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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 (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.000215), suggesting oligogenic contribution of non-EE\/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20092.04\u2009\u00d7\u200910\n                    <jats:sup>\u22126<\/jats:sup>\n                    ) enrichment of damaging de novo mutations in\n                    <jats:italic>NF1<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-019-10482-9","type":"journal-article","created":{"date-parts":[[2019,6,7]],"date-time":"2019-06-07T06:02:44Z","timestamp":1559887364000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic 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