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Novel disease loci
Original research
NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways
  1. Sipeng Zhang1,
  2. Jie Yang1,
  3. Dandan Ji1,
  4. Xinyi Meng1,
  5. Chonggui Zhu2,
  6. Gang Zheng3,
  7. Joseph Glessner4,5,6,
  8. Hui-Qi Qu4,
  9. Yuechen Cui1,
  10. Yichuan Liu4,
  11. Wei Wang7,
  12. Xiumei Li1,
  13. Hao Zhang1,
  14. Zhanjie Xiu1,8,
  15. Yan Sun1,
  16. Ling Sun9,
  17. Jie Li9,
  18. Hakon Hakonarson4,5,6,
  19. Jin Li1,10,
  20. Qianghua Xia1,8
  1. 1 Department of Cell Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Tianjin Institute of Immunology, Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
  2. 2 Department of Endocrinology, Tianjin Medical University General Hospital, Tianjin, China
  3. 3 National Supercomputer Center in Tianjin (NSCC-TJ), Tianjin, China
  4. 4 Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
  5. 5 Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
  6. 6 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  7. 7 The Institute of Psychology of the Chinese Academy of Sciences, Beijing, China
  8. 8 Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
  9. 9 Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Tianjin Medical University, Tianjin, China
  10. 10 Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, China
  1. Correspondence to Dr Jin Li, Department of Cell Biology, Tianjin Medical University, Tianjin, China; jli01{at}tmu.edu.cn; Dr Qianghua Xia, Department of Bioinformatics, Tianjin Medical University, Tianjin, China; qhxia{at}tmu.edu.cn

Abstract

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.

  • Genetic Variation
  • Psychiatry
  • Epigenomics
  • Mutation
  • Pediatrics

Data availability statement

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.

https://doi.org/10.1136/jmg-2023-109385

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    Data availability statement

    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.

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    Footnotes

    • JL and QX are joint senior authors.

    • SZ, JY, DJ and XM contributed equally.

    • Contributors JinL and QX led the conception and design of the study. CZ and WW collected and provided data of the participating families. SZ and DJ conducted molecular and biochemical experiments and generated sequencing data. JY and XM were mainly involved in the data analysis, processing and summarisation. JinL, QX, SZ, JY, DJ and XM drafted the manuscript. Other authors have partially participated in the study and revised the manuscript critically for important intellectual content. All listed authors have seen and approved the manuscript. JinL acts as a guarantor.

    • Funding This project was funded by the National Natural Science Foundation of China (no: 82202009), Science and Technology Development Fund of Tianjin Education Commission for Higher Education (no: 2020KJ196), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-040A) and Tianjin Outstanding Health Professional Selection and Training Program (TJSJMYXYC-D2-031).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.