M48 - DECONSTRUCTING THE NEUREXIN1 DELETION PHENOTYPE: A NEUROPSYCHOLOGICAL, NEUROCOGNITIVE AND NEUROIMAGING PERSPECTIVE

Abstract

Background 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. Methods 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 ). Results 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 Discussion 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.