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On the basis of massive sequencing data, functional interactions among different genes are suggested to explain the common molecular pathway underlying the pathogenic process of these disorders. However, the relevance of such interactions with the phenotypic severity or variety in an affected individual remains elusive. In this report, we present a 45\u2010year\u2010old woman with neurofibromatosis type 1 (NF1), infantile\u2010onset epileptic encephalopathy, and severe developmental delay. Whole\u2010exome sequencing identified de novo pathogenic mutations in <jats:italic>NF1<\/jats:italic> and the Schaaf\u2010Yang syndrome\u2010associated gene, <jats:italic>MAGEL2<\/jats:italic>. Literature\u2010curated interaction data predicted that NF1 and MAGEL2 proteins were closely connected in this network via their common interacting proteins. Direct conversion of fibroblasts into neurons in\u00a0vitro showed that neuronal cells from 9 patients with NF1 expressed significantly lower levels of <jats:italic>MAGEL2<\/jats:italic> (54%, p\u00a0=\u00a00.0047) than those from healthy individuals. These data provide the first evidence that pathogenic mutations of <jats:italic>NF1<\/jats:italic> deregulate the expression of other neurodevelopmental disease\u2010associated genes. De novo mutations in multiple genes may lead to severe developmental phenotypes through their cumulative effects or synergistic interactions.<\/jats:p>","DOI":"10.1002\/epi4.12085","type":"journal-article","created":{"date-parts":[[2017,11,2]],"date-time":"2017-11-02T16:23:40Z","timestamp":1509639820000},"page":"81-85","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Early\u2010onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in <i>NF1<\/i> and <i>MAGEL2<\/i>"],"prefix":"10.1002","volume":"3","author":[{"given":"Satoshi","family":"Akamine","sequence":"first","affiliation":[{"name":"Department of Pediatrics Graduate School of Medical Sciences Kyushu University Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriaki","family":"Sagata","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Graduate School of Medical Sciences Kyushu University Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasunari","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Graduate School of Medical Sciences Kyushu University Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro A.","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Graduate School of Medical Sciences Kyushu University Fukuoka Japan"},{"name":"Innovation Center for Medical Redox Navigation Graduate School of Medical Sciences Kyushu University Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Nakahara","sequence":"additional","affiliation":[{"name":"Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka 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Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomichi","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiro","family":"Hara","sequence":"additional","affiliation":[{"name":"Fukuoka Children's Hospital Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Sawa","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry Mental Health, Neuroscience, and Biomedical Engineering Johns Hopkins University School of Medicine and Bloomberg School of Public Health Baltimore Maryland U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichi","family":"Kano","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine and Bloomberg 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