De Novo and Inherited SETD1A Variants in Early-onset Epilepsy

  • Xiuya Yu
  • Lin Yang
  • Jin Li
  • Wanxing Li
  • Dongzhi Li
  • Ran Wang
  • Kai Wu
  • Wenhao Chen
  • Yi ZhangEmail author
  • Zilong QiuEmail author
  • Wenhao ZhouEmail author
Original Article


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.


Early-onset epilepsy Whole-exome sequencing SETD1A Neural development 



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).

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

12264_2019_400_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1130 kb)


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Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  1. 1.Division of NeonatologyChildren’s Hospital of Fudan UniversityShanghaiChina
  2. 2.Clinical Genetic CenterChildren’s Hospital of Fudan UniversityShanghaiChina
  3. 3.Key Laboratory of Birth DefectsChildren’s Hospital of Fudan UniversityShanghaiChina
  4. 4.Institute of Biomedicine SciencesFudan UniversityShanghaiChina
  5. 5.Department of Prenatal DiagnosisThe Women and Children’s Medical CenterGuangzhouChina
  6. 6.Euler GenomicsBeijingChina
  7. 7.School of Life SciencesPeking UniversityBeijingChina
  8. 8.Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina
  9. 9.Laboratory of Neonatal Diseases, Ministry of HealthChildren’s Hospital of Fudan UniversityShanghaiChina

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