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

被引：43

作者：

Takata, Atsushi ^{[1
]}

Nakashima, Mitsuko ^{[1
,2
]}

Saitsu, Hirotomo ^{[1
,2
]}

Mizuguchi, Takeshi ^{[1
]}

Mitsuhashi, Satomi ^{[1
]}

Takahashi, Yukitoshi ^{[3
]}

Okamoto, Nobuhiko ^{[4
]}

Osaka, Hitoshi ^{[5
]}

Nakamura, Kazuyuki ^{[6
]}

Tohyama, Jun ^{[7
]}

Haginoya, Kazuhiro ^{[8
]}

Takeshita, Saoko ^{[9
]}

Kuki, Ichiro ^{[10
]}

Okanishi, Tohru ^{[11
]}

Goto, Tomohide ^{[12
]}

Sasaki, Masayuki ^{[13
]}

Sakai, Yasunari ^{[14
]}

Miyake, Noriko ^{[1
]}

Miyatake, Satoko ^{[1
]}

Tsuchida, Naomi ^{[1
]}

Iwama, Kazuhiro ^{[1
]}

Minase, Gaku ^{[1
]}

Sekiguchi, Futoshi ^{[1
]}

Fujita, Atsushi ^{[1
]}

Imagawa, Eri ^{[1
]}

Koshimizu, Eriko ^{[1
]}

Uchiyama, Yuri ^{[1
]}

Hamanaka, Kohei ^{[1
]}

Ohba, Chihiro ^{[1
]}

Itai, Toshiyuki ^{[1
]}

Aoi, Hiromi ^{[1
]}

Saida, Ken ^{[1
]}

Sakaguchi, Tomohiro ^{[1
]}

Den, Kouhei ^{[1
]}

Takahashi, Rina ^{[1
]}

Ikeda, Hiroko ^{[3
]}

Yamaguchi, Tokito ^{[3
]}

Tsukamoto, Kazuki ^{[3
]}

Yoshitomi, Shinsaku ^{[3
]}

Oboshi, Taikan ^{[3
]}

Imai, Katsumi ^{[3
]}

Kimizu, Tomokazu ^{[15
]}

Kobayashi, Yu ^{[7
]}

Kubota, Masaya ^{[16
]}

Kashii, Hirofumi ^{[16
]}

Baba, Shimpei ^{[11
]}

Iai, Mizue ^{[12
]}

Kira, Ryutaro ^{[17
]}

Hara, Munetsugu ^{[18
]}

Ohta, Masayasu ^{[19
]}

机构：

[1] Yokohama City Univ, Dept Human Genet, Grad Sch Med, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan

[2] Hamamatsu Univ Sch Med, Dept Biochem, Higashi Ku, 1-20-1 Handayama, Hamamatsu, Shizuoka 4313192, Japan

[3] NHO Shizuoka Inst Epilepsy & Neurol Disorders, Natl Epilepsy Ctr, Aoi Ku, 886 Urushiyama, Shizuoka 4208688, Japan

[4] Osaka Womens & Childrens Hosp, Dept Med Genet, 840 Murodo Cho, Izumi, Osaka 5941101, Japan

[5] Jichi Med Univ, Dept Pediat, 3311-1 Yakushiji, Shimotsuke, Tochigi 3290498, Japan

[6] Yamagata Univ, Dept Pediat, Fac Med, 2-2-2 Iida Nishi, Yamagata 9909585, Japan

[7] NHO Nishiniigata Chuo Hosp, Dept Child Neurol, Nishi Ku, 1-14-1 Masago, Niigata 9502085, Japan

[8] Miyagi Childrens Hosp, Dept Pediat Neurol, Aoba Ku, 4-3-17 Ochiai, Sendai, Miyagi 9893126, Japan

[9] Yokohama City Univ, Dept Pediat, Med Ctr, Minami Ku, 4-57 Urafunecho, Yokohama, Kanagawa 2320024, Japan

[10] Osaka City Gen Hosp, Dept Pediat Neurol, Miyakojima Ku, 2-13-22 Miyakojimahondori, Osaka 5340021, Japan

[11] Seirei Hamamatsu Gen Hosp, Comprehens Epilepsy Ctr, Dept Child Neurol, Naka Ku, 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka 4308558, Japan

[12] Kanagawa Childrens Med Ctr, Div Neurol, Minami Ku, 2-138-4 Mutsukawa, Yokohama, Kanagawa 2328555, Japan

[13] Natl Ctr Neurol & Psychiat, Dept Child Neurol, 4-1-1 Ogawahigashi, Kodaira, Tokyo 1878551, Japan

[14] Kyushu Univ, Grad Sch Med Sci, Dept Pediat, Higashi Ku, 3-1-1 Maidashi, Fukuoka, Fukuoka 8128582, Japan

[15] Osaka Womens & Childrens Hosp, Dept Pediat Neurol, 840 Murodo Cho, Izumi, Osaka 5941101, Japan

[16] Natl Ctr Child Hlth & Dev, Div Neurol, Setagaya Ku, 2-10-1 Okura, Tokyo 1578535, Japan

[17] Fukuoka Childrens Hosp, Dept Pediat Neurol, Higashi Ku, 5-1-1 Kashiiteriha, Fukuoka, Fukuoka 8130017, Japan

[18] Kurume Univ, Dept Pediat & Child Hlth, Sch Med, 67 Asahi Machi, Kurume, Fukuoka 8300011, Japan

[19] Aiseikai Mem Ibaraki Welf Med Ctr, Dept Neuropediat, 1872-1 Motoyoshida Cho, Mito, Ibaraki 3100836, Japan

[20] Tokyo Metropolitan Neurol Hosp, Dept Neuropediat, 2-6-1 Musashidai, Fuchu, Tokyo 1830042, Japan

[21] Tokyo Kita Med Ctr, Dept Pediat, Kita Ku, 4-17-56 Akabanedai, Tokyo 1150053, Japan

[22] Tokyo Womens Med Univ, Dept Pediat, Yachiyo Med Ctr, 477-96 Owadashinden, Yachiyo 2768524, Japan

[23] Shiga Univ Med Sci, Dept Pediat, Setatsukinowacho, Otsu, Shiga 5202192, Japan

[24] Seirei Mikatahara Gen Hosp, Dept Pediat Neurol, Kita Ku, 3453 Mikatahara Cho, Hamamatsu, Shizuoka 4311304, Japan

[25] Univ Occupat & Environm Hlth, Dept Pediat, Sch Med, Yahatanishi Ku, 1-1 Iseigaoka, Kitakyushu, Fukuoka 8078555, Japan

[26] Kutakyushu Municipal Yahata Hosp, Pediat Emergency Ctr, Yahatahigashi Ku, 4-18-1 Nishihonmachi, Kutakyushu 8058534, Japan

[27] Hokkaido Med Ctr Child Hlth & Rehabil, Teine Ku, 1-240-6 Kanayama 1 Jo, Sapporo, Hokkaido 0060041, Japan

[28] Nagano Childrens Hosp, Div Neurol, 3100 Toyoshina, Azumino 3998288, Japan

[29] Toyohashi Municipal Hosp, Dept Pediat, 50 Aza Hachiken Nishi,Aotake Cho, Toyohashi, Aichi 4418570, Japan

[30] Natl Def Med Coll, Dept Pediat, 3-2 Namiki, Tokorozawa, Saitama 3598513, Japan

[31] Osaka Univ, Grad Sch Med, Dept Pediat, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan

[32] Gunma Childrens Med Ctr, Dept Neurol, 779 Shimohakoda,Hokkitsu Machi, Shibukawa 3778577, Japan

[33] Showa Univ, Dept Pediat, Sch Med, Shinagawa Ku, 1-5-8 Hatanodai, Tokyo 1428666, Japan

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

日本学术振兴会;

关键词：

DE-NOVO MUTATIONS; NEUROFIBROMATOSIS TYPE-1; PHENOTYPIC HETEROGENEITY; ILAE COMMISSION; AUTISM; ASSOCIATION; DISORDERS; SEIZURES; GENOME; COMMON;

D O I：

10.1038/s41467-019-10482-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

共 50 条

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