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Background\ud 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.\ud Methods\ud 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.\ud Findings\ud 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.\ud Interpretation\ud 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.

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

Shigellosis, a leading cause of diarrhoeal mortality and morbidity globally, predominantly affects children under five years of age living in low- and middle-income countries. While whole genome sequence analysis (WGSA) has been effectively used to further our understanding of shigellosis epidemiology, antimicrobial resistance, and transmission, it has been under-utilised in sub-Saharan Africa. In this study, we applied WGSA to large sub-sample of surveillance isolates from South Africa, collected from 2011 to 2015, focussing on Shigella flexneri 2a and Shigella sonnei. We found each serotype was epidemiologically distinct. The four identified S. flexneri 2a clusters having distinct geographical distributions, and antimicrobial resistance (AMR) and virulence profiles, while the four sub-Clades of S. sonnei varied in virulence plasmid retention. Our results support serotype specific ecology as a driver for epidemiological differences, show AMR is not required for epidemiological success in S. flexneri, and that the HIV epidemic may have promoted Shigella population expansion.

SummaryThe constant arms race between bacteria and their phages has resulted in a large diversity of bacterial defence systems1,2, with many bacteria carrying several systems3,4. In response, phages often carry counter-defence genes5–9. If and how bacterial defence mechanisms interact to protect against phages with counter-defence genes remains unclear. Here, we report the existence of a novel defence system, coined MADS (Methylation Associated Defence System), which is located in a strongly conserved genomic defence hotspot inPseudomonas aeruginosaand distributed across Gram-positive and Gram-negative bacteria. We find that the natural co-existence of MADS and a Type IE CRISPR-Cas adaptive immune system in the genome ofP. aeruginosaSMC4386 provides synergistic levels of protection against phage DMS3, which carries an anti-CRISPR (acr) gene. Previous work has demonstrated that Acr-phages need to cooperate to overcome CRISPR immunity, with a first sacrificial phage causing host immunosuppression to enable successful secondary phage infections10,11. Modelling and experiments show that the co-existence of MADS and CRISPR-Cas provides strong and durable protection against Acr-phages by disrupting their cooperation and limiting the spread of mutants that overcome MADS. These data reveal that combining bacterial defences can robustly neutralise phage with counter-defence genes, even if each defence on its own can be readily by-passed, which is key to understanding how selection acts on defence combinations and their coevolutionary consequences.

Objectives: To investigate the use of tracheostoma humidification by people with total laryngectomy (PTL) in the UK and explore influencing factors. Design: National cross-sectional survey and case note review. Setting: 26 UK National Health Service (NHS) centres providing care to PTL. Participants: PTL reviewed by speech and language therapy (SLT) between March and September 2020. Methods: Secondary analysis of data collected during a national multi-centre audit of PTL completed in response to the Covid-19 pandemic. Data were collected on type of humidification used by PTL and demographic information. Type of humidification was dichotomised as ‘HME’ (closed-system heat moisture exchanger) or ‘non-HME’ (alternative stoma cover or no stoma cover). Univariable analysis was performed to determine the association with several potential explanatory variables including gender, age, living circumstances, distance from treatment centre, communication method and time elapsed since laryngectomy. A backwards selection procedure was used to determine the final model for multiple regression analysis. Results: Data were obtained from 1216 PTL from 26 centres across the UK; information on type of tracheostoma humidification used was available for 1097 PTL. Most PTL (69%) used an HME. Following multiple regression analysis, time elapsed since laryngectomy (p=

BackgroundParents of individuals with intellectual disabilities (ID) are vulnerable to mental health difficulties, which vary between parents and within parents over time. The underlying cause of ID can influence parents’ mental health, via uncertain pathways and within unknown time-windows. MethodsWe analysed baseline data from the IMAGINE-ID cohort, comprising 2655 parents of children and young people with ID of known genetic origin. First, we conducted a factor analysis of the SDQ Impact scale to isolate specific pathways from genetic aetiology to parents’ mental health. Second, we tested via structural equation modelling (SEM) whether genetic diagnosis affects Impact and mental health directly, or indirectly via children’s characteristics. Third, we conducted moderation analysis to explore the influence of time elapsed since genetic diagnosis. ResultsFactor analysis suggested a two-factor structure for the SDQ Impact scale, with a “home & distress” dimension and a “participation” dimension. SEM analysis identified an indirect pathway linking genetic aetiology to parents’ mental health, serially through child characteristics (physical disabilities, emotional and behavioural difficulties) and Impact: home & distress. This serial mediation model was moderated by time since diagnosis, with strongest mediating effects among recently diagnosed cases.Conclusions There are multiple steps on the pathway from ID-associated genetic diagnoses to parents’ mental health. Pathway links are strongest within 5 years of receiving a genetic diagnosis, highlighting opportunities for better post-diagnostic support. Recognition and enhanced support for children’s physical and behavioural needs might reduce impact on family life, ameliorating parents’ vulnerabilities to mental health difficulties.

Microscopic evaluation of cytologic specimens can provide rapid diagnostic information and aid in formulating diagnostic and treatment plans. The primary benefit of cytologic evaluation is the rapid collection, processing, and evaluation of samples. However, physical transport of glass slides and body fluids to a diagnostic laboratory takes time and can negatively affect patient management. Digital cytology allows specimens to be processed in the clinic and immediately sent to pathologists. With technology becoming more affordable, digital cytology is revolutionizing the field of clinical pathology and patient care.

Escherichia albertii is a recently identified gastrointestinal bacterial pathogen of humans and animals which is typically misidentified and generally only detected during genomic surveillance of other Enterobacteriaceae. The incidence of E. albertii is likely underestimated and its epidemiology and clinical relevance are poorly characterised. Here, we whole genome sequenced E. albertii isolates from humans (n = 83) and birds (n = 79) in Great Britain and analysed a broader public dataset (n = 475) to address these gaps. We found human and avian isolates typically (90%; 148/164) belonged to host-associated monophyletic groups with distinct virulence and antimicrobial resistance profiles. Overlaid patient epidemiological data suggested that human infection was likely related to travel and possibly foodborne transmission. The Shiga toxin encoding stx2f gene was associated with clinical disease (OR = 10.27, 95% CI = 2.98–35.45 p = 0.0002) in finches. Our results suggest that improved future surveillance will further elucidate disease ecology and public and animal health risks associated with E. albertii.

Kate Baker of the Veterinary Cytology Schoolhouse and Pocket Pathologist in Tennessee, USA presents some challenging and interesting feline cytology cases.

Shigellosis is an intestinal infection caused by Shigella bacteria. Shigella cause an estimated ~200,000 global deaths annually. Antimicrobial resistant (AMR) shigellosis is a significant cause of morbidity in high-income nations, with both multidrug resistant (MDR) and extensively drug resistant (XDR) cases being increasingly reported in Australia, England, and the USA. Sexually transmissible shigellosis was first described in San Francisco, 1974, but it would be a further 30 years before its first description in England. In 2004, London experienced an outbreak of Shigella sonnei (S. sonnei) mediated sexually transmitted shigellosis, associated with men-who-have-sex-with-men (MSM). Since then, sexually transmissible shigellosis has become endemic in England, with a greater than two-fold increase in Shigella diagnoses within sexual health services from 2015 to 2019. Through genomic exploration of samples from the original 2004 outbreak (provided by Public Health England (PHE)), we identified that the 2004 London outbreak isolates clustered within the base of genotype 3.1, lineage III, a lineage which has since gone on to dominate the global epidemiology of S. sonnei. The isolates displayed early evidence of varying degrees of antimicrobial resistance to several drug classes: macrolides, tetracyclines, beta-lactams and sulphonamides. Reconstructing the chronological process of how shigellosis has arrived at its current position in AMR and transmissibility is critical. Further investigation is underway to link this outbreak with MSM-associated shigellosis outbreaks occurring in the early 2000s in other countries to establish whether this lineage globally disseminated; determine the timeframe for global connectivity of shigellosis; and examine the outbreak isolates for virulence determinants.

We introduce a new touchscreen-based method measuring aspects of cognitive control and memory, in children and young people with neurodevelopmental difficulties, including intellectual disability (ID). FarmApp is a gamified, tablet-based assessment tool measuring go/no-go response speed, response inhibition, visuospatial short-term memory span, and long-term memory. Here, we assessed the feasibility, validity, and utility of the method, including the benefits of measuring change in performance over two weeks. We observed that: 1) a higher proportion of participants completed FarmApp than traditional psychometric tests; 2) this proportion increased when participants had opportunity for two weeks of self-paced testing at home; 3) ADHD-relevant behavioral difficulties were associated with average go/no-go performance across all attempts, and change in go/no-go performance over time, indicating sensitivity of the method to cognitive differences with real-world relevance. We also addressed the potential utility of the FarmApp for exploring links between ID etiology and cognitive processes. We observed differences in go/no-go task between two groups of ID participants stratified by the physiological functions of associated genetic variants (chromatin-related and synaptic-related). Moreover, the synaptic group demonstrated higher degree of improvement in go/no-go performance over time. This outcome is potentially informative of dynamic mechanisms contributing to cognitive difficulties within this group. In sum, FarmApp is a feasible, valid, and useful tool increasing access to cognitive assessment for individuals with neurodevelopmental difficulties of variable severity, with an added opportunity to monitor variation in performance over time and determine capacity to acquire task competence.

DDX3X variants are a common cause of intellectual disability (ID) in females, and have been associated with autism spectrum disorder and emotional-behavioural difficulties. In this study, we compared phenotypic data for 23 females with DDX3X variants, to 23 females with ID and other genetic diagnoses. We found a wide range of adaptive, social and emotional function within the DDX3X group. Autism characteristics did not differ between DDX3X and comparison groups, while levels of anxiety and self-injurious behaviour (SIB) were significantly higher in the DDX3X group. Within the DDX3X group, adaptive function, autism characteristics, anxiety and SIB scores were positively correlated, with evidence for group-specific associations with SIB. Future work is warranted to explore the multilevel mechanisms contributing to social and emotional development in individuals with DDX3X variants.

In dogs, primary bone tumors can be difficult to distinguish with histopathology. Of those tumors, osteosarcoma (OSA) is the most common and aggressive. In this study, 4 immunohistochemistry markers—alkaline phosphatase (ALP), osteonectin (ON), osteopontin (OP), and runx2—were evaluated for their ability to distinguish OSA from other primary bone tumors. The 42 formalin-fixed, paraffin-embedded, primary canine bone tumors included 15 OSAs, 8 chondrosarcomas, 11 fibrosarcomas, and 8 histiocytic sarcomas. All 4 antibodies were highly sensitive for detection of osteosarcoma. ALP was the most sensitive at 100% and runx2 the most specific at 78%. Running ALP and runx2 in series resulted in a sensitivity of 87% and a specificity of 85%. This combination of immunomarkers resulted in a diagnostic panel for distinguishing osteosarcoma from other primary bone tumors.

Background: The impact of the COVID-19 pandemic on the wellbeing of parents and children in the general population has been well-documented. This study investigated wellbeing in parents of and children with rare neurogenetic conditions, who may have been at greater risk of negative impact on mental health and behavioural challenges during the first UK lockdown. Method: An online survey data was completed by parents of children with a rare neurogenetic condition between May and July 2020 (CoIN sample; N=123) and compared to responses from parents of children in the wider population (Co-SPACE sample; N=2121). Measures of wellbeing included the 21-item Depression, Anxiety and Stress Scale for parents and the Strength and Difficulties Questionnaire for child behaviour. Results: Parent anxiety was significantly higher in CoIN (MedianAnx = 4) than Co-SPACE (MedianAnx = 2). Parent-rated internalising, externalising and impact of child behavioural difficulties were also significantly higher in CoIN (MedianInt = 9.5; MedianExt = 11, MedianImp = 8) than Co-SPACE (MedianInt = 6; MedianExt = 7, MedianImp = 1). Only group differences in child behaviour and impact remained significant when matching for demographic factors and were also larger than previously reported pre-pandemic differences. Discussion: Families of children with rare neurogenetic conditions reported poorer wellbeing during the first lockdown compared to the wider population, affecting both parents and children. This likely reflects pre-existing complex needs, which should be prioritised during future national crises. Investigation of changes in wellbeing in this population over the course of the pandemic is warranted.

In this article we discuss Mpala Research Centre in Laikipia County, Kenya as a distinctly colonial space. Drawing on historical materials, fieldwork observations and in-depth interviews, we build an account of British colonial expropriation of land, European and American modes of enclosure, and the development of a prominent site of knowledge production in the fields of ecology, conservation and evolutionary biology. Mpala is product and productive of colonial relations, ones where land use serves mainly Western interests in ways that sustain and entrench categories of coloniser/colonised. We support this claim by identifying three ways in which colonial legacies endure at Mpala in terms of (i) ontology, or the particular ways in which land is made landscape; (ii) race and the organisation of space and labour and (iii) silence (and silencing) as a mechanism that sustains colonial power relations. We further argue that turning to such a nameable site of contemporary academic extraction enables a shift from postcolonial critique to decolonial praxis. By naming Mpala in specific terms, the possibility of politics opens out from critical analysis towards a project of undoing the epistemological and material legacies of colonialism.

BackgroundDDX3X variants are a common cause of intellectual disability (ID) in females. Previous studies have reported high rates of autism spectrum disorder and emotional-behavioural difficulties within this group. However, no study has compared social and emotional characteristics in individuals with DDX3X variants to individuals with other monogenic causes of ID.MethodsTwenty-three females with pathogenic or likely pathogenic DDX3X variants were recruited via UK regional genetics centres, genetic research cohorts, and family support groups. Twenty-three females with ID and variants in other genes were recruited via the same routes. Phenotypic data were collected through semi-structured interviews and standardised questionnaires.ResultsIn line with previous research, we found a wide range of adaptive, social and emotional function within the DDX3X group. Autism characteristics assessed via the Social Responsiveness Scale (SRS) did not differ between DDX3X and comparison groups, while levels of anxiety and self-injurious behaviour (SIB) scores assessed via the Developmental Behaviour Checklist (DBC) were significantly higher in the DDX3X group. Autistic characteristics, anxiety and SIB scores were positively correlated within the DDX3X group. Individuals with DDX3X missense variants had poorer adaptive abilities than those with protein truncating variants as previously reported, but DDX3X variant type did not significantly predict emotional and behavioural characteristics.ConclusionsWe provide quantitative evidence that overall incidence of autistic characteristics is not higher amongst girls and women with DDX3X variants than expected for ID. However, the DDX3X group demonstrates more SIBs and anxiety symptoms than expected, with close relationships between SIBs and anxiety, and between anxiety and autistic characteristics. Future work is warranted to explore the multilevel mechanisms contributing to social and emotional development in individuals with DDX3X variants, and consider whether these mechanisms are specific to this genetic diagnosis or shared with a subset of people with ID due to other causes.

Given the move toward competency-based veterinary education and the subsequent reevaluation of veterinary curricula, there is a need for specialties to provide guidance to veterinary college administrators and educators on the core knowledge and skills pertaining to their specialty to ensure their inclusion in revised or redesigned curricula. The American Society for Veterinary Clinical Pathology (ASVCP) Education Committee sought to create a list of competencies specific to clinical pathology expected of graduating veterinarians. The stimulus for this project was the American Veterinary Medical Association Council on Education Standards of Accreditation for Colleges of Veterinary Medicine, further driven by the 2018 publication of the Association of American Veterinary Medical Colleges Competency-Based Veterinary Education Working Group framework. The recommendations made in this document are the culmination of the 2016 ASVCP Education Forum for Discussion, multiple remote subcommittee communications, and feedback obtained from ASVCP membership. The final framework includes 8 clinical pathology–focused domains of competence with 20 clinical pathology competencies and 61 clinical pathology illustrative sub-competencies. The clinical pathology–focused domains of competence are: the pre-analytical phase of testing, laboratory medicine and instrumentation, principles of test selection and interpretation, hematology and hemostasis, chemistry, endocrinology, urinalysis, and cytology. These are not intended to replace the nine established AAVMC domains of competence with supportive competencies and illustrative sub-competencies but to guide institutions for how clinical pathology aligns within the competency-based veterinary education (CBVE) framework for the practice-ready veterinary graduate. This clinical pathology competency framework may prove useful and empowering during discussions of curriculum revisions and redesigns.

PurposeSynaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioural disturbance and EEG abnormalities. Here, we expand the genotypes and phenotypes and identify discriminating features of this disorder.MethodsWe describe 22 individuals with 15 de novo missense SYT1 variants. Evidence for pathogenicity is discussed, including ACMG criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioural data for 14 cases are compared to other monogenic neurodevelopmental disorders.ResultsFour variants lie in the C2A domain with the remainder in the C2B. We classify 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes include delayed developmental milestones, ophthalmic problems, abnormal EEG, movement disorders and sleep disturbance. Discriminating behavioural characteristics were severity of motor and communication impairment, presence of motor stereotypies and mood instability.ConclusionSYT1 variants associated with neurodevelopmental disorder extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severity than initially reported. This work guides diagnosis and molecular understanding of this rare neurodevelopmental disorder, and highlights a key role for SYT1 function in emotional regulation, motor control and emergent cognitive function.

Author(s): Kennedy, Burton; Blankenship, Doug; Doe, Thomas; Riahi, Azadeh; Damjanac, Branko; Finnila, Aleta; Fu, Pengcheng; Sonnenthal, Eric; Baker, Kate; Ingebritsen, Steve; Augustine, Chad; Carrigan, Charles; Dewers, Tom; Elsworth, Derek; Fairhurst, Charles; Fehler, Michael; Warpinski, Norm

Summary Rotten food, maggots, bodily waste—all elicit disgust in humans. Disgust promotes survival by encouraging avoidance of disease vectors 1 but is also implicated in prejudice toward minority groups; avoidance of environmentally beneficial foods, such as insect protein; and maladaptive avoidance behavior in neuropsychiatric conditions. 2 , 3 , 4 , 5 Unlike fear, pathological disgust is not improved substantially by exposure therapy clinically, 6 nor in experimental work does behavioral avoidance of disgusting images habituate following prolonged exposure. 7 , 8 Under normal physiological conditions, perception of disgusting stimuli disrupts myoelectrical rhythms in the stomach, 9 , 10 , 11 , 12 , 13 inducing gastric dysrhythmias that correlate with neural signatures of disgust. 11 However, the causal role of gastric rhythm in disgust avoidance is unknown. We manipulated gastric rhythm using domperidone, a peripheral dopamine D2/D3 antagonist and common anti-emetic, at a dose (10 mg) that acts to convert gastric dysrhythmias to normal rhythms. 9 In a preregistered, randomized, double-blind, placebo-controlled crossover design in 25 healthy volunteers (aged 18–25), we measured the effects of domperidone on core disgust avoidance, using eye tracking to measure implicit (oculomotor) avoidance of disgusting images (feces) before and after an “exposure” intervention (monetary reinforcement for looking at disgusting images). 7 , 8 We find that domperidone significantly reduces oculomotor disgust avoidance following incentivized exposure. This suggests that domperidone may weaken the “immunity” of disgust to habituation, putatively by reducing gastric dysrhythmias during incentivized engagement with disgusting stimuli. This indicates a causal role for disgust-related visceral changes in disgust avoidance, supporting the hypothesis that physiological homeostasis contributes to emotional experience.

Dynamic connectivity in functional brain networks is a fundamental aspect of cognitive development, but we have little understanding of the mechanisms driving variability in these networks. Genes are likely to influence the emergence of fast network connectivity via their regulation of neuronal processes, but novel methods to capture these rapid dynamics have rarely been used in genetic populations. The current study redressed this by investigating brain network dynamics in a neurodevelopmental disorder of known genetic origin, by comparing individuals with a ZDHHC9‐associated intellectual disability to individuals with no known impairment. We characterised transient network dynamics using a Hidden Markov Model (HMM) on magnetoencephalography (MEG) data, at rest and during auditory oddball stimulation. The HMM is a data‐driven method that captures rapid patterns of coordinated brain activity recurring over time. Resting‐state network dynamics distinguished the groups, with ZDHHC9 participants showing longer state activation and, crucially, ZDHHC9 gene expression levels predicted the group differences in dynamic connectivity across networks. In contrast, network dynamics during auditory oddball stimulation did not show this association. We demonstrate a link between regional gene expression and brain network dynamics, and present the new application of a powerful method for understanding the neural mechanisms linking genetic variation to cognitive difficulties.

BackgroundA major challenge when investigating intellectual disability (ID) is the selection of assessment tools that are sensitive to cognitive diversity within the ID population. This study introduces a new touchscreen-based method, FarmApp, which aims to measure competence in relatively low-level cognitive processes (selective attention, short-term visuospatial memory, longer-term recognition memory) which contribute to complex aspects of learning and behaviour.MethodsHere we describe the FarmApp design, testing and analysis procedures. We report the feasibility and validity of the method, and demonstrate its utility for measuring change over time, and for comparing groups defined by aetiology.ResultsWe found that FarmApp can be completed by a higher proportion of young people with ID than traditional psychometric tests. FarmApp performance correlates with standardised neuropsychological tests of attention and working memory, and with questionnaire measures of ADHD-relevant behavioural difficulties. Individual performance slopes over a two-week period correlate with general ability and behavioural difficulties, indicating that FarmApp is sensitive to meaningful dynamic variation in cognitive performance. Finally, we compared the FarmApp performance of two groups of young people with ID, defined by the physiological function of ID-associated genetic variants (functional network groups: chromatin-related and synaptic-related), and found that groups differ on attention parameters but not on memory ones.ConclusionFarmApp is a feasible, valid and useful alternative to traditional neuropsychological tests. It can increase access to cognitive assessment for individuals with ID. It adds the opportunity to monitor variation in performance over time and determine capacity to acquire task competence in addition to baseline ability. Our comparison between functional network groups supports the proposal that cognitive processes contributing to ID are differentially influenced by specific genetic aetiologies. In summary, we introduce a new tool for cognitive assessment in ID, with the potential for multiple future applications in clinical practice and research.

Funder: Baily Thomas Charitable Fund; doi: http://dx.doi.org/10.13039/501100001262, Background: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants. Methods: Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n = 29) or chromatin regulation (n = 23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components—Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks. Results: We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety. Limitations: Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups. Conclusion: We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful.