Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies.
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.
Institute of Neurobiology, Xi'an Jiaotong University Health Science Center, Xian, China.|Department of Pediatric Neurology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Zhongdong
Z
Lin
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.
Zhenwei
Z
Liu
Department of Pediatric Neurology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Xiucui
X
Li
Department of Pediatric Neurology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Feng
F
Li
Department of Pediatric Neurology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Ying
Y
Hu
Research Center of Blood Transfusion Medicine, Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial People's Hospital, Hangzhou, China.
Bingyu
B
Chen
Research Center of Blood Transfusion Medicine, Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial People's Hospital, Hangzhou, China. yuchen6046@163.com.
Zhen
Z
Wang
Institute of Neurobiology, Xi'an Jiaotong University Health Science Center, Xian, China. liuy5599@mail.xjtu.edu.cn.
Yong
Y
Liu
D056445:Cytoplasmic Dyneins / Q000235:genetics*; D005192:Family Health; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D013036:Spasms, Infantile / Q000235:genetics*; D000073359:Exome Sequencing
C511240:DYNC1H1 protein, human; D026901:Membrane Transport Proteins; C495316:RTP1 protein, human; D056445:Cytoplasmic Dyneins