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

Author

Listed:
  • Atsushi Takata

    (Yokohama City University Graduate School of Medicine)

  • Mitsuko Nakashima

    (Yokohama City University Graduate School of Medicine
    Hamamatsu University School of Medicine)

  • Hirotomo Saitsu

    (Yokohama City University Graduate School of Medicine
    Hamamatsu University 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
    Showa University School of Medicine)

  • Naomichi Matsumoto

    (Yokohama City University Graduate School of Medicine)

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.

Suggested Citation

  • Atsushi Takata & Mitsuko Nakashima & Hirotomo Saitsu & Takeshi Mizuguchi & Satomi Mitsuhashi & Yukitoshi Takahashi & Nobuhiko Okamoto & Hitoshi Osaka & Kazuyuki Nakamura & Jun Tohyama & Kazuhiro Hagin, 2019. "Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10482-9
    DOI: 10.1038/s41467-019-10482-9
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