Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications.

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.

Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs).

A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating the presentation of irritability in young people with ND-CNVs. This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ). Irritability and broader psychopathology were assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment. Autism was assessed using the social communication questionnaire, and intelligence quotient (IQ) by the Wechsler abbreviated scale of intelligence. Fifty four percent of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07-7.90, p = 5.31 × 10-11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ. Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.

Atypical cortical networks in children at high-genetic risk of psychiatric and neurodevelopmental disorders.

Although many 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. In this study, magnetoencephalography (MEG) was used to investigate electrophysiological markers of local and global network function in 34 children with 22q11.2DS and 25 controls aged 10-17 years old. Resting-state oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, neurodevelopmental symptoms and IQ. Children with 22q11.2DS had altered network activity and connectivity in high and low frequency bands, reflecting modified local and long-range cortical circuitry. Alpha and theta band connectivity were negatively associated with ASD symptoms while frontal high frequency (gamma band) activity was positively associated with ASD symptoms. Alpha band activity was positively associated with cognitive ability. These findings suggest that haploinsufficiency at the 22q11.2 locus impacts short and long-range cortical circuits, which could be a mechanism underlying neurodevelopmental and psychiatric vulnerability in this high-risk group.

Prevalence and recurrence of pica behaviors in early childhood within the ALSPAC birth cohort.

OBJECTIVE: The present study examined prevalence and correlates of pica behaviors during childhood using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) study. METHOD: Data on 10,109 caregivers from the ALSPAC study who reported pica behavior at 36, 54, 65, 77, and 115 months on their child were included. Autism was obtained through clinical and education records, while DD was derived from the Denver Developmental Screening Test. RESULTS: A total of 312 parents (3.08%) reported pica behaviors in their child. Of these, 19.55% reported pica at least at two waves (n = 61). Pica was most common at 36 months (N = 226; 2.29%) and decreased as children aged. A significant association was found between pica and autism at all five waves (p < .001). There was a significant relationship between pica and DD, with individuals with DD more likely to experience pica than those without DD at 36 (p = .01), and 54 (p < .001), 65 (p = .04), 77 (p < .001), and 115 months (p = .006). Exploratory analyses examined pica behaviors with broader eating difficulties and child body mass index. DISCUSSION: This study enhances understanding of childhood pica behaviors, addressing a significant gap in knowledge. Pica occurrence in the general population is poorly understood due to few epidemiological studies. Findings from the present study indicate pica is an uncommon behavior in childhood; however, children with DD or autism may benefit from pica screening and diagnosis between ages 36 and 115 months. Children who exhibit undereating, overeating, and food fussiness may also engage in pica behaviors.

Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs).

Background: A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating presentation of irritability in young people with ND-CNVs. Aims: This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ). Methods: Irritability and broader psychopathology was assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment (CAPA). Autism was assessed using the Social Communication Questionnaire (SCQ), and Intelligence Quotient (IQ) by the Wechsler Abbreviated Scale of Intelligence (WASI). Results: 54% of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07-7.90, p= 5.31 × 10-11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ. Conclusions: Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.

Neurodevelopmental dimensional assessment of young children at high genomic risk of neuropsychiatric conditions.

Background: Individuals with 22q11.2 deletion are at considerably increased risk of neurodevelopmental and psychiatric conditions. There have been very few studies investigating how this risk manifests in early childhood and what factors may underlie developmental variability. Insights into this can elucidate transdiagnostic markers of risk that may underlie later development of neuropsychiatric outcomes. Methods: Thirty two children with 22q11.2 Deletion Syndrome (22q11.2DS) (mean age = 4.1 [SD = 1.2] years) and 12 sibling controls (mean age = 4.1 [SD = 1.5] years) underwent in-depth dimensional phenotyping across several developmental domains selected as being potential early indicators of neurodevelopmental and psychiatric liability. Comparisons were conducted of the dimensional developmental phenotype of 22q11.2DS and sibling controls. For autistic traits, both parents and children were phenotyped using the Social Responsiveness Scale. Results: Young children with 22q11.2DS exhibited large impairments (Hedge's g ≥ 0.8) across a range of developmental domains relative to sibling controls, as well as high rates of transdiagnostic neurodevelopmental and psychiatric traits. Cluster analysis revealed a subgroup of children with 22q11.2DS (n = 16; 53%) in whom neurodevelopmental and psychiatric liability was particularly increased and who differed from other children with 22q11.2DS and non-carrier siblings. Exploratory analyses revealed that early motor and sleep impairments indexed liability for neurodevelopmental and psychiatric outcomes. Maternal autism trait scores were predictive of autism traits in children with 22q11.2DS (intraclass correlation coefficients = 0.47, p = 0.046, n = 31). Conclusions: Although psychiatric conditions typically emerge later in adolescence and adulthood in 22q11.2DS, our exploratory study was able to identify a range of early risk indicators. Furthermore, findings indicate the presence of a subgroup who appeared to have increased neurodevelopmental and psychiatric liability. Our findings highlight the scope for future studies of early risk mechanisms and early intervention within this high genetic risk patient group.

DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts.

BACKGROUND: Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood. AIMS: Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. METHOD: As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. RESULTS: We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. CONCLUSIONS: DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.

Sleep disturbance as a transdiagnostic marker of psychiatric risk in children with neurodevelopmental risk genetic conditions.

Children with rare neurodevelopmental genetic conditions (ND-GCs) are at high risk for a range of neuropsychiatric conditions. Sleep symptomatology may represent a transdiagnostic risk indicator within this patient group. Here we present data from 629 children with ND-GCs, recruited via the United Kingdom's National Health Service medical genetic clinics. Sibling controls (183) were also invited to take part. Detailed assessments were conducted to characterise the sleep phenotype of children with ND-GCs in comparison to controls. Latent class analysis was conducted to derive subgroups of children with an ND-GC based on sleep symptomatology. Assessment of cognition and psychopathology allowed investigation of whether the sleep phenotypic subgroup was associated with neuropsychiatric outcomes. We found that children with an ND-GC, when compared to control siblings, were at elevated risk of insomnia (ND-GC = 41% vs Controls = 17%, p < 0.001) and of experiencing at least one sleep symptom (ND-GC = 66% vs Controls = 39%, p < 0.001). On average, insomnia was found to have an early onset (2.8 years) in children with an ND-GC and to impact across multiple contexts. Children in subgroups linked to high sleep symptomatology were also at high risk of psychiatric outcomes (OR ranging from 2.0 to 21.5 depending on psychiatric condition). Our findings demonstrate that children with high genetic vulnerability for neurodevelopmental outcomes exhibit high rates of insomnia and sleep symptomatology. Sleep disruption has wide-ranging impacts on psychosocial function, and indexes those children at greater neuropsychiatric risk. Insomnia was found to onset in early childhood, highlighting the potential for early intervention strategies for psychiatric risk informed by sleep profile.

Psychopathology in mothers of children with pathogenic Copy Number Variants.

BACKGROUND: Caring for children with pathogenic neurodevelopmental Copy Number Variants (CNVs) (ie, deletions and duplications of genetic material) can place a considerable burden on parents and their quality of life. Our study is the first to examine the frequency of psychiatric diagnoses in mothers of children with CNVs compared with the frequency of psychiatric problems in age-matched mothers from a large community study. METHODS: Case-control study. 268 mothers of children with a CNV diagnosed in a medical genetics clinic and 2680 age-matched mothers taking part in the Avon Longitudinal Study of Parents and Children study. RESULTS: Mothers of children with CNVs reported higher frequency of depression, anorexia, bulimia, alcohol abuse and drug addiction problems compared with the age-matched mothers from the community sample. Focusing on psychiatric problems arising immediately after the birth of the index child, we found that the levels of depression symptoms were similar between the two groups (48% in mothers of children with CNVs vs 44% in mothers of the community sample, p=0.43), but mothers of children with CNVs had higher frequency of anxiety symptoms (55%) compared with mothers from the community sample (30%, p=0.03). CONCLUSION: Our study highlights the need for healthcare providers to devise treatment plans that not only focus on meeting the child's needs but also assess and, if needed, address the mental health needs of the parent.

Autism: A model of neurodevelopmental diversity informed by genomics.

Definitions of autism are constantly in flux and the validity and utility of diagnostic criteria remain hotly debated. The boundaries of autism are unclear and there is considerable heterogeneity within autistic individuals. Autistic individuals experience a range of co-occurring conditions notably including other childhood onset neurodevelopmental conditions such as intellectual disability, epilepsy and ADHD, but also other neuropsychiatric conditions. Recently, the neurodiversity movement has challenged the conception of autism as a medical syndrome defined by functional deficits. Whereas others have argued that autistic individuals with the highest support needs, including those with intellectual disability and limited functional communication, are better represented by a medical model. Genomic research indicates that, rather than being a circumscribed biological entity, autism can be understood in relation to two continua. On the one hand, it can be conceived as lying on a continuum of population variation in social and adaptive functioning traits, reflecting in large part the combination of multiple alleles of small effect. On the other, it can be viewed as lying on a broader neurodevelopmental continuum whereby rare genetic mutations and environmental risk factors impact the developing brain, resulting in a diverse spectrum of outcomes including childhood-onset neurodevelopmental conditions as well as adult-onset psychiatric conditions such as schizophrenia. This model helps us understand heterogeneity within autism and to reconcile the view that autism is a part of natural variability, as advocated by the neurodiversity movement, with the presence of co-occurring disabilities and impairments of function in some autistic individuals.

Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: UK Medical Research Council and Medical Research Foundation.

Genes To Mental Health (G2MH): A Framework to Map the Combined Effects of Rare and Common Variants on Dimensions of Cognition and Psychopathology.

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.

Neurodevelopmental Trajectories and Psychiatric Morbidity: Lessons Learned From the 22q11.2 Deletion Syndrome.

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 psychiatric phenotypes of 1q21 distal deletion and duplication.

Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4-40.1)], 55% for duplication carriers [8.3 (1.4-55.5)]) and anxiety disorders (24% [1.8 (0.4-8.4)] and 55% [10.0 (1.9-71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.

A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants.

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. 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. 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. 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.

Pan-european landscape of research into neurodevelopmental copy number variants: A survey by the MINDDS consortium.

BACKGROUND: Several rare copy number variants have been identified to confer risk for neurodevelopmental disorders (NDD-CNVs), and increasingly NDD-CNVs are being identified in patients. There is a clinical need to understand the phenotypes of NDD-CNVs. However due to rarity of NDD-CNVs in the population, within individual countries there is a limited number of NDD-CNV carriers who can participate in research. The pan-european MINDDS (Maximizing Impact of Research in Neurodevelopmental Disorders) consortium was established in part to address this issue. METHODOLOGY: A survey was developed to scope out the current landscape of NDD-CNV research across member countries of the MINDDS consortium, and to identify clinical cohorts with potential for future research. RESULTS: 36 centres from across 16 countries completed the survey. We provide a list of centres who can be contacted for future collaborations. 3844 NDD-CNV carriers were identified across clinical and research centres spanning a range of medical specialties, including psychiatry, paediatrics, medical genetics. A broad range of phenotypic data was available; including medical history, developmental history, family history and anthropometric data. In 12/16 countries, over 75% of NDD-CNV carriers could be recontacted for future studies. CONCLUSION: This survey has highlighted the potential within Europe for large multi-centre studies of NDD-CNV carriers, to improve knowledge of the complex relationship between NDD-CNV and clinical phenotype. The MINNDS consortium is in a position to facilitate collaboration, data-sharing and knowledge exchange on NDD-CNV phenotypes across Europe.

Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD.

Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets.

Cognitive deficits in childhood, adolescence and adulthood in 22q11.2 deletion syndrome and association with psychopathology.

22q11.2 Deletion Syndrome (22q11.2DS) is associated with high risk of psychiatric disorders and cognitive impairment. It remains unclear to what extent key cognitive skills are associated with psychopathology, and whether cognition is stable over time in 22q11.2DS. 236 children, adolescents and adults with 22q11.2DS and 106 typically developing controls were recruited from three sites across Europe. Measures of IQ, processing speed, sustained attention, spatial working memory and psychiatric assessments were completed. Cognitive performance in individuals was calculated relative to controls in different age groups (children (6-9 years), adolescents (10-17 years), adults (18+ years)). Individuals with 22q11.2DS exhibited cognitive impairment and higher rates of psychiatric disorders compared to typically developing controls. Presence of Autism Spectrum Disorder symptoms was associated with greater deficits in processing speed, sustained attention and working memory in adolescents but not children. Attention deficit hyperactivity disorder in children and adolescents and psychotic disorder in adulthood was associated with sustained attention impairment. Processing speed and working memory were more impaired in children and adults with 22q11.2DS respectively, whereas the deficit in sustained attention was present from childhood and remained static over developmental stages. Psychopathology was associated with cognitive profile of individuals with 22q11.2DS in an age-specific and domain-specific manner. Furthermore, magnitude of cognitive impairment differed by developmental stage in 22q11.2DS and the pattern differed by domain.

Genotype-phenotype associations in children with copy number variants associated with high neuropsychiatric risk in the UK (IMAGINE-ID): a case-control cohort study.

BACKGROUND: Several copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (referred to as ND-CNVs). We aimed to characterise the effect of ND-CNVs on childhood development and investigate whether different ND-CNVs lead to distinct and specific patterns of cognitive and behavioural outcomes. METHODS: In this case-control study, we used data from the Intellectual Disability and Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study. Children aged 4 years and older with pathogenic CNV or single nucleotide variants were recruited via the UK National Health Service (NHS) medical genetic clinic network and via patient support groups to complete broad online phenotyping, from whom children aged 6-19 years with at least one of a specific group of ND-CNVs (1q21.1 [proximal duplication, and distal deletion and duplication], 2p16.3 deletion, 9q34.3 deletion, 15q11.2 deletion, 15q13.3 deletion and duplication, 16p11.2 [proximal deletion and duplication, and distal deletion], and 22q11.2 deletion and duplication) and their families were approached for a deep phenotyping, home-based assessment, and we report on this sample here. We invited siblings of index children to participate as controls, for whom the presence of ND-CNVs was excluded by use of microarray results and also medical records where possible. We systematically assessed the children for psychiatric disorders and broader traits of neurodevelopmental, cognitive, and psychopathological origin and compared results of ND-CNV carriers with control siblings to test the hypothesis that phenotypes would differ by genotype, both quantitatively in terms of severity and qualitatively in the pattern of associated impairments. FINDINGS: Between Oct 1, 2014, and Dec 31, 2018, of 2819 children recruited, 258 (9%) had one ND-CNV of interest, with 13 CNVs across nine loci, and underwent a home-based assessment. 106 control siblings were enrolled. 186 (80%) of ND-CNV carriers met criteria for one or more psychiatric disorder (odds ratio [OR] 13·8, 95% CI 7·2-26·3, compared with controls). The risk of attention-deficit hyperactivity disorder (OR 6·9, 3·2-15·1), oppositional defiant disorder (OR 3·6, 1·4-9·4), any anxiety disorder (OR 2·9, 1·2-6·7), and autism spectrum disorder traits (OR 44·1, 15·3-127·5) was particularly high compared with controls. ND-CNV carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits compared with controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. Overall, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, with rank-based analyses showing moderate qualitative and quantitative profile differences between ND-CNVs; however, the specific genotype accounted for a low proportion of variance in cognitive and behavioural outcomes (approximately 5-20% depending on the trait). INTERPRETATION: The 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits and indicates that future research should avoid being narrowly focused on single phenotypes. FUNDING: UK Medical Research Council and Medical Research Foundation.