NRXN1 deletion (NRXN1 del) is a rare copy number variant associated with several neurodevelopmental, neuropsychiatric, and cognitive outcomes. The NRXN1 gene encodes for a pre-synaptic cell adhesion molecule that is important for synapse formation, regulation and neurotransmission. We used a gene-first approach to investigate neurocognitive and brain phenotypes in NRXN1 del carriers. Forty-two participants (21 NRXN1 del carriers and 21 neurotypical age and sex-matched comparisons) completed IQ assessments, and a neurocognitive battery, including, executive function, attention, and social cognition tasks. Magnetic resonance imaging (MRI) data, including T1-weighted anatomical scans, resting state functional MRI and diffusion tensor imaging, were acquired in 36 participants (17 NRXN1 del carriers and 19 comparisons). NRXN1 del carriers had lower mean IQ and poorer spatial working memory performance compared to comparisons (p ≤ 0.05). Neuroimaging results revealed group differences in visual and ventral attention resting state networks (p < 0.05). Network-based statistical analysis showed a significant effect of group status for 28/115 connections, with poorer segregation between visual and default networks in NRXN1 del carriers relative to comparisons. No differences in brain structural volume or cortical thickness, or diffusion measures of white matter structural architecture were observed between groups. This exploratory study provides evidence for neurocognitive impacts and brain functional differences related to underlying synaptic mechanisms. Brain functional differences in NRXN1 del carriers may support altered excitation/inhibition dynamics within the brain. Gene-first approaches may establish brain-based translational markers to identify neurobiologically informed subgroups within neurodevelopmental and neuropsychiatric conditions, and ultimately transdiagnostic therapeutic strategies.

Background Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. Methods Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. Results Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. Conclusions Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

Chromosomal abnormalities are now considered a common cause of intellectual disability. With increased genetic testing, phenotyping and technological advancements, many new syndromes have been identified. This review sought to explore parental stress and adjustment in the context of rare genetic syndromes to evaluate their clinical impact. A systematic review of English peer-reviewed literature across three databases (PsycINFO, Medline, CINAHL) was completed and 69 articles were included. Parents of children with rare genetic syndromes experienced greater distress relative to other disabilities. Differences in parental wellbeing were syndrome-specific relative to ASD thus demonstrating the need to consider the contribution of syndrome-specific phenotypes. Child emotional and behavioural difficulties were the most consistent predictor of parental distress. Research reflecting other factors such as physical health, syndrome-specific behaviours, benefit finding and, parental appraisal in the context of a rare genetic aetiology is required in order to support parental adjustment in these conditions.

Background NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1 α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1 α +/- and showed increased calcium transients in patient neurons. Methods In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1 α +/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism. Results NRXN1α +/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels ( GRIN1 , GRIN3B , SLC17A6 , CACNG3 , CACNA1A , SHANK1 ), which are likely to couple with the increased excitability in NRXN1α +/- cortical neurons. Conclusions Together with recent evidence of increased calcium transients, our results showed that human NRXN1α +/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α +/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.

NRXN1 encodes thousands of splicing variants categorized into long NRXN1α, short NRXN1β and extremely short NRXN1γ, which exert differential roles in neuronal excitation/inhibition. NRXN1α deletions are common in autism spectrum disorder (ASD) and other neurodevelopmental/neuropsychiatric disorders. We derived induced pluripotent stem cells (iPSCs) from one sibling control and two ASD probands carrying NRXN1α+/−, using non-integrating Sendai viral method. All iPSCs highly expressed pluripotency markers and could be differentiated into ectodermal/mesodermal/endodermal cells. The genotype and karyotype of the iPSCs were validated by whole genome SNP array. The availability of the iPSCs offers an opportunity for understanding NRXN1α function in human neurons and in ASD.

Background: Chromosomal microarray (CMA) testing has been adopted as the first-tier diagnostic test for developmental disabilities. However, determining the clinical significance of the results is often complex. This qualitative study seeks to explore parental interpretation, adaption and coping in the context of ambiguous rare genetic findings in order to support parental adjustment and wellbeing. Methods: In-depth interviews were conducted with parents (n = 30) of children identified with a rare genetic chromosomal abnormality. Results: Three major themes were identified following a thematic analysis: ?Learning of the Genetic Diagnosis?, ?The Reality of the Rarity? and ?Beyond Genetics: The Child Takes Centre Stage?. Findings demonstrated that parental adjustment to their child?s genetic results are mediated by several factors including child difficulties and stage of development, clinician communication, perception of genetics, intrinsic coping strategies, access to practical and emotional support as well as broader contextual experiences. Conclusion: This study highlights the importance of considering the parental perspective in the context of genetic testing in clinical practice.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Background Intragenic NRXN1 deletions are susceptibility variants for neurodevelopmental disorders; however, their clinical interpretation is often unclear. Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided. Methods The literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives, and was used for clinical hypothesis testing. Exact breakpoint determination was performed for 43 in-house deletions. Results The prevalence of exonic NRXN1 deletions in controls was ~1/3000 as compared with ~1/800 in patients with neurodevelopmental/neuropsychiatric disorders. The differential distribution of deletions across the gene between controls and probands allowed to distinguish distinct areas within the gene. Exon 6–24 deletions appeared only twice in over 100000 control individuals, had an estimated penetrance for neurodevelopmental disorders of 32.43%, a de novo rate of 50% and segregated mainly with intellectual disability (ID) and schizophrenia. In contrast, exon 1–5 deletions appeared in 20 control individuals, had an estimated penetrance of 12.59%, a de novo rate of 32.5% and were reported with a broad range of neurodevelopmental phenotypes. Exact breakpoint determination revealed six recurrent intron 5 deletions. Conclusion Exon 6–24 deletions have a high penetrance and are mainly associated with ID and schizophrenia. In contrast, the actual contribution of exon 1–5 deletions to a neurodevelopmental/neuropsychiatric disorder in an individual patient and family remains very difficult to assess. To enhance the clinical interpretation, this study provides practical considerations for counselling and an interactive table for comparing a deletion of interest with the available literature data.

Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high co-morbidity of epilepsy and associated with hundreds of rare risk factors. NRXN1 deletion is among the commonest rare genetic factors shared by ASD, schizophrenia, intellectual disability, epilepsy, and developmental delay. However, how NRXN1 deletions lead to different clinical symptoms is unknown. Patient-derived cells are essential to investigate the functional consequences of NRXN1 lesions to human neurons in different diseases. Methods Skin biopsies were donated by five healthy donors and three ASD patients carrying NRXN1α +/− deletions. Seven control and six NRXN1α +/− iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca 2+ ) imaging was performed using Fluo4-AM, and the properties of Ca 2+ transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with NRXN1α +/− neurons. Results NRXN1α +/− neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca 2+ transients. Whole genome RNA sequencing also revealed altered ion transport and transporter activity, with upregulated voltage-gated calcium channels as one of the most significant pathways in NRXN1α +/− neurons identified by STRING and GSEA analyses. Conclusions This is the first report to show that human NRXN1α +/− neurons derived from ASD patients’ iPSCs present novel phenotypes of upregulated VGCCs and increased Ca 2+ transients, which may facilitate the development of drug screening assays for the treatment of ASD.

Autism Spectrum Disorders (ASDs) are characterised by impaired social communication and restricted repetitive behaviours. Researchers posit that these core features may be underpinned by disrupted structural connectivity. A tract based spatial statistical analysis of diffusion MRI data was performed to investigate white matter organisation (an indication of structural connectivity) in a well-defined cohort of 45 ASD and 45 age and IQ matched control participants. Aberrant structural connectivity characterised by reduced fractional anisotropy was observed in several fiber pathways in ASD relative to controls. Disrupted white matter organisation was associated with social deficits and restricted repetitive behaviours in ASD. Abnormal structural connectivity is apparent in ASD and may be linked to the core behavioural features of the disorder.

The Neurexin1 (NRXN1; 2p16.3) gene has been identified as a rare but significant genetic risk factor for neurodevelopmental disorders including Autism Spectrum Disorder (ASD) schizophrenia, Intellectual Disability (ID) and bipolar disorder. NRXN1 encodes Neurexins, neuronal adhesion molecules on axon terminals, which bind postsynaptic Neuroligins (encoded by NLGN). The primary function of NRXN1 is to stabilise synapse formation and facilitate neuronal transmission. Common clinical features are associated with NRXN1 deletions but these have not been deconstructed using in-depth neuropsychological, neurocognitive and neuroimaging techniques. This project aims to deep phenotype individuals and characterise the clinicopathological features of NRXN1 deletions. 21 participants with NRXN1 deletions and 21 age and gender matched controls were recruited. Semi-structured neuropsychological assessments (CAPA, PAS-ADD) were performed and questionnaires to probe for existing and/or sub-threshold psychiatric disorders or symptoms were collated. The Wechsler Abbreviated Scale of Intelligence-second edition (WASI-II) and a comprehensive cognition battery (CANTAB; http://www.cambridgecognition.com/) was administered to all participants to assess neurocognitive functioning. High Angular Resolution Diffusion Imaging (HARDI) data (61 directions, b-value=1500 s/mm2) were acquired (n=17 per group) to evaluate neuroanatomical differences. Preprocessing was completed using ExploreDTI software (http://www.ExploreDTI.com). Data quality checks were performed and subject motion and eddy current induced geometric distortions were corrected for in one interpolation step to minimise blurring effects. Fractional anisotropy (FA) values were extracted and voxelwise statistical analysis of the FA data was carried out using Tract-Based Spatial Statistics (TBSS) in FSL (https://fsl.fmrib.ox.ac.uk/fsl). The groups did not differ in age (t(40)=-0.015, p=0.988) but there was a significant difference in IQ (t(40)=-6.3, p=0.00) thus IQ was included as a covariate in all statistical analyses. Neuropsychological assessments indicated that 6 individuals have met criteria for ASD, 3 for mild ID, 2 for ADHD, 1 for a psychotic disorder and 1 for a conduct disorder. Neurocognitive assessments indicate a trend towards executive dysfunction and aberrant social cognition in individuals with NRXN1 deletions characterised by greater number of errors on spatial working memory, spatial organisation and emotion recognition tasks, p<0.1. TBSS analyses demonstrated reduced FA in the left body of the corpus callosum, left superior longitudinal fasciculus and the left inferior longitudinal fasciculus in the NRXN group relative to controls, p < 0.1, corrected for multiple comparisons. Interesting clinical characteristics of NRXN1 deletions are emerging. This study indicates that NRXN1 deletions may contribute to neurocognitive deficits related to executive functioning and social cognition, two domains that are consistently described as aberrant in neurodevelopmental disorders. Furthermore, individuals with NRXN1 deletions demonstrate a pattern of disrupted structural connectivity, which has also been described in neurodevelopmental disorders such as ASD and schizophrenia. Further clinical and neurobiological phenotyping in addition to mapping of the NRXN1 genotype may elucidate the underlying neurobiological processes contributing to neurodevelopmental disorders.

Core features of autism spectrum disorder (ASD) may be underpinned by disrupted functional and structural neural connectivity. Abnormal fronto‐parietal functional connectivity has been widely reported in the literature; this may be underpinned by disrupted microstructural organisation of white matter. The superior longitudinal fasciculus (SLF) is a major fronto‐parietal white matter tract, the structure of which has been little studied in ASD. The fronto‐parietal projections of this tract (SLF I, II and III) are thought to play an important role in a number of cognitive functions including attention and visuospatial processing. To date, the isolation of the fronto‐parietal branches of the SLF has been hampered by limitations of traditional tractography approaches. Constrained spherical deconvolution (CSD)‐based tractography is an advanced approach that allows valid isolation of the fronto‐parietal branches of the SLF. Diffusion MRI data were acquired from 45 participants with ASD and 45 age‐ and IQ‐matched controls. The SLF I, II and III branches were isolated using CSD‐based tractography in ExploreDTI. Significantly greater fractional anisotropy (FA) was observed in the right SLF II relative to controls. The ASD group also showed greater linear diffusion coefficient in the left SLF I and the right SLF II. In the SLF II, the ASD group had significantly greater right lateralisation of FA in comparison with the control group. The clinical and functional implications of increased FA in white matter are poorly understood; however, it is possible that this increased white matter organisation in the SLF in ASD may contribute to relative processing advantages in the condition.

The spectrum of phenotypes associated with heterozygous deletions of neurexin-1 (NRXN1) is diverse and includes: autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, seizures, schizophrenia, mood disorders and congenital malformations. Reduced penetrance and variable expressivity of deletions in this gene remain a challenge for genetic counselling. We clinically reviewed 67 NRXN1 deletions from 34 families to document the phenotype and determine odds ratio. Thirty-four probands (5 adults, 29 children (<16 years)) were initially identified from a cohort clinically referred for arrayCGH. A further 33 NRXN1 deletions (16 with established phenotype) from the families were identified following cascade screening. Speech and language delay was a consistent clinical presentation. Pedigree analysis of the inherited group revealed numerous untested relatives with a history of mental health and developmental issues, most notably in the NRXN1β isoform patients. Our study highlights the complex nature of the NRXN1 phenotype in this population.

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II includes a range of psychiatric variables to inform our understanding of the neural correlates of co-occurring psychopathology; 284 diffusion imaging datasets are also included. It is anticipated that these enhancements will contribute to unraveling key sources of ASD heterogeneity.

This article explores the contributions of human rights ideas and norms to the rise and content of the notion of inclusive development, with special emphasis on experiences with the Millennium Development Goals (MDGs), the Sustainable Development Goals (SDGs) and with human rights-based approaches (HRBAs) to development and to environmental issues. On the latter aspect in particular, it is striking that, even though human rights instruments still take up environmental issues only scarcely, human rights-based approaches to global challenges such as climate change have gained momentum.

White matter impairment is associated with opioid dependence. However, the specific neuropathology related to opioid dependence is still not fully understood. The main aims of this study were to: (1) assess the association between white matter impairment and duration of dependence; (2) examine whether this impairment correlates with treatment outcome measures in opioid-dependent patients post-detoxification. Fifty-eight opioid-dependent patients participated, 20 females and 38 males, across three groups: less than 10 years use (n = 18), 10-15 years use (n = 26) and 16-25+ years use (n = 14). Diffusion tensor imaging was used to assess white matter impairment; whole brain voxel-wise analysis of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were performed by Tract-Based-Spatial-Statistics to pinpoint abnormalities in white matter. The longer the subjects were dependent on opioids, the more widespread and severely the white-matter integrity was disrupted. A general linear model was used to examine patients who relapsed compared to those who were abstinent at follow-up. No statistical difference was found between groups (p > 0.05). Partial correlations were performed to investigate the relationship between clinical outcome measures (physical health, psychological well being and quality of life and hope for the future) and white-matter microstructural differences. Significant correlations were found between AD in the posterior corona radiata (L) and MD in the superior longitudinal fasciculus and a clinical measure for HOPE at 9-month follow-up. Nevertheless, it must be noted that the calculation of numerous correlations raises the possibility of a type I error, namely; to incorrectly conclude the occurrence of a significant correlation. The ability to investigate the structure-clinical relationship may improve our understanding of the pathological abnormalities associated with opioid dependence and has promise for use in evaluating future therapeutic outcomes in this population.

Background Attention orienting is a cognitive process that facilitates the movement of attention focus from one location to another: this may be impaired in autism spectrum disorder ( ASD ). Dorsal and ventral attention networks ( DAN and VAN ) sub‐serve the process of attention orienting. This study investigated the functional connectivity of attention orienting in these networks in ASD using the Posner Cueing Task. Method Twenty‐one adolescents with ASD and 21 age and IQ matched controls underwent functional magnetic resonance imaging. A psychophysical interaction ( PPI ) analysis was implemented to investigate task‐dependent functional connectivity, measuring synchronicity of brain regions during the task. Regions of interest ( ROI ) were selected to explore functional connectivity in the DAN during cue‐only conditions and in the VAN during invalid and valid trials. Results Behaviourally, the ASD and control groups performed the task in a similar manner. Functional MRI results indicated that the ASD and control groups activated similar brain regions. During invalid trials ( VAN ), the ASD group showed significant positive functional connectivity to multiple brain regions, whilst the control group demonstrated negative connectivity. During valid trials ( VAN ), the two groups also showed contrasting patterns of connectivity. In the cue‐only conditions ( DAN ), the ASD group showed weaker functional connectivity. Conclusion The DAN analysis suggests that the ASD group has weaker coherence between brain areas involved in goal‐driven, endogenous attention control. The strong positive functional connectivity exhibited by the ASD group in the VAN during the invalid trials suggests that individuals with ASD may generate compensatory mechanisms to achieve neurotypical behaviour. These results support the theory of abnormal cortical connectivity in autism. Autism Res 2015, 8: 136–152 . © 2014 International Society for Autism Research, Wiley Periodicals, Inc.