The inequity of education, health and care plan provision for children and young people with intellectual and developmental disabilities.

BACKGROUND: Children and young people (CYP) with intellectual and developmental disabilities (IDDs) have significant additional educational needs compared with the general population. In England, the government has established a system of education, health and care plans (EHCPs) to support children with special educational needs and disabilities, but disparities exist between the degree of need and the availability of support. We conducted a prospective UK national cohort study (IMAGINE) of children with rare pathogenic genomic variants, all of which are associated with IDD, to investigate associated neuropsychiatric risk. Subsequently, we obtained information from the UK's National Pupil Database on their educational progress through the state school system. We aimed to identify whether they had received EHCP provision and whether that support was associated with their family's socioeconomic status, region of domicile, ethnicity, sex, primary special educational needs (SEN) type, academic performance and mental health well-being. METHODS: We recruited 2738 CYP from England into the IMAGINE study between 2014 and 2019. The educational histories of the participants (6-28 years old, mean ± standard deviation = 14 ± 4 years, 56% male) were obtained from the Department for Education's National Pupil Database in 2021. Educational data included attainment scores from the Early Year Foundation Stage (<5 years) to key stage 4 (15-16 years). Each family was assigned an index of multiple deprivation (IMD) score based on their home address postcode. Parents or carers rated their child's emotional and behavioural adjustment on the Strengths and Difficulties Questionnaire (SDQ). The association between receiving an EHCP and the child's IMD score, eligibility for free school meals, English region of domicile, ethnicity, sex, primary SEN type, academic attainment and SDQ score was investigated. RESULTS: In this cohort, 78% of participants had received an EHCP. CYP living in the most deprived IMD deciles were substantially less likely to receive EHCP support than those in the least deprived decile, irrespective of their degree of intellectual developmental disability, academic performance or associated mental health problems. There were no sex differences. Children of Asian heritage were more likely to have been granted an EHCP than White children from equivalent IMD deciles. There were striking regional disparities. Participants living in London were significantly more likely to have been awarded an EHCP than participants living anywhere else in England, regardless of their IMD decile; those in the least deprived decile had almost 100% EHCP provision. CONCLUSIONS: This study found evidence for nationwide regional inconsistencies in the awarding of EHCP to CYP with significant intellectual impairments of known genetic aetiology. Disparities in funds available to education authorities could be a contributory factor. EHCP support was potentially influenced by how strongly a parent advocates for their child.

Sleep problems and associations with psychopathology and cognition in young people with 22q11.2 deletion syndrome (22q11.2DS).

BACKGROUND: Young people with 22q11.2 deletion syndrome (22q11.2DS) are at high risk for neurodevelopmental disorders. Sleep problems may play a role in this risk but their prevalence, nature and links to psychopathology and cognitive function remain undescribed in this population. METHOD: Sleep problems, psychopathology, developmental coordination and cognitive function were assessed in 140 young people with 22q11.2DS (mean age = 10.1, s.d. = 2.46) and 65 unaffected sibling controls (mean age = 10.8, s.d.SD = 2.26). Primary carers completed questionnaires screening for the children's developmental coordination and autism spectrum disorder. RESULTS: Sleep problems were identified in 60% of young people with 22q11.2DS compared to 23% of sibling controls (OR 5.00, p < 0.001). Two patterns best-described sleep problems in 22q11.2DS: restless sleep and insomnia. Restless sleep was linked to increased ADHD symptoms (OR 1.16, p < 0.001) and impaired executive function (OR 0.975, p = 0.013). Both patterns were associated with elevated symptoms of anxiety disorder (restless sleep: OR 1.10, p = 0.006 and insomnia: OR 1.07, p = 0.045) and developmental coordination disorder (OR 0.968, p = 0.0023, and OR 0.955, p = 0.009). The insomnia pattern was also linked to elevated conduct disorder symptoms (OR 1.53, p = 0.020). CONCLUSIONS: Clinicians and carers should be aware that sleep problems are common in 22q11.2DS and index psychiatric risk, cognitive deficits and motor coordination problems. Future studies should explore the physiology of sleep and the links with the neurodevelopment in these young people.

16p11.2 Locus modulates response to satiety before the onset of obesity.

BACKGROUND: The 600 kb BP4-BP5 copy number variants (CNVs) at the 16p11.2 locus have been associated with a range of neurodevelopmental conditions including autism spectrum disorders and schizophrenia. The number of genomic copies in this region is inversely correlated with body mass index (BMI): the deletion is associated with a highly penetrant form of obesity (present in 50% of carriers by the age of 7 years and in 70% of adults), and the duplication with being underweight. Mechanisms underlying this energy imbalance remain unknown. OBJECTIVE: This study aims to investigate eating behavior, cognitive traits and their relationships with BMI in carriers of 16p11.2 CNVs. METHODS: We assessed individuals carrying a 16p11.2 deletion or duplication and their intrafamilial controls using food-related behavior questionnaires and cognitive measures. We also compared these carriers with cohorts of individuals presenting with obesity, binge eating disorder or bulimia. RESULTS: Response to satiety is gene dosage-dependent in pediatric CNV carriers. Altered satiety response is present in young deletion carriers before the onset of obesity. It remains altered in adolescent carriers and correlates with obesity. Adult deletion carriers exhibit eating behavior similar to that seen in a cohort of obesity without eating disorders such as bulimia or binge eating. None of the cognitive measures are associated with eating behavior or BMI. CONCLUSIONS: These findings suggest that abnormal satiety response is a strong contributor to the energy imbalance in 16p11.2 CNV carriers, and, akin to other genetic forms of obesity, altered satiety responsiveness in children precedes the increase in BMI observed later in adolescence.

Testing for gene x environment interaction effects in attention deficit hyperactivity disorder and associated antisocial behavior.

Gene x environment (G x E) interactions are increasingly thought to have substantial influence on the aetiology and clinical manifestations of complex disorders. In ADHD, although main effects of specific genetic variants and pre- or peri-natal variables have been reported and replicated using pooled analyses, few studies have looked at possible interactions. In a clinical sample of 266 children with ADHD, we tested for interaction between gene variants (in DRD4, DAT1, DRD5, and 5HTT) found to be associated with ADHD in pooled analyses and maternal smoking, alcohol use during pregnancy and birth weight. First, G x E effects on a diagnosis of ADHD were tested using conditional logistic regression analyses. Second, possible modifying effects of G x E on symptoms of associated conduct disorder and oppositional defiant disorder (ODD) were investigated using linear regression analysis. The sample size associated with each of the analyses differed as not each variant had been genotyped for each individual. No effects of G x E on ADHD diagnosis were observed. The results suggest that lower birth weight and maternal smoking during pregnancy may interact with DRD5 and DAT1 (birth weight only) in influencing associated antisocial behavior symptoms (ODD and conduct disorder). These preliminary findings showed no evidence of interaction between previously implicated variants in ADHD and specific environmental risk factors, on diagnosis of the disorder. There may be evidence of G x E on associated antisocial behavior in ADHD, but further investigation is needed.

Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour. A review.

Attention deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder which affects between 3% and 5% of school aged children. Despite much research, little is known regarding the aetiology of the disorder. Maternal cigarette smoking during pregnancy has been linked to a number of negative effects in offspring in infancy, childhood and even into adulthood and has been proposed as a possible risk factor for ADHD. The aim of this review was to discuss the evidence associating maternal smoking during pregnancy and ADHD as well as methodological issues concerning this association. A literature search using PubMed was employed using relevant keywords. The relevant reference sections of articles found were also searched. All English language studies published before June 2005 were assessed. A pooled odds ratio derived from case-control studies was also obtained. Despite methodological limitations, the majority of studies identify maternal smoking during pregnancy as a risk factor for ADHD behaviours. A pooled odds ratio indicates more than a two-fold increase in risk for a diagnosis of ADHD in those individuals whose mothers smoked during pregnancy (odds ratio 2.39, 95% confidence intervals 1.61, 3.52 P<0.001). Maternal smoking during pregnancy is a risk factor for ADHD behaviour and diagnoses, although the mechanisms through which such risks work is unknown.

Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset.

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.

Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa.

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.