Abstract
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.
Highlights
Epileptic encephalopathies (EE) are typically defined as a devastating group of severe childhood epilepsy disorders characterized by early onset of seizures associated with ongoing epileptic activity[1]
In a study in which exome sequencing was performed in 264 patient-parent trios with EE, de novo mutations were recurrently observed in probands within known causative genes for West syndrome, such as STXBP1 (n = 4) and CDKL5 (n = 2)[9]
These findings showed that West syndrome is a genetically heterogeneous condition, and de novo mutations play a significant role in the onset of West syndrome
Summary
Epileptic encephalopathies (EE) are typically defined as a devastating group of severe childhood epilepsy disorders characterized by early onset of seizures associated with ongoing epileptic activity[1]. In a study in which exome sequencing was performed in 264 patient-parent trios with EE, de novo mutations were recurrently observed in probands within known causative genes for West syndrome, such as STXBP1 (n = 4) and CDKL5 (n = 2)[9]. De novo mutations in GRIN2B10, GNAO111, KCNT112 and SPTAN113 found in probands have been recognized as being associated with West syndrome. These findings showed that West syndrome is a genetically heterogeneous condition, and de novo mutations play a significant role in the onset of West syndrome. The de novo mutations in DYNC1H1 were found to be shared among different neuropsychiatric disorders of EE, ASD and ID, which further implicated DYNC1H1 in the onset of sporadic neuropsychiatric disorders
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