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

Atsushi Takata (), Mitsuko Nakashima, Hirotomo Saitsu, Takeshi Mizuguchi, Satomi Mitsuhashi, Yukitoshi Takahashi, Nobuhiko Okamoto, Hitoshi Osaka, Kazuyuki Nakamura, Jun Tohyama, Kazuhiro Haginoya, Saoko Takeshita, Ichiro Kuki, Tohru Okanishi, Tomohide Goto, Masayuki Sasaki, Yasunari Sakai, Noriko Miyake, Satoko Miyatake, Naomi Tsuchida, Kazuhiro Iwama, Gaku Minase, Futoshi Sekiguchi, Atsushi Fujita, Eri Imagawa, Eriko Koshimizu, Yuri Uchiyama, Kohei Hamanaka, Chihiro Ohba, Toshiyuki Itai, Hiromi Aoi, Ken Saida, Tomohiro Sakaguchi, Kouhei Den, Rina Takahashi, Hiroko Ikeda, Tokito Yamaguchi, Kazuki Tsukamoto, Shinsaku Yoshitomi, Taikan Oboshi, Katsumi Imai, Tomokazu Kimizu, Yu Kobayashi, Masaya Kubota, Hirofumi Kashii, Shimpei Baba, Mizue Iai, Ryutaro Kira, Munetsugu Hara, Masayasu Ohta, Yohane Miyata, Rie Miyata, Jun-ichi Takanashi, Jun Matsui, Kenji Yokochi, Masayuki Shimono, Masano Amamoto, Rumiko Takayama, Shinichi Hirabayashi, Kaori Aiba, Hiroshi Matsumoto, Shin Nabatame, Takashi Shiihara, Mitsuhiro Kato and Naomichi Matsumoto ()
Additional contact information
Atsushi Takata: Yokohama City University Graduate School of Medicine
Mitsuko Nakashima: Yokohama City University Graduate School of Medicine
Hirotomo Saitsu: Yokohama City University Graduate School of Medicine
Takeshi Mizuguchi: Yokohama City University Graduate School of Medicine
Satomi Mitsuhashi: Yokohama City University Graduate School of Medicine
Yukitoshi Takahashi: NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Nobuhiko Okamoto: Osaka Women’s and Children’s Hospital
Hitoshi Osaka: Jichi Medical University
Kazuyuki Nakamura: Yamagata University Faculty of Medicine
Jun Tohyama: NHO Nishiniigata Chuo Hospital
Kazuhiro Haginoya: Miyagi Children’s Hospital
Saoko Takeshita: Yokohama City University Medical Center
Ichiro Kuki: Osaka City General Hospital
Tohru Okanishi: Seirei Hamamatsu General Hospital
Tomohide Goto: Kanagawa Children’s Medical Center
Masayuki Sasaki: National Center of Neurology and Psychiatry
Yasunari Sakai: Kyushu University
Noriko Miyake: Yokohama City University Graduate School of Medicine
Satoko Miyatake: Yokohama City University Graduate School of Medicine
Naomi Tsuchida: Yokohama City University Graduate School of Medicine
Kazuhiro Iwama: Yokohama City University Graduate School of Medicine
Gaku Minase: Yokohama City University Graduate School of Medicine
Futoshi Sekiguchi: Yokohama City University Graduate School of Medicine
Atsushi Fujita: Yokohama City University Graduate School of Medicine
Eri Imagawa: Yokohama City University Graduate School of Medicine
Eriko Koshimizu: Yokohama City University Graduate School of Medicine
Yuri Uchiyama: Yokohama City University Graduate School of Medicine
Kohei Hamanaka: Yokohama City University Graduate School of Medicine
Chihiro Ohba: Yokohama City University Graduate School of Medicine
Toshiyuki Itai: Yokohama City University Graduate School of Medicine
Hiromi Aoi: Yokohama City University Graduate School of Medicine
Ken Saida: Yokohama City University Graduate School of Medicine
Tomohiro Sakaguchi: Yokohama City University Graduate School of Medicine
Kouhei Den: Yokohama City University Graduate School of Medicine
Rina Takahashi: Yokohama City University Graduate School of Medicine
Hiroko Ikeda: NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Tokito Yamaguchi: NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Kazuki Tsukamoto: NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Shinsaku Yoshitomi: NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Taikan Oboshi: NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Katsumi Imai: NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Tomokazu Kimizu: Osaka Women’s and Children’s Hospital
Yu Kobayashi: NHO Nishiniigata Chuo Hospital
Masaya Kubota: National Center for Child Health and Development
Hirofumi Kashii: National Center for Child Health and Development
Shimpei Baba: Seirei Hamamatsu General Hospital
Mizue Iai: Kanagawa Children’s Medical Center
Ryutaro Kira: Fukuoka Children’s Hospital
Munetsugu Hara: Kurume University School of Medicine
Masayasu Ohta: Aiseikai Memorial Ibaraki Welfare Medical Center
Yohane Miyata: Tokyo Metropolitan Neurological Hospital
Rie Miyata: Tokyo-kita Medical Center
Jun-ichi Takanashi: Tokyo Women’s Medical University Yachiyo Medical Center
Jun Matsui: Shiga University of Medical Science, Setatsukinowacho
Kenji Yokochi: Seirei-Mikatahara General Hospital
Masayuki Shimono: University of Occupational and Environmental Health
Masano Amamoto: Kutakyushu Municipal Yahata Hospital Pediatric Emergency Center
Rumiko Takayama: Hokkaido Medical Center for Child Health and Rehabilitation
Shinichi Hirabayashi: Nagano Children’s Hospital
Kaori Aiba: Toyohashi Municipal Hospital
Hiroshi Matsumoto: National Defense Medical College
Shin Nabatame: Osaka University
Takashi Shiihara: Gunma Children’s Medical Center
Mitsuhiro Kato: Yamagata University Faculty of Medicine
Naomichi Matsumoto: Yokohama City University Graduate School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10482-9

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