Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy

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-ra...

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Detalles Bibliográficos
Autores principales: Takata, Atsushi, Nakashima, Mitsuko, Saitsu, Hirotomo, Mizuguchi, Takeshi, Mitsuhashi, Satomi, Takahashi, Yukitoshi, Okamoto, Nobuhiko, Osaka, Hitoshi, Nakamura, Kazuyuki, Tohyama, Jun, Haginoya, Kazuhiro, Takeshita, Saoko, Kuki, Ichiro, Okanishi, Tohru, Goto, Tomohide, Sasaki, Masayuki, Sakai, Yasunari, Miyake, Noriko, Miyatake, Satoko, Tsuchida, Naomi, Iwama, Kazuhiro, Minase, Gaku, Sekiguchi, Futoshi, Fujita, Atsushi, Imagawa, Eri, Koshimizu, Eriko, Uchiyama, Yuri, Hamanaka, Kohei, Ohba, Chihiro, Itai, Toshiyuki, Aoi, Hiromi, Saida, Ken, Sakaguchi, Tomohiro, Den, Kouhei, Takahashi, Rina, Ikeda, Hiroko, Yamaguchi, Tokito, Tsukamoto, Kazuki, Yoshitomi, Shinsaku, Oboshi, Taikan, Imai, Katsumi, Kimizu, Tomokazu, Kobayashi, Yu, Kubota, Masaya, Kashii, Hirofumi, Baba, Shimpei, Iai, Mizue, Kira, Ryutaro, Hara, Munetsugu, Ohta, Masayasu, Miyata, Yohane, Miyata, Rie, Takanashi, Jun-ichi, Matsui, Jun, Yokochi, Kenji, Shimono, Masayuki, Amamoto, Masano, Takayama, Rumiko, Hirabayashi, Shinichi, Aiba, Kaori, Matsumoto, Hiroshi, Nabatame, Shin, Shiihara, Takashi, Kato, Mitsuhiro, Matsumoto, Naomichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845/
https://www.ncbi.nlm.nih.gov/pubmed/31175295
http://dx.doi.org/10.1038/s41467-019-10482-9
Descripción
Sumario: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 × 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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