De Novo and Inherited SETD1A Variants in Early-onset Epilepsy

作     者：Xiuya Yu Lin Yang Jin Li Wanxing Li Dongzhi Li Ran Wang Kai Wu Wenhao Chen Yi Zhang Zilong Qiu Wenhao Zhou 

作者机构：Division of NeonatologyChildren's Hospital of Fudan UniversityShanghai 201102China Clinical Genetic CenterChildren's Hospital of Fudan UniversityShanghai 201102China Key Laboratory of Birth DefectsChildren's Hospital of Fudan UniversityShanghai 201102China Institute of Biomedicine SciencesFudan UniversityShanghai 200032China Department of Prenatal DiagnosisThe Women and Children's Medical CenterGuangzhou 510623China Euler GenomicsBeijing 102206China School of Life SciencesPeking UniversityBeijing 100191China Institute of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China Laboratory of Neonatal DiseasesMinistry of HealthChildren's Hospital of Fudan UniversityShanghai 201102China 

出 版 物：《Neuroscience Bulletin》 (神经科学通报（英文版）)

年 卷 期：2019年第35卷第6期

页      面：1045-1057页

核心收录：

学科分类：1002[医学-临床医学] 10[医学] 

基　　金：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) the Postdoctoral Science Foundation of China (2017M621361) 

主　　题：Early-onset epilepsy Whole-exome sequencing SETD1A Neural development 

摘      要：Early-onset epilepsy is a neurological abnormality in childhood, and it is especially common in the first2 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 SETD1 A gene(SET domain-containing 1 A, 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 SETD1 A have been implicated in schizophrenia and developmental disorders, so we examined the role of the four mutations(R913 C, Q269 R, G1369 R, and R1392 H) in neural development. We found that their expression in mouse primary cortical neurons affected excitatory synapse development. Moreover, expression of the R913 C mutation also affected the migration of cortical neurons in the mouse *** further identified two common genes(Neurl4 and Usp39) affected by mutations of SETD1 A. These results suggested that the mutations of SETD1 A play a fundamental role in abnormal synaptic function and the development of neurons, so they may be pathogenic factors for neurodevelopmental disorders.