SA13 - INVESTIGATION OF NOVEL RARE VARIANTS IN NRXN1 CONTRIBUTES TO THE INCREASED RISK OF AUTISM SPECTRUM DISORDERS AND SCHIZOPHRENIA

Abstract

Background NRXN1 is a transmembrane protein having a fundamental role in synaptogenesis, synaptic maintenance, neurotransmitter release, and the function of voltage-gated calcium channels in the synapses of brainstem and neocortex. Impairments in NRXN1 caused by genetic variants are thought to be critical for the pathomechanisms in neuropsychiatric disorders including autism spectrum disorders and schizophrenia. Methods In this study, we conducted exon-targeted resequencing of the NRXN1 gene with next-generation sequencing technology in 562 Japanese patients (192 with idiopathic autism and 370 with schizophrenia). We then performed in silico analyses, trio analyses, and association analyses on 1,892 cases (381 autism and 1,511 schizophrenia) and 1,291 controls with these variants. Results We detected six heterozygous variants with allele frequencies of ≤1%. We regarded three missense variants (p.T777M, p.D812G, p.R896W) as novel ones because they were predicted to be damaging based on in silico predictions and because each was not registered in either HGVD or iJGVD, the Japanese public databases. Among these three cases, two involved transmission from a healthy mother to her autistic son, and one involved transmission from a healthy mother to her schizophrenia daughter. We found no statistically significant association for any of three rare point variants in NRXN1 with case-control analysis. Discussion We explored the role of rare NRXN1 variants in Japanese neuropsychiatric disorders. To assess the impact of the variants discovered here, further investigation by sample size expansion and biological analysis will be performed.