Marianne B. M. van Den Bree

Background: Children and young people (CYP) with intellectual developmental disabilities (IDD) experience substantial health needs and higher healthcare utilisation compared with the general paediatric population. However, factors affecting the emergency healthcare use among children with IDD of genetic aetiology remain poorly understood. This study aimed to examine demographic, socioeconomic, behavioural, genetic, and clinical factors of emergency service use among CYP with IDD in England. Methods: This retrospective cohort study used linked administrative healthcare data from Hospital Episode Statistics (HES) emergency service records obtained from National Health Service (NHS) England. Participants were CYP aged between 4 and 15.5 years with confirmed pathogenic genetic variants associated with IDD identified via NHS medical genetic clinics. The outcome was the yearly emergency service use rate, calculated as the total number of lifetime emergency visits divided by age (years). Independent variables included demographic and socioeconomic factors, genetic characteristics, region of residence, adaptive functioning, behavioural and emotional adjustment, prosocial behaviour, general health status, and system-specific medical conditions. Primary caregivers completed questionnaires and provided information regarding the child’s medical history and demographic information. Results: The average emergency attendance rate in this cohort was 0.73 visits per annum, which was much higher than that among children in the same age range from the general population. Emergency services were used more by younger IDD children with poorer adaptive functioning, more externalising and less prosocial behaviour, as well as those with complex multisystem conditions. Frequent attendance was associated with high rates of medical comorbidities especially seizures and respiratory problems. Regional differences were found with relatively higher usage in London and the North East of England. Attendance rates were not influenced by sex, ethnicity, socioeconomic deprivation, genetic variant type or inheritance status. Conclusions: This novel study demonstrated emergency healthcare utilisation among CYP with IDD of known genetic aetiology in England was primarily associated with clinical complexity, functional impairment, and younger age rather than socioeconomic or genetic factors. Their vulnerability to multisystem morbidity as well as regional disparities highlight the need for improved coordinated care and targeted service planning to reduce emergency healthcare dependence among children with disabilities.

Background: Children and young people (CYP) with intellectual developmental disability (IDD) have a high prevalence of mental health and behavioural problems, which might be influenced by socioeconomical status as well as the severity of their disabilities. This is however an understudied topic, and the present study investigated the association between mental health and socioeconomic deprivation as well as severity/type of disability in CYP with IDD of genetic origin. Methods: Participants comprised a national cohort of 2778 participants with diagnosed genetic disorders associated with IDD, 10.1 ± 4.3 years of age (mean ± SD), 55.7% males. The cohort was linked to routinely collected UK school record data from the National Pupil Database. Socioeconomical status was assessed by free school meals (FSM) eligibility, the index of multiple deprivation (IMD), and parental educational level. IDD severity/type was reported by reviewing statements of primary special educational needs. Participant's mental health diagnoses were established by parental report using the Development and Well‐Being Assessment. Parents also completed the Strengths and Difficulties Questionnaire (SDQ). Results: Socioeconomic factors including lower parental education, greater deprivation (lower IMD decile) and FSM eligibility were associated with the higher prevalence of mental health disorders, as well as greater difficulties in emotional and behavioural adjustment (as measured by the SDQ). In contrast, IDD severity/type was not linked to diagnostic characteristics nor the prevalence of emotional and behavioural difficulties. Conclusion: This study revealed that CYP with IDD of genetic origin living in relatively deprived circumstances had a high risk of mental health disorders and poor emotional and behavioural adjustment, irrespective of the severity/type of their learning disabilities. Tackling deprivation (such as FSM as indicator for targeted additional support) and enhancing access to support services (e.g., psychotherapy) could be by implication key strategies to improve the mental health of this vulnerable population with IDD of genetic aetiology.

22q11.2 deletion syndrome (22q11.2DS) is a strong genetic risk factor for neuropsychiatric conditions, including schizophrenia, yet the underlying synaptic mechanisms remain unclear. Sleep EEG suggests thalamocortical dysfunction, but scalp data alone lack mechanistic resolution. Computational modelling can bridge this gap by inferring receptor-level dynamics from EEG. We applied a conductance-based thalamocortical Dynamic Causal Model (DCM) to sleep-wake EEG from children with 22q11.2DS ( n =28) and their neurotypical siblings ( n =17), estimating contributions of AMPA, NMDA, GABAA, and GABAB conductances. Building on these estimates, we investigated which receptor systems, if perturbed, could shift circuit dynamics toward sibling patterns. To address this, we implemented in silico pharmacology by systematically scaling receptor-mediated conductances. Increasing NMDA receptor (NMDA-R) efficacy consistently produced the strongest improvements in alignment with sibling spectra (effect size = 0.32 in light NREM, 0.45 in deep NREM), whereas AMPA- or GABA-based manipulations were weaker. The most influential pathways were recurrent NMDA-R excitation among superficial pyramidal cells and NMDA-R excitation from spiny stellates to superficial pyramidal populations. Exploratory regressions linked greater thalamocortical delay during deep sleep to greater sleep problems ( β =0.34, p _FDR =0.006), and AMPA-mediated excitation of interneurons during wakefulness to anxiety symptoms ( β =−0.32, p _FDR =0.032). These findings implicate NMDA receptor hypofunction as a key mechanism in 22q11.2DS and suggest it may serve as a treatment target. We further show that DCM-based virtual pharmacology can simulate drug-level interventions, and we are now testing whether NMDA receptor modulation restores network activity in preclinical models (e.g., mouse models of 22q11.2DS).

Background: Avoidant/restrictive food intake disorder (ARFID) is a serious eating disorder, with considerable clinical heterogeneity; however, its genetic basis remains poorly understood. Neurodevelopmental copy number variants (ND-CNVs) represent potential, but yet to be investigated, risk factors for ARFID, as ND-CNVs are associated with psychiatric and anthropometric traits.Methods: Children and young people (CYP) diagnosed with one of 15 ND-CNVs (n = 196) were identified via UK National Health Service medical genetic clinics and charities alongside control siblings (n =47). ND-CNV carriers and their siblings were compared for lifetime presence of ARFID as measured by the ARFID-Brief Screener (ARFID-lifetime) and dimensional ARFID traits assessed using the Nine-Item ARFID Screen (NIAS). Within CYP with an ND-CNV, associations of ARFID with neurodevelopmental and mental health conditions, IQ and body mass index (BMI) and genotype and familial factors (sibling ARFID traits and household income) were investigated.Outcomes: There was a higher prevalence of ARFID-lifetime in CYP with an ND-CNV than in controls (20% vs 4%, p = 0.032). Within CYP with an ND-CNV; those with ARFID-lifetime had greater symptoms of ASD, ADHD, anxiety, obsessive-compulsive disorder, and sleep difficulties (Cohen’s d =0.44-0.79) compared to those without ARFID-lifetime, and genotype-specific patterns of ARFID symptoms were found. The association between ND-CNV status and ARFID-lifetime was mediated by Autistic spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) traits, explaining 52% and 21% of the relationship, respectively. Familial factors were not predictive of ARFID risk.Interpretation: This study provides the first evidence that CYP with an ND-CNV have increased risk of ARFID, advancing understanding of the genetic architecture of ARFID and providing potential important implications for genetic counselling. Our findings indicate that ND-CNVs influence ARFID risk indirectly through autistic and ADHD traits, highlighting the importance of neuroinclusive clinical support for ARFID.

Copy number variants (CNVs) are genomic rearrangements that carry a substantial risk for neurodevelopmental and neuropsychiatric disorders. Among these, recurrent deletions and duplications at the 16p11.2 locus are robustly associated with autism spectrum disorders, schizophrenia, epilepsy, and related conditions, yet also display marked variability in penetrance and phenotypic expression. Accumulating evidence indicates that 16p11.2 gene dosage influences multiple stages of brain development, from early progenitor dynamics and neuronal migration to synaptic formation, refinement, and plasticity. However, how disruptions across these processes are integrated over time, and how they relate to the observed variability and incomplete penetrance, remains poorly understood. In this review, we summarize the current evidence on the impact of 16p11.2 CNVs on brain development, focusing on cellular and circuit-level processes that shape neural connectivity. We discuss how gene dosage imbalance influences early developmental trajectories, synaptic formation and pruning, interneuron maturation, and activity-dependent plasticity, and consider how these processes interact across developmental stages. We suggest a conceptual framework wherein 16p11.2 CNVs do not impose fixed pathogenic outcomes, but rather they contribute towards developmental constraints that shape the timing and stability of neural circuit development. Consequently, these constraints increase vulnerability to neurodevelopmental and psychiatric outcomes in a context-dependent manner.

Background A range of rare chromosomal micro-deletions or -duplications (Copy Number Variants - CNVs) are associated with high risk of neurodevelopmental and mental health conditions (ND-CNVs). There is great individual variability in outcomes, but we lack insights into the contributing social factors, including family functioning. Methods Caregivers of 598 children and young people (CYP) with a range of 16 ND-CNVs and 222 siblings without ND-CNVs (controls) completed questionnaires on overall family climate (cohesion and conflict) as well as caregiver-CYP relationship warmth and hostility and took part in a research diagnostic interview about CYPs9 psychiatric symptoms. CYPs9 intelligence quotient (IQ) was also measured. Results Comparisons with published data from neurotypical families indicated that families affected by ND-CNVs are characterised by higher family cohesion and conflict as well as lower caregiver-CYP warmth and hostility. Symptoms of oppositional defiant disorder reduced more steeply in CYP with ND-CNVs compared to controls with increasing family cohesion (interaction effect: β = -0.14, p = 4.65 x 10² ). In contrast, they rose more steeply with increasing family conflict (interaction effect: β = 0.18, p = 1.05 x 10²). Furthermore, symptoms of mood disorder increased more steeply with increased caregiver-CYP hostility in CYP with ND-CNVs (β = 0.15, p = 4.55 x 10²). Conclusions Raising a CYP with a rare genetic condition is challenging. Timely access to interventions that support caregivers in fostering a positive family environment may reduce behavioural difficulties in CYP, with subsequent benefits for family functioning.

Background: Children with cleft lip and/or palate (CL/P) experience increased rates of neurodevelopmental difficulties, including ADHD, autism spectrum disorder, and educational challenges. While rare neurodevelopmental copy number variants (ND-CNVs) are enriched in this population and associated with poorer outcomes, these variants are present in only a small proportion of children born with cleft. Whether shared common genetic variation contributes to neurodevelopmental comorbidities in CL/P remains unknown. Methods: We investigated this question using data from 2,313 children with CL/P from the Cleft Collective and 7,913 population controls from the Millennium Cohort Study. We tested for shared genetic architecture using linkage disequilibrium score regression, examined associations between polygenic risk scores for eight cognitive, neurodevelopmental, and psychiatric traits and developmental and behavioural outcomes within the cleft population, compared polygenic risk scores between cases and controls, burden between ND-CNV carriers and non-carriers, and employed two-sample Mendelian randomization to test whether genetic liability to cleft causally influences neurodevelopmental outcomes. Results: Linkage disequilibrium score regression revealed little evidence of genetic correlations between CL/P and any of the eight traits examined. Within the cleft population, polygenic risk scores demonstrated expected associations with developmental and behavioural outcomes; however, children with CL/P did not have increased polygenic risk scores for ADHD, autism, depression, anxiety, schizophrenia, bipolar disorder, or lower scores for educational attainment or intelligence compared to controls. Mendelian randomization provided no robust evidence that genetic liability to cleft causally influences neurodevelopmental outcomes. ND-CNV carriers did not differ from non-carriers in polygenic burden. Conclusions: The increased neurodevelopmental risk observed in CL/P does not appear to be explained by shared common genetic architecture with psychiatric disorders, contrasting with established rare variant contributions. Polygenic risk scores for neurodevelopmental traits predict behavioural outcomes within the cleft population similarly to the general population, indicating these genetic factors operate independently of cleft status but remain clinically relevant.

Structural variants, including copy number variants (CNVs), confer substantial risk for neurodevelopmental and psychiatric disorders (NPDs), yet whether their cortical effects relate to those observed in the psychiatric conditions they predispose to remains unclear. Here, we present the first systematic comparison of cortical phenotypes across 18 NPD-associated CNVs and aneuploidies, disorder-associated common variants, and 8 psychiatric disorders. Rare CNVs preferentially affected total surface area (SA), with 11-fold larger effects than psychiatric diagnoses, while NPDs preferentially affected mean cortical thickness (CT), with most CT effects observed in medicated subgroups, suggesting non-genetic contributions. NPD-associated common variants showed enrichment in SA but not CT associations. Regionally, both rare and common genetic variants showed larger effects in sensorimotor regions, aligning with the sensorimotor-to-association cortical gradient as well as regional heritability estimates. In contrast, psychiatric diagnoses showed larger effects in association regions. Individual NPD-associated variants were evenly split between those increasing and decreasing surface area. This heterogeneity likely explains why aggregating variants using polygenic scores shows only weak associations with SA. Overall, cortical signatures of psychiatric diagnoses diverge from those associated with genetic risk. Genetic variants preferentially impact SA and sensorimotor regions through early developmental mechanisms, while psychiatric diagnoses are associated with CT and association regions likely reflecting medication, illness chronicity, and environmental factors.

Background: Internalizing disorders and cardiometabolic disease are common conditions that frequently co-occur in later life and may be attributed to shared genetic influences. While phenotypic effects of polygenic liability of adult disorders may emerge early in life, studies have not investigated this in the context of multimorbidity. This study set out to investigate early manifestations of polygenic liability to adult internalizing-cardiometabolic multimorbidity (ICM-MM) in a UK population birth cohort. Methods: We used data from 5,821 individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC). We modelled trajectories of 12 mental and cardiometabolic health outcomes using mixed effects models, and investigated effects of adult ICM-MM polygenic liability on these trajectories. We also investigated associations of adult ICM-MM polygenic liability with circulating inflammatory proteins (Olink Target 96 Inflammation panel) at ages 9 and 24. Results: Adult ICM-MM polygenic liability is associated with cardiometabolic traits and inflammation, and with changes in depressive symptoms and cardiometabolic traits over time in childhood through to early adulthood. A notable early life biological footprint is inflammation. We found that higher ICM-MM polygenic liability is consistently associated with higher interleukin-6 (IL6), tumor necrosis family superfamily member 14 (TNFSF14) and hepatocyte growth factor (HGF) levels in both childhood and early adulthood. Conclusions: Adult ICM-MM polygenic liability manifests early in life through changes in mental and cardiometabolic health and blood biomarkers, especially in increases of circulating inflammatory proteins related to obesity, immune cell chemotaxis and migration that may contribute to disease pathogenesis by seeding inflammation in relevant tissues.

Background: Multimorbidity, also known as multiple long-term conditions, is a major public health concern. Internalising and CardioMetabolic MultiMorbidity (ICM-MM) is a common form of mental-physical health multimorbidity, yet its genetic predisposition is largely unknown. We examined the polygenic nature of ICM-MM by assessing single trait-specific polygenic risk scores (PRSTRAIT) and whether combining them could increase the proportion of variance in liability to ICM-MM explained by genetic variation. Methods: We developed PRSTRAIT using PRS-CS and summary statistics from the largest trait-specific GWAS excluding UK Biobank (UKB). We evaluated PRSTRAIT on ICM-MM risk in 206 452 UKB participants (n = 39 311 (19.0%) with ICM-MM) using logistic regression adjusted for gender and 10 genetic principal components, defining ICM-MM as lifetime occurrence of: ≥1 internalising (depression, anxiety, somatoform disorder) traits AND ≥ 1 cardiometabolic traits (type 2 diabetes, obesity, hypertension, dyslipidemia, chronic kidney disease). We used elastic net regression in a 50% training sample to generate ICM-MM-PRSTRAIT: a weighted combination of PRSTRAIT targeting ICM-MM. Results: The strongest associations were between ICM-MM and PRSTRAIT for depression and type 2 diabetes—both odds ratios (OR) 1.18, [95% confidence interval (CI) 1.17–1.20] per standard deviation increase in PRSTRAIT. ICM-MM-PRSTRAIT retained five PRSTRAIT, with stronger associations (OR = 1.31, [95%CI 1.29–1.34]) than any PRSTRAIT in the testing sample. Discussion: Combining several PRS explains more variance in ICM-MM liability than single-trait PRSs alone. ICM-MM-PRSTRAIT is a measure of genetic risk that could be used to examine premorbid stages of ICM-MM in external and youth cohorts, supporting awareness of earlier presentation and potentially avoidance or intervention.