode in the course of schizophrenia and is considered a hallmark symptom of the disorder. Given the low incidence of schizophrenia, it remains a challenge to investigate whether cognitive decline coincides with disease-related changes in brain structure, such as white matter abnormalities. The 22q11.2 deletion syndrome (22q11DS) is an appealing model in this context, as 25% of patients develop psychosis. Furthermore, we recently showed that cognitive decline also precedes the onset of psychosis in individuals with 22q11DS. Here, we investigate whether the early cognitive decline in patients with 22q11DS is associated with alterations in white matter microstructure., Methods: We compared the fractional anisotropy (FA) of white matter in 22q11DS patients with cognitive decline [n = 16; -18.34 (15.8) VIQ percentile points over 6.80 (2.39) years] to 22q11DS patients without cognitive decline [n = 18; 17.71 (20.17) VIQ percentile points over 5.27 (2.03) years] by applying an atlas-based approach to diffusion-weighted imaging data., Results: FA was significantly increased (p < 0.05, FDR) in 22q11DS patients with a cognitive decline in the bilateral superior longitudinal fasciculus, the bilateral cingulum bundle, all subcomponents of the left internal capsule and the left superior frontal-occipital fasciculus as compared with 22q11DS patients without cognitive decline., Conclusions: Within 22q11DS, the early cognitive decline is associated with microstructural differences in white matter. At the mean age of 17.8 years, these changes are reflected in increased FA in several tracts. We hypothesize that similar brain alterations associated with cognitive decline take place early in the trajectory of schizophrenia.

Children with 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial-syndrome) are at risk for the developmental disorders, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this study, the relation between executive functioning (EF) and the severity of ADHD and ASD symptoms is examined, since EF is known to be important in relation to emotional and behavioral problems. The participants consist of 58 children (38 females) with a mean age of 13.5 years (SD 2.6). Standardized assessment was used to evaluate the severity of ASD and ADHD symptomatology. The major aspects of EF, i.e., cognitive flexibility, inhibition, sustained attention, distractibility, working memory and reaction speed, were evaluated. The profile of EF in 22q11DS was found to be characterized by weaker performance compared to the norms on all subdomains of EF. Poor cognitive flexibility and inhibition, as well as high distractibility, were found to be related to more severe ASD symptoms, while poor quality of sustained attention and high distractibility were found to be related to more severe ADHD symptoms. It is concluded that children with 22q11DS experience impairments in EF, and that the degree of impairment on specific EF subdomains is related to the severity of ASD and/or ADHD symptomatology. These results may help in defining the mediating role of neurocognitive dysfunctions in the development of social and behavioral problems in 22q11DS.