De Novo and Inherited SETD1A Variants in Early-onset Epilepsy

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.