Longitudinal follow-up of 22q11.2 Deletion Syndrome: a study of individuals at high risk of schizophrenia

22q11.2 Deletion Syndrome (22q11.2DS) is one of the strongest known risk factors for schizophrenia. The syndrome provides a rare opportunity to prospectively examine development that precedes schizophrenia. 22q11.2DS is also associated with a range of psychiatric disorders and cognitive deficits. The overall aim of this thesis is to examine the neuropsychiatric phenotype of 22q11.2DS through a developmental lens. This thesis uses data from Cardiff University’s ECHO (Experiences of CHildren with cOpy number variants) study which includes a longitudinal cohort of children with 22q11.2DS. Development in 22q11.2DS is contrasted to that of the unaffected siblings of children with 22q11.2DS. First psychopathology is examined longitudinally across early adolescence in 22q11.2DS. Children with 22q11.2DS have a significant burden of psychopathology across early adolescence, including attention-deficit/hyperactivity disorder (ADHD), anxiety disorders and autism spectrum disorder (ASD). There is a striking increase in the prevalence of psychotic experiences and a decrease in ADHD prevalence. The ASD phenotype is examined further using a diagnostic interview of developmental history. ASD and subthreshold phenomenology is found to be highly prevalent in the early development of children with 22q11.2DS. Next cognitive development in 22q11.2DS is considered and contrasted to that in unaffected siblings. Cognitive deficits across a range of domains are present in 22q11.2DS. Cognitive development in 22q11.2DS is found to be similar to that reported in children who later develop idiopathic schizophrenia. This is followed by an exploration of the relations between psychopathology and cognitive development in 22q11.2DS. Cognitive development is found to predict the emergence of psychotic experiences and the persistence of ADHD in 22q11.2DS. This thesis extends what is known about the development of the neuropsychiatric phenotype in 22q11.2DS. Furthermore, findings give an insight into the developmental pathways associated with a high risk of developing schizophrenia

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

Vulnerable periods for cognitive development in individuals at high genomic risk of schizophrenia [Conference Abstract]

22q11.2 Deletion Syndrome (22q11.2DS) is caused by the deletion of approximately 60 genes on chromosome 22 and represents one of the strongest known genetic risk factors for schizophrenia. Approximately 1 in 4 adults with 22q11.2DS are diagnosed with schizophrenia spectrum disorders, presenting with psychotic symptomatology analogous to that exhibited in idiopathic schizophrenia. Cognitive deficits are a core feature of schizophrenia. 22q11.2DS presents a valuable model for understanding vulnerable periods of cognitive development which may be associated with psychosis development. Most previous studies report greater deficits in older individuals with 22q11.2DS than younger individuals but these studies have often focused solely on IQ, neglecting other neurocognitive domains associated with schizophrenia. Additionally, many studies of 22q11.2DS have not included adults, missing a crucial group at increased risk for schizophrenia. The first aim was therefore to examine whether there are increasing deficits in cognitive functioning on a wide range of domains in 22q11.2DS across developmental stages (children, adolescents and adults) compared to typically developing (TD) controls. The second aim was to take into account the presence of a psychotic disorder, and whether this explained variance in functioning. Methods We conducted the largest study to date of neurocognitive functioning beyond IQ in 22q11.2DS. This work was the result of international collaboration across 3 sites. The same battery of tasks measuring processing speed, attention and spatial working memory were completed by 219 participants with 22q11.2DS and 107 TD controls. Wechsler IQ tests were completed, yielding Full Scale (FSIQ), Verbal (VIQ) and Performance IQ scores (PIQ). An age-standardised difference score was produced for each participant taking into account TD control performance. The average performance of children (6–10 years), adolescents (10–18 years) and adults (18–56 years) was compared using an ANOVA approach. No children or adolescents reached diagnostic criteria for a psychotic disorder, but 13% of adults with 22q11.2DS were either diagnosed with a DSM-IV psychotic disorder. The cognitive performance of adults with or without a psychotic disorder was compared with independent t-tests with correction for unequal variance. Results Children and adults with 22q11.2DS displayed a greater deficit in working memory than adolescents (p=0.017 and p<0.001 respectively). Adults displayed greater deficits in FSIQ and PIQ than adolescents (p=0.018 and p=0.001 respectively). Adults diagnosed with a psychotic disorder displayed a greater deficit in VIQ than those without a psychotic disorder (p=0.040). Discussion Magnitude of cognitive deficit in individuals with 22q11.2DS varied by cognitive domain and developmental stage. There were specific deficits in working memory, PIQ and FSIQ in adults with 22q11.2DS compared to children and adolescents. The lack of differences between children and adolescents contradicts previous research which proposes that older children exhibit greater cognitive deficits, and suggests that there may be a longer developmental window to intervene and maintain cognitive functioning in a group at high genomic risk of schizophrenia. Adults with 22q11.2DS and psychotic disorder had a greater deficit in VIQ, which supports previous research. This international sample provides unique insights into cognitive functioning in 22q11.2DS across developmental stages

Childhood cognitive development in 22q11.2 deletion syndrome: case–control study

Background 22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of childhood as well as adult psychiatric disorders, in particular schizophrenia. Childhood cognitive deterioration in 22q11.2DS has previously been reported, but only in studies lacking a control sample. Aims To compare cognitive trajectories in children with 22q11.2DS and unaffected control siblings. Method A longitudinal study of neurocognitive functioning (IQ, executive function, processing speed and attention) was conducted in children with 22q11.2DS (n = 75, mean age time 1 (T1) 9.9, time 2 (T2) 12.5) and control siblings (n = 33, mean age T1 10.6, T2 13.4). Results Children with 22q11.2DS exhibited deficits in all cognitive domains. However, mean scores did not indicate deterioration. When individual trajectories were examined, some participants showed significant decline over time, but the prevalence was similar for 22q11.2DS and control siblings. Findings are more likely to reflect normal developmental fluctuation than a 22q11.2DS-specific abnormality. Conclusions Childhood cognitive deterioration is not associated with 22q11.2DS. Contrary to previous suggestions, we believe it is premature to recommend repeated monitoring of cognitive function to identifying individual children with 22q11.2DS at high risk of developing schizophrenia

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

Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk: Findings from the Intellectual Disability & Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study.

Background: A variety of copy number variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Different ND-CNVs could lead to distinct and specific patterns of cognitive and behavioural outcomes, but supporting evidence is currently lacking. Methods: 258 children with ND-CNVs (13 CNVs across 9 loci) were systematically assessed for psychiatric disorders as well as broader traits of neurodevelopmental, cognitive and psychopathological origin. A comparison was made with 106 non-carrier control siblings, in order to test the hypothesis that phenotypes would differ by genotype, both quantitatively, in terms of severity, and qualitatively in the pattern of associated impairments. Outcomes: 79.8% of ND-CNVs carriers met criteria for one or more psychiatric disorders (OR=13.8 compared to controls): the risk of ADHD (OR=6.9), ODD (OR=3.6), anxiety disorders (OR=2.9), and ASD traits (OR=44.1) was particularly high. ND-CNVs carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits relative to controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. In general, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, however the specific genotype accounted for a low proportion of variance in outcome (5-20% depending on trait). Interpretation: The 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Our findings suggest that genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits, and provides important implications for research into genotype-phenotype relationships within psychiatry

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.</p

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

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.</p