Clinical Characterisation of Neurexin1 Deletions and Their Role in Neurodevelopmental Disorders

Thursday, May 11, 2017: 12:00 PM-1:40 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
J. E. Fitzgerald1, M. Al-Shehhi2, S. A. Lynch2, H. Peeters3, N. Cosemans4, A. C. Tabet5, R. Delorme6, T. Bourgeron7, M. van den Bree8, J. Hall9, S. Shen10 and L. Gallagher11, (1)Trinity College, Trinity College Dublin, Dublin 2, Ireland, (2)National Centre for Medical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland, (3)Centre for Human Genetics, KU Leuven and Leuven Autism Reasearch, Leuven, BELGIUM, (4)KU Leuven, Leuven, Belgium, (5)AP HP, Robert Debre Hospital, PARIS, FRANCE, (6)Institut Pasteur, Paris, France, (7)Neuroscience, Institut Pasteur, Paris, France, (8)Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales, United Kingdom, (9)Neuroscience Mental Health Research Institute, Cardiff University, Wales, United Kingdom, (10)REMEDI, National University Ireland Galway, Galway, Ireland, (11)Trinity Centre for Health Sciences, Institute of Molecular Medicine, Dublin, IRELAND

The Neurexin1 (NRXN1; 2p16.3) gene has been identified as a rare but significant genetic risk factor for a number of neurodevelopmental disorders including autism spectrum disorder (ASD), schizophrenia, intellectual disability and bipolar disorder. NRXN1 encodes neurexins, presynaptic neuronal adhesion molecules that bind to postsynaptic neuroligins 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 collaboration aims to use a multi-modal approach to deep phenotype individuals and characterise the clinicopathological features of NRXN1 deletions in order to establish diagnostic biomarkers and targeted therapeutic interventions.


To date, 19 families (n = 31) identified with NRXN1 deletions have been recruited. Participants completed a battery of semi-structured neuropsychological assessments (CAPA, PAS-ADD) and questionnaires to probe for existing and/or sub-threshold psychiatric disorders or symptoms. The WASI-II and a comprehensive cognition battery (CANTAB) which, included tests of reaction time (RTI), attention (MTS, RVP), executive functioning (SOC), working memory (SWM), cognitive flexibility (IED) and social cognition (ERT), was administered to assess neurocognitive functioning. Abnormal brain structure and function was investigated using MRI. High-resolution T1, diffusion, spectroscopy and resting state data was collected. Structural T1 and diffusion data have been analysed using FSL (TBSS/VBM) and ExploreDTI software. Age and gender matched controls were used to explore preliminary findings.


Clinical assessments indicated that of the 31 individuals with NRXN1 deletions, 14 met criteria for ASD, 8 for ID (3 mild ID and 5 severe ID), 3 for ADHD, 3 for an anxiety disorder, 1 for a psychotic disorder and 1 for conduct disorder. The NRXN group (n=15) had significantly lower IQ scores than the control group (n=9), (t(22)= -3.272, p = 0.004). Neurocognitive assessments indicated that the NRXN group performed significantly poorer on tasks of attention (MTS; t(22) = -2.263, p = 0.011), executive functioning (SOC; t(22) = -2.940, p = 0.005), cognitive flexibility (IED; t(22)= 1.863, p = 0.047) and social cognition (ERT; t(22) = 2.168, p = 0.032). TBSS results indicated that that there was lower FA in the NRXN group relative to the control group in the body of the corpus callosum, the inferior longitudinal fasciculus and the posterior radiate trending towards significance. VBM results revealed no difference in grey matter volume between the groups. The remaining individuals were either too low functioning or too young to complete assessments.


Although the study data are preliminary, interesting clinical characteristics of NRXN1 deletions are emerging. Psychological assessments indicate a clear link between the presentation of clinical symptoms and a NRXN1 deletion. Neurocognitive testing illustrated that poor attention, executive dysfunction and reduced social cognition are most characteristic of individuals with NRXN1 deletions. Furthermore, disrupted white matter organisation may potentially be established as a neuroanatomical phenotype underpinning the clinical and cognitive deficits observed. Additional clinical and neurobiological phenotyping in large numbers of individuals with NRXN1 deletions in addition to mapping of the NRXN1 genotype may elucidate the underlying neurobiological processes contributing to neurodevelopmental disorders.

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See more of: Genetics