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De Novo and Inherited SETD1A Variants in Early-onset Epilepsy

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Abstract

Early-onset epilepsy is a neurological abnormality in childhood, and it is especially common in the first 2 years after birth. Seizures in early life mostly result from structural or metabolic disorders in the brain, and the genetic causes of idiopathic seizures have been extensively investigated. In this study, we identified four missense mutations in the SETD1A gene (SET domain-containing 1A, histone lysine methyltransferase): three de novo mutations in three individuals and one inherited mutation in a four-generation family. Whole-exome sequencing indicated that all four of these mutations were responsible for the seizures. Mutations of SETD1A have been implicated in schizophrenia and developmental disorders, so we examined the role of the four mutations (R913C, Q269R, G1369R, and R1392H) in neural development. We found that their expression in mouse primary cortical neurons affected excitatory synapse development. Moreover, expression of the R913C mutation also affected the migration of cortical neurons in the mouse brain. We further identified two common genes (Neurl4 and Usp39) affected by mutations of SETD1A. These results suggested that the mutations of SETD1A play a fundamental role in abnormal synaptic function and the development of neurons, so they may be pathogenic factors for neurodevelopmental disorders.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81741087, 91432111, 31625013, and 81471484), the Science and Technology Commission of Shanghai Municipality, China (14411950402), a Shanghai Municipal Science and Technology Major Project (#018SHZDZX05), and the Postdoctoral Science Foundation of China (2017M621361).

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Author notes

  1. Xiuya Yu and Lin Yang have contributed equally to this work.

Authors and Affiliations

  1. Division of Neonatology, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Xiuya Yu, Wanxing Li & Wenhao Zhou

  2. Clinical Genetic Center, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Lin Yang

  3. Key Laboratory of Birth Defects, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Lin Yang & Wenhao Zhou

  4. Institute of Biomedicine Sciences, Fudan University, Shanghai, 200032, China

    Jin Li

  5. Department of Prenatal Diagnosis, The Women and Children’s Medical Center, Guangzhou, 510623, China

    Dongzhi Li

  6. Euler Genomics, Beijing, 102206, China

    Ran Wang, Kai Wu, Wenhao Chen & Yi Zhang

  7. School of Life Sciences, Peking University, Beijing, 100191, China

    Yi Zhang

  8. Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Zilong Qiu

  9. Laboratory of Neonatal Diseases, Ministry of Health, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Wenhao Zhou

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  1. Xiuya Yu
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  2. Lin Yang
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  3. Jin Li
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  4. Wanxing Li
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  6. Ran Wang
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  8. Wenhao Chen
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  9. Yi Zhang
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  10. Zilong Qiu
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  11. Wenhao Zhou
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Corresponding authors

Correspondence to Yi Zhang, Zilong Qiu or Wenhao Zhou.

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Yu, X., Yang, L., Li, J. et al. De Novo and Inherited SETD1A Variants in Early-onset Epilepsy. Neurosci. Bull. 35, 1045–1057 (2019). https://doi.org/10.1007/s12264-019-00400-w

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  • DOI: https://doi.org/10.1007/s12264-019-00400-w

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