Whole Exome sequencing for genetic modifiers associated with phenotype of epileptic encephalopathy

• Project/Area Number: 26860781
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Yamagata University
• Principal Investigator: Nakamura Kazuyuki 山形大学, 医学部, 助教 (20436215)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: てんかん / 遺伝子 / 小児神経学 / 脳形成異常 / てんかん性脳症 / 全エクソン解析

Outline of Final Research Achievements

We analyzed with genetic basis of epileptic encephalopathy using whole exome sequencing. First, we identified GRIN2A mutations in two families: atypical Rett syndrome and unclassified epileptic encepalopathy. Our study suggests that GRIN2A mutations can be associated with atypical Rett syndrome. A variety of severity is to be noted in patients with GRIN2A mutations.
Secondly, we found compound heterozygous ASPM mutations in a case of primary microcephaly and epilepsy. This patient showed more severe intelectual disability and motor delay than individuals with ASPM mutations previously reported, and pachygyria with frontal lobe predominance. Our findings expand the variable severity of cortical malformations in patients with ASPM mutations, and suggest that frontal lesion predominance may be characteristic for ASPM mutations.

Research Products

• [Journal Article] Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay (2016)
  • Author(s): Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, Torio M, Akamine S, Takahashi N, Osaka H, Yamagata T, Nakamura K, Tsurusaki Y, Nakashima M, Miyake N, Shiina M, Ogata K, Matsumoto N
  • Journal Title: Eur J Hum Genet Volume: 24(1) Issue: 1 Pages: 129-134
  • DOI: 10.1038/ejhg.2015.92
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia (2016)
  • Author(s): Makrythanasis P, Kato M, Zaki MS, Saitsu H, Nakamura K, Santoni FA, Miyatake S, Nakashima M, Issa MY, Guipponi M, Letourneau A, Logan CV, Roberts N, Parry DA, Johnson CA, Matsumoto N, Hamamy H, Sheridan E, Kinoshita T, Antonarakis SE, Murakami Y.
  • Journal Title: Am J Hum Genet Volume: 98 Issue: 4 Pages: 615-626
  • DOI: 10.1016/j.ajhg.2016.02.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Primary Microcephaly With Anterior Predominant Pachygyria Caused by Novel Compound Heterozygous Mutations in ASPM (2015)
  • Author(s): Nakamura K, Inui T, Kanemura Y, Okamoto N, Saitoh S, Yamasaki M, Tsunoda T, Kosaki K, Tanaka S, Kato M
  • Journal Title: Pediatr Neurol Volume: 52 Issue: 5 Pages: e7-e8
  • DOI: 10.1016/j.pediatrneurol.2015.01.019
  • Peer Reviewed
• [Journal Article] 特集 けいれん性疾患の最新の治療 Ⅲ.最近の進歩 原因遺伝子の解明から新しい治療薬の開発へ． (2015)
  • Author(s): 中村和幸，加藤光広
  • Journal Title: 小児科診療 Volume: 2 Pages: 253-258
• [Journal Article] Paternal Germline Mosaicism of a SCN2A Mutation Results in Ohtahara Syndrome in Half Siblings. (2014)
  • Author(s): Zerem A, Blumkin L, Goldberg-Stern H,Michaeli-Yossef Y, Halevy A, Kivity S, Nakamura K, Matsumoto N, Leshinsky-Silver E, Saitsu H, Lerman-Sagie T
  • Journal Title: Eur J Pediatr Neurol Volume: 18 Issue: 5 Pages: 567-571
  • DOI: 10.1016/j.ejpn.2014.04.008
  • Peer Reviewed
• [Journal Article] 年齢依存性てんかん性脳症 (2014)
  • Author(s): 中村和幸，加藤光広
  • Journal Title: こどもケア Volume: 9 Pages: 7-11
• [Presentation] Evidence that variants in PIGG cause intellectual disability with early onset seizures and hypotonia (2015)
  • Author(s): Makrythanasis P, Kinoshita T, Zaki MS, Saitsu H, Santoni FA, Miyatake S, Nakashima N, Matsumoto N, Mahmoud I, Guipponi M, Kato M, Nakamura K, Hamamy H, Antonarakis SE, Murakami M
  • Organizer: American Society of Human Genetics Annual Meeting
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Presentation] Expanding clinical spectrum of GRIN2A mutations to atypical Rett syndrome (2015)
  • Author(s): Nakamura K, Kato M, Togawa M, Maegaki Y, Ito M, Kawasaki M, Shinozaki T, Nakashima M, Matsumoto M, Saitsu H
  • Organizer: 31st International Epilepsy Congress
  • Place of Presentation: Istunbul, Turkey
  • Year and Date: 2015-09-05
  • Int'l Joint Research
• [Presentation] A case of rapid-progressive bilateral Rasmussen’s encephalitis (2015)
  • Author(s): Nakamura K, Takahashi N, Onoda T, Kakita A, Takahashi Y, Honma N, Mitsui T, Kato M
  • Organizer: 13th Asian and Oceania Congress of Child Neurology
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Presentation] A Newly identified congenital disorder of glycosylation caused by de novo mutations in SLC35A2 encoding a UDP-galactose transporter is associated with early-onset epileptic encephalopathy (2014)
  • Author(s): 中村 和幸、小寺 啓文、加藤 光広、小坂 仁、前垣 義弘、萩野谷 和裕、岡本 伸彦、井合 瑞江、湯浅 勲、和田 芳直、才津 浩智、松本 直通
  • Organizer: 第48回日本てんかん学会
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2014-10-02