期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-10482-9
关键词
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资金
- grant for Research on Measures for Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) [JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18dm0107133, JP18ek0109381, JP18kk020500]
- grant for Comprehensive Research on Disability, Health and Welfare from the Japan Agency for Medical Research and Development (AMED) [JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18dm0107133, JP18ek0109381, JP18kk020500]
- Strategic Research Program for Brain Science (SRPBS) from the Japan Agency for Medical Research and Development (AMED) [JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18dm0107133, JP18ek0109381, JP18kk020500]
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)
- Japan Society for the Promotion of Science (JSPS) [JP17H01539, JP16H05160, JP16H05357, JP16H06254, JP15K10367, JP17K10080, JP 17K15630, JP17H06994]
- Takeda Science Foundation
- Ministry of Health, Labour and Welfare of Japan
- Yokohama Foundation for Advancement of Medical Science
- Hayashi Memorial Foundation for Female Natural Scientists
- Ichiro Kanehara Foundation for the Promotion of Medical Science Medical Care
- Japan Epilepsy Research Foundation
Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 x 10(-6)) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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