RT Journal Article SR Electronic T1 NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 677 OP 688 DO 10.1136/jmg-2023-109385 VO 61 IS 7 A1 Zhang, Sipeng A1 Yang, Jie A1 Ji, Dandan A1 Meng, Xinyi A1 Zhu, Chonggui A1 Zheng, Gang A1 Glessner, Joseph A1 Qu, Hui-Qi A1 Cui, Yuechen A1 Liu, Yichuan A1 Wang, Wei A1 Li, Xiumei A1 Zhang, Hao A1 Xiu, Zhanjie A1 Sun, Yan A1 Sun, Ling A1 Li, Jie A1 Hakonarson, Hakon A1 Li, Jin A1 Xia, Qianghua YR 2024 UL http://jmg.bmj.com/content/61/7/677.abstract AB Background Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology.Methods Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene.Results We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene.Conclusion We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.Data are available upon reasonable request. Data which support the findings of this study are included within the article and the supplementary materials. Additional supporting information, including human whole exome sequencing data, is available from the corresponding authors upon request and in accordance with the Data Usage Agreement.