21535
Clinical Characterisation of Neurexin1 Deletions and Their Role in Neurodevelopmental Disorders
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.
Objectives:
This European-wide collaboration aims to deep phenotype individuals and characterise the clinicopathological features of NRXN1 deletions in order to establish diagnostic biomarkers and targeted therapeutic interventions.
Methods:
Individuals with NRXN1 deletions are currently being identified and recruited through clinical genetic services at each site. All consented participants are completing a battery of semi-structured neuropsychological assessments and questionnaires to probe for existing and/or sub-threshold psychiatric disorders or symptoms. A comprehensive cognition battery (CANTAB), which includes tests of reaction time, attention, executive functioning, working memory, cognitive flexibility and social cognition are administered to all participants to assess neurocognitive functioning. Abnormal brain structure and function is investigated using both MRI and EEG techniques. High resolution T1, diffusion weighted, magnetic resonance spectroscopy and resting state functional data are acquired using MRI. EEG measured brain activity is probed during resting state in addition to visual and auditory oddball paradigms. Parallel investigations of patient derived iPSCs are also ongoing.
Results:
To date, 117 individuals from 61 families have been identified with NRXN1 deletions across 6 European sites and recruitment is ongoing. Neuropsychological assessments have been administered to 26 individuals (8 de novo, 8 inherited and 10 familial carriers). From these, 12 individuals have met criteria for ASD, 7 for intellectual disability (3 mild ID and 4 severe ID), 5 for epilepsy, 5 for an anxiety disorder, 3 for a psychotic disorder, 3 for ADHD and 2 for a mood disorder. Neurocognitive assessments to date (n=6) indicate that poor attention and executive dysfunction are most characteristic of individuals with NRXN1 deletions. Preliminary MRI data (n=6) suggests individuals with NRXN1 deletions have an altered cortical structure, characterised by reduced cortical thickness, greater surface area and disrupted white matter organisation.
Conclusions:
Although the study data are preliminary, interesting clinical characteristics of NRXN1 deletions are emerging. NRXN1 deletions are an important risk factor for neurodevelopmental disorders. Additional clinical and neurobiological phenotyping in addition to mapping of the NRXN1 genotype may elucidate the underlying neurobiological processes contributing to neurodevelopmental disorders.