Anxiety in Williams Syndrome: The role of social behaviour, executive functions and change over time

Anxiety is a prevalent mental health issue for individuals with Williams syndrome (WS). Relatively little is known about the developmental course of anxiety, or how it links with core features of WS, namely social and executive functioning (EF). In this study, parent-reports of anxiety were compared across a 4-year period (N = 17), and links between anxiety, social and EF were explored from concurrent parent-reports (N = 26). Results indicated that high anxiety persisted over time, and anxiety was related to impairments in both social and executive functioning. Importantly, results indicated that impairments in EFs may drive the links between anxiety and social functioning. This timely investigation provides new insights into anxiety in WS and highlights potential areas for intervention

STXBP1 -associated neurodevelopmental disorder: a comparative study of behavioural characteristics

Abstract: Background: De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. Methods: To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1-associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). Results: The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. Conclusions: De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families

Childhood intellectual disability and parents' mental health: integrating social, psychological and genetic influences.

BACKGROUND: Intellectual disability has a complex effect on the well-being of affected individuals and their families. Previous research has identified multiple risk and protective factors for parental mental health, including socioeconomic circumstances and child behaviour. AIMS: This study explored whether genetic cause of childhood intellectual disability contributes to parental well-being. METHOD: Children from across the UK with intellectual disability due to diverse genetic causes were recruited to the IMAGINE-ID study. Primary carers completed the Development and Well-being Assessment, including a measure of parental distress (Everyday Feeling Questionnaire). Genetic diagnoses were broadly categorised into aneuploidy, chromosomal rearrangements, copy number variants (CNVs) and single nucleotide variants. RESULTS: Compared with the UK general population, IMAGINE-ID parents (n = 888) reported significantly elevated emotional distress (Cohen's d = 0.546). Within-sample variation was related to recent life events and the perceived impact of children's difficulties. Impact was predicted by child age, physical disability, autistic characteristics and other behavioural difficulties. Genetic diagnosis also predicted impact, indirectly influencing parental well-being. Specifically, CNVs were associated with higher impact, not explained by CNV inheritance, neighbourhood deprivation or family structure. CONCLUSIONS: The mental health of parents caring for a child with intellectual disability is influenced by child and family factors, converging on parental appraisal of impact. We found that genetic aetiologies, broadly categorised, also influence impact and thereby family risks. Recognition of these risk factors could improve access to support for parents, reduce their long-term mental health needs and improve well-being of individuals with intellectual disability.This work was supported by the UK Medical Research Council (grant number G101400 to K.B.), UK Medical Research Council and Medical Research Foundation (grant number MR-N022572-1 to the IMAGINE-ID study; Principle Investigators: David H. Skuse, F Lucy Raymond, Jeremy Hall, Marianne Van den Bree, Michael J. Hall) and the Baily Thomas Charitable Trust (to K.B.)

The neurodevelopmental spectrum of synaptic vesicle cycling disorders

Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100004440Abstract: In this review, we describe and discuss neurodevelopmental phenotypes arising from rare, high penetrance genomic variants which directly influence synaptic vesicle cycling (SVC disorders). Pathogenic variants in each SVC disorder gene lead to disturbance of at least one SVC subprocess, namely vesicle trafficking (e.g. KIF1A and GDI1), clustering (e.g. TRIO, NRXN1 and SYN1), docking and priming (e.g. STXBP1), fusion (e.g. SYT1 and PRRT2) or re‐uptake (e.g. DNM1, AP1S2 and TBC1D24). We observe that SVC disorders share a common set of neurological symptoms (movement disorders, epilepsies), cognitive impairments (developmental delay, intellectual disabilities, cerebral visual impairment) and mental health difficulties (autism, ADHD, psychiatric symptoms). On the other hand, there is notable phenotypic variation between and within disorders, which may reflect selective disruption to SVC subprocesses, spatiotemporal and cell‐specific gene expression profiles, mutation‐specific effects, or modifying factors. Understanding the common cellular and systems mechanisms underlying neurodevelopmental phenotypes in SVC disorders, and the factors responsible for variation in clinical presentations and outcomes, may translate to personalized clinical management and improved quality of life for patients and families. imag

Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study

Funder: Baily Thomas Charitable Fund; doi: http://dx.doi.org/10.13039/501100001262Abstract: 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

STXBP1-associated neurodevelopmental disorder: a comparative study of behavioural characteristics.

BACKGROUND: De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. METHODS: To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1-associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). RESULTS: The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. CONCLUSIONS: De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families

Mechanisms of FAI cartilage damage: experimental & simulation studies

Femoral acetabular impingement (FAI) is thought to be a key underlying reason for the development of osteoarthritis of the hip. There are two main types of FAI, cam-type and pincer-type. The cam-type FAI gives riseto cartilage delamination initially thought to occur on the acetabular side of the joint. The purpose of the current study was to look at the effects of cam-type impingement on the generation of shear strains at the bone/cartilage interface, using both experimental and finite element simulation methods. Sagittal slices (n=9) of femoral porcine cartilage-bone, 10 mm thick, were loaded using a five-axis custom test machine with a curved (radius 90 mm) steel indenter. The five-axis test machine allowed the samples to be subjected to compression and mixed compression/shearloading regimens. The specimen strains were measured using twodimensional digital image correlation (DIC). Each test was also simulated using finite element analysis, and the results compared with the DIC data.The specimens were then cyclically loaded either with or without damage to the cartilage layers; damage simulated clinically reported lesions.Maximal shear strain was found at the cartilage-bone interface, and was a function of compressive loading level. The finite element predictions matched the DIC measurements. The two parameters that were mostimportant in terms of shear strain were the cartilage thickness and contact area radius. It was found that increased cartilage thickness and increased contact radius gave rise to higher shear strains. Cyclically loading the damaged specimens produced features of cartilage delaminationconsistent with clinical observations. The results of this study indicate high shear strain at the bone/cartilage interface is a possible mechanism leading to cartilage delamination, and may be the mechanism behind cartilage degradation in patients with cam-type FAI

Exploring the Diversity of Plant DNA Viruses and Their Satellites Using Vector-Enabled Metagenomics on Whiteflies

Current knowledge of plant virus diversity is biased towards agents of visible and economically important diseases. Less is known about viruses that have not caused major diseases in crops, or viruses from native vegetation, which are a reservoir of biodiversity that can contribute to viral emergence. Discovery of these plant viruses is hindered by the traditional approach of sampling individual symptomatic plants. Since many damaging plant viruses are transmitted by insect vectors, we have developed “vector-enabled metagenomics” (VEM) to investigate the diversity of plant viruses. VEM involves sampling of insect vectors (in this case, whiteflies) from plants, followed by purification of viral particles and metagenomic sequencing. The VEM approach exploits the natural ability of highly mobile adult whiteflies to integrate viruses from many plants over time and space, and leverages the capability of metagenomics for discovering novel viruses. This study utilized VEM to describe the DNA viral community from whiteflies (Bemisia tabaci) collected from two important agricultural regions in Florida, USA. VEM successfully characterized the active and abundant viruses that produce disease symptoms in crops, as well as the less abundant viruses infecting adjacent native vegetation. PCR assays designed from the metagenomic sequences enabled the complete sequencing of four novel begomovirus genome components, as well as the first discovery of plant virus satellites in North America. One of the novel begomoviruses was subsequently identified in symptomatic Chenopodium ambrosiodes from the same field site, validating VEM as an effective method for proactive monitoring of plant viruses without a priori knowledge of the pathogens. This study demonstrates the power of VEM for describing the circulating viral community in a given region, which will enhance our understanding of plant viral diversity, and facilitate emerging plant virus surveillance and management of viral diseases

Intra- and Inter-Tumor Heterogeneity of BRAFV600EMutations in Primary and Metastatic Melanoma

The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAFV600E as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAFV600E mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAFV600E allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAFV600E-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAFV600Eand BRAFwild-type cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAFV600E mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAFV600E mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful

Tracking the X-ray Polarization of the Black Hole Transient Swift J1727.8-1613 during a State Transition

We report on a campaign on the bright black hole X-ray binary Swift J1727.8$-$1613 centered around five observations by the Imaging X-ray Polarimetry Explorer (IXPE). This is the first time it has been possible to trace the evolution of the X-ray polarization of a black hole X-ray binary across a hard to soft state transition. The 2--8 keV polarization degree slowly decreased from $\sim$4\% to $\sim$3\% across the five observations, but remained in the North-South direction throughout. Using the Australia Telescope Compact Array (ATCA), we measure the intrinsic 7.25 GHz radio polarization to align in the same direction. Assuming the radio polarization aligns with the jet direction (which can be tested in the future with resolved jet images), this implies that the X-ray corona is extended in the disk plane, rather than along the jet axis, for the entire hard intermediate state. This in turn implies that the long ($\gtrsim$10 ms) soft lags that we measure with the Neutron star Interior Composition ExploreR (NICER) are dominated by processes other than pure light-crossing delays. Moreover, we find that the evolution of the soft lag amplitude with spectral state differs from the common trend seen for other sources, implying that Swift J1727.8$-$1613 is a member of a hitherto under-sampled sub-population.Comment: Submitted to ApJ. 20 pages, 8 figure