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Epileptic encephalopathies (EE) are a group of severe childhood epilepsy disorders characterized by intractable seizures, cognitive impairment and neurological deficits. Recent whole-exome sequencing (WES) studies have implicated significant contribution of  de novo  mutations to EE. In this study, we utilized WES for identifying causal  de novo  mutations in 4 parent-offspring trios affected by West syndrome. As a result, we found two deleterious  de novo  mutations in  DYNC1H1  and  RTP1  in two trios. Expression profile analysis showed that  DYNC1H1  and  RTP1  are expressed in almost all brain regions and developmental stages. Interestingly, co-expression and genetic interaction network analyses suggested that  DYNC1H1  and  RTP1  are tightly associated with known epilepsy genes. Furthermore, we observed that the  de novo  mutations of  DYNC1H1  were identified in several different neuropsychiatric disorders including EE, autism spectrum disorders and intellectual disabilities by previous studies, and these mutations primarily occurred in the functional domain of the protein. Taken together, these results demonstrate  DYNC1H1  as a strong candidate and  RTP1  as a potential candidate on the onset of EE. In addition, this work also proves WES as a powerful tool for the molecular genetic dissection of children affected by sporadic EE.

Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies