E-viri
PDF
Recenzirano
Odprti dostop
-
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
Nature communications, 06/2019, Letnik: 10, Številka: 1Journal Article
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 ) 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.
