Comprehensive genomic analysis on perisylvian syndrome

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K10080
• Research Institution: Yokohama City University
• Principal Investigator: 宮武 聡子 横浜市立大学, 附属病院, 講師 (50637890)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 全エクソーム解析 / 傍シルビウス裂症候群 / 多少脳回

Outline of Annual Research Achievements

傍シルビウス裂症候群は大脳のシルビウス裂周辺の脳形成異常や機能異常を呈する難治性疾患である。本研究は日本人の本疾患コホートに対して次世代シーケンサーを駆使した包括的なゲノム解析を行い、本疾患の責任遺伝子の同定と病態解明を目的とする。
本年度はさらに19家系に対して全エクソーム解析を行った。遺伝子のコーディング領域を中心に、塩基置換、微小欠失や挿入配列変化、もしくはコピー数異常について、昨年度全エクソーム解析を行った103例と合わせ、症例で共通する病的な配列変化や構造異常の探索を継続している。
本年度は傍シルビウス裂症候群を引き起こすあらたな疾患責任遺伝子Xを確定し、論文投稿中である。本遺伝子は、機能性脳疾患の原因遺伝子として知られているが、従来大脳の形成異常は伴わないと考えられていたので、今回の発見は臨床的に非常に重要と考えられる。今回7症例の解析から、7つの病的変異を同定した。また結晶構造モデル解析やin vitroの機能解析から、すでに知られている機能性脳疾患の原因変異とは性質が異なることを明らかにした。モデル動物を用いて、今回同定した変異によって患者さんの表現型を裏付ける所見が確認され、その病態が示唆される結果を得た。
これまで3年間の研究で、2019年に論文発表したSCN3A、現在論文投稿中の遺伝子Xに加え、3つの新規遺伝子において、傍シルビウス裂症候群の疾患責任遺伝子と考えられる所見を見だしている。このうち1つの遺伝子については現在までに国内外の7症例を集積し、in vitroおよびin vivoの検証を進めている。また２つの遺伝子については、他施設共同研究を進めている。

Research Products

• [Journal Article] Epilepsy in Christianson syndrome: Two cases of Lennox?Gastaut syndrome and a review of literature (2020)
  • Author(s): Ikeda Azusa、Yamamoto Ayako、Ichikawa Kazushi、Tsuyusaki Yu、Tsuji Megumi、Iai Mizue、Enomoto Yumi、Murakami Hiroaki、Kurosawa Kenji、Miyatake Satoko、Matsumoto Naomichi、Goto Tomohide
  • Journal Title: Epilepsy & Behavior Reports Volume: 13 Pages: 100349～100349
  • DOI: 10.1016/j.ebr.2019.100349
  • Peer Reviewed / Open Access
• [Journal Article] Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities (2020)
  • Author(s): Miyake N, Takahashi H, Nakamura K, Isidor B, Hiraki Y, Koshimizu E, Shiina M, Sasaki K, Suzuki H, Abe R, Kimura Y, Akiyama T, Tomizawa SI, Hirose T, Hamanaka K, Miyatake S, Mitsuhashi S, Mizuguchi T, Takata A, Obo K, Kato M, Ogata K, Matsumoto N.
  • Journal Title: Am J Hum Genet Volume: 106 Pages: 13-25
  • DOI: 10.1016/j.ajhg.2019.11.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phenotype-genotype correlations in patients with GNB1 gene variants, including the first three reported Japanese patients to exhibit spastic diplegia, dyskinetic quadriplegia, and infantile spasms (2020)
  • Author(s): Endo W, Ikemoto S, Togashi N, Miyabayashi T, Nakajima E, Hamano SI, Shibuya M, Sato R, Takezawa Y, Okubo Y, Inui T, Kato M, Sengoku T, Ogata K, Hamanaka K, Mizuguchi T, Miyatake S, Nakashima M, Matsumoto N, Haginoya K.
  • Journal Title: Brain Dev Volume: 42 Pages: 199-204
  • DOI: 10.1016/j.braindev.2019.10.006
  • Peer Reviewed
• [Journal Article] Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS (2020)
  • Author(s): Nakamura H, Doi H, Mitsuhashi S, Miyatake S, Katoh K, Frith MC, Asano T, Kudo Y, Ikeda T, Kubota S, Kunii M, Kitazawa Y, Tada M, Okamoto M, Joki H, Takeuchi H, Matsumoto N, Tanaka F.
  • Journal Title: J Hum Genet Volume: 65 Pages: 475-480
  • DOI: 10.1038/s10038-020-0733-y
  • Peer Reviewed
• [Journal Article] De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy (2020)
  • Author(s): Hamanaka K, Imagawa E, Koshimizu E, Miyatake S, Tohyama J, Yamagata T, Miyauchi A, Ekhilevitch N, Nakamura F, Kawashima T, Goshima Y, Mohamed AR, Ch'ng GS, Fujita A, Azuma Y, Yasuda K, Imamura S, Nakashima M, Saitsu H, Mitsuhashi S, Mizuguchi T, Takata A, Miyake N, Matsumoto N.
  • Journal Title: Am J Hum Genet Volume: 106 Pages: 549-558
  • DOI: 10.1016/j.ajhg.2020.02.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Infantile macrocephaly and multiple subcutaneous lipomas diagnosed with PTEN hamartoma tumor syndrome: A case report (2020)
  • Author(s): Yotsumoto Y, Harada A, Tsugawa J, Ikura Y, Utsunomiya H, Miyatake S, Matsumoto N, Kanemura Y, Hashimoto-Tamaoki T.
  • Journal Title: Mol Clin Oncol Volume: 12 Pages: 329-335
  • DOI: 10.3892/mco.2020.1988
  • Peer Reviewed / Open Access
• [Journal Article] Skin and hair abnormalities of Cantu syndrome: A congenital hypertrichosis due to a genetic alteration mimicking the pharmacological effect of minoxidil (2020)
  • Author(s): Ohko K, Nakajima K, Nakajima H, Hiraki Y, Kubota K, Fukao T, Miyatake S, Matsumoto N, Sano S.
  • Journal Title: J Dermatol Volume: 47 Pages: 306-310
  • DOI: 10.1111/1346-8138.15216
  • Peer Reviewed
• [Journal Article] Novel variants of ABCC9 in Japanese children with Cantテコ syndrome (2020)
  • Author(s): Kubota K, Yamamoto T, Miyatake S, Matsumoto N, Fukao T.
  • Journal Title: Pediatr Int Volume: 62 Pages: 410-412
  • DOI: 10.1111/ped.14098
  • Peer Reviewed
• [Journal Article] Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients (2019)
  • Author(s): Sekiguchi F, Tsurusaki Y, Okamoto N, Teik KW, Mizuno S, Suzumura H, Isidor B, Ong WP, Haniffa M, White SM, Matsuo M, Saito K, Phadke S, Kosho T, Yap P, Goyal M, Clarke LA, Sachdev R, McGillivray G, Leventer RJ, Patel C, Yamagata T, Osaka H, Hisaeda Y, Ohashi H, Miyatake S, Mizuguchi T, Miyake N, Matsumoto N, et al.
  • Journal Title: J Hum Genet Volume: 64 Pages: 1173-1186
  • DOI: 10.1038/s10038-019-0667-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy (2019)
  • Author(s): Takata A, Nakashima M, Saitsu H, Mizuguchi T, Mitsuhashi S, Takahashi Y, Okamoto N, Osaka H, Nakamura K, Tohyama J, Haginoya K, Takeshita S, Kuki I, Okanishi T, Goto T, Sasaki M, Sakai Y, Miyake N, Miyatake S, Amamoto M, Takayama R, Hirabayashi S, Aiba K, Matsumoto H, Nabatame S, Shiihara T, Kato M, Matsumoto N, et al.
  • Journal Title: Nature Communications Volume: 10 Pages: 2506-2506
  • DOI: 10.1038/s41467-019-10482-9
  • Peer Reviewed / Open Access
• [Journal Article] GGC Repeat Expansion of NOTCH2NLC in Adult Patients with Leukoencephalopathy (2019)
  • Author(s): Okubo M, Doi H, Fukai R, Fujita A, Mitsuhashi S, Hashiguchi S, Kishida H, Ueda N, Morihara K, Ogasawara A, Kawamoto Y, Takahashi T, Takahashi K, Nakamura H, Kunii M, Tada M, Katsumoto A, Fukuda H, Mizuguchi T, Miyatake S, Miyake N, Suzuki J, Ito Y, Sone J, Sobue G, Takeuchi H, Matsumoto N, Tanaka F.
  • Journal Title: Ann Neurol Volume: 86 Pages: 962-968
  • DOI: 10.1002/ana.25586
  • Peer Reviewed
• [Journal Article] Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome (2019)
  • Author(s): Aoi H, Mizuguchi T, Ceroni JR, Kim VEH, Furquim I, Honjo RS, Iwaki T, Suzuki T, Sekiguchi F, Uchiyama Y, Azuma Y, Hamanaka K, Koshimizu E, Miyatake S, Mitsuhashi S, Takata A, Miyake N, Takeda S, Itakura A, Bertola DR, Kim CA, Matsumoto N.
  • Journal Title: J Hum Genet Volume: 64 Pages: 967-978
  • DOI: 10.1038/s10038-019-0643-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases (2019)
  • Author(s): Murakami Y, Nguyen TTM, Baratang N, Raju PK, Knaus A, Ellard S, Jones G, Lace B, Rousseau J, Ajeawung NF, Kamei A, Minase G, Akasaka M, Araya N, Koshimizu E, van den Ende J, Erger F, Rocha ME, Hashem MO, Aldhalaan HM, Alkuraya FS, Miyatake S, Matsumoto N, Krawitz PM, Rossignol E, Kinoshita T, Campeau PM, et al.
  • Journal Title: Am J Hum Genet Volume: 105 Pages: 384-394
  • DOI: 10.1016/j.ajhg.2019.05.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3 is clinically distinct from Beh?et’s disease (2019)
  • Author(s): Tsuchida Naomi、Kirino Yohei、Soejima Yutaro、Onodera Masafumi、Arai Katsuhiro、Tamura Eiichiro、Ishikawa Takashi、Kawai Toshinao、Uchiyama Toru、Nomura Shigeru、Kobayashi Daisuke、Taguri Masataka、Mitsuhashi Satomi、Mizuguchi Takeshi、Takata Atsushi、Miyake Noriko、Nakajima Hideaki、Miyatake Satoko、Matsumoto Naomichi
  • Journal Title: Arthritis Research & Therapy Volume: 21 Pages: 137-137
  • DOI: 10.1186/s13075-019-1928-5
  • Peer Reviewed / Open Access
• [Journal Article] A novel de novo frameshift variant in SETD1B causes epilepsy (2019)
  • Author(s): Den K, Kato M, Yamaguchi T, Miyatake S, Takata A, Mizuguchi T, Miyake N, Mitsuhashi S, Matsumoto N.
  • Journal Title: J Hum Genet Volume: 64 Pages: 821-827
  • DOI: 10.1038/s10038-019-0617-1
  • Peer Reviewed
• [Journal Article] Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42 (2019)
  • Author(s): Hashiguchi S, Doi H, Kunii M, Nakamura Y, Shimuta M, Suzuki E, Koyano S, Okubo M, Kishida H, Shiina M, Ogata K, Miyatake S, Miyake N, Saitsu H, Sato N, Ozaki K, Ohta K, Yokota T, Mizusawa H, Mitsui J, Ishiura H, Yoshimura J, Morishita S, Tsuji S, Takeuchi H, Ishikawa K, Matsumoto N, Ishikawa T, Tanaka F, et al.
  • Journal Title: Neurobiology of Disease Volume: 130 Pages: 104516～104516
  • DOI: 10.1016/j.nbd.2019.104516
  • Peer Reviewed
• [Journal Article] Pathogenic variants of DYNC2H1, KIAA0556, and PTPN11 associated with hypothalamic hamartoma (2019)
  • Author(s): Fujita Atsushi、Higashijima Takefumi、Shirozu Hiroshi、Masuda Hiroshi、Sonoda Masaki、Tohyama Jun、Kato Mitsuhiro、Nakashima Mitsuko、Tsurusaki Yoshinori、Mitsuhashi Satomi、Mizuguchi Takeshi、Takata Atsushi、Miyatake Satoko、Miyake Noriko、Fukuda Masafumi、Kameyama Shigeki、Saitsu Hirotomo、Matsumoto Naomichi
  • Journal Title: Neurology Volume: 93 Pages: e237～e251
  • DOI: 10.1212/WNL.0000000000007774
  • Peer Reviewed
• [Journal Article] Leaky splicing variant in sepiapterin reductase deficiency (2019)
  • Author(s): Nakagama Yu、Hamanaka Kohei、Mimaki Masakazu、Shintaku Haruo、Miyatake Satoko、Matsumoto Naomichi、Hirohata Koji、Inuzuka Ryo、Oka Akira
  • Journal Title: Neurology Genetics Volume: 5 Pages: e319～e319
  • DOI: 10.1212/NXG.0000000000000319
  • Peer Reviewed / Open Access
• [Journal Article] MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration (2019)
  • Author(s): Hamanaka K, Takata A, Uchiyama Y, Miyatake S, Miyake N, Mitsuhashi S, Iwama K, Fujita A, Imagawa E, Alkanaq AN, Koshimizu E, Azuma Y, Nakashima M, Mizuguchi T, Saitsu H, Wada Y, Minami S, Katoh-Fukui Y, Masunaga Y, Fukami M, Hasegawa T, Ogata T, Matsumoto N.
  • Journal Title: Human Molecular Genetics Volume: 28 Pages: 2319～2329
  • DOI: 10.1093/hmg/ddz066
  • Peer Reviewed
• [Journal Article] A missense variant of SMC1A causes periodic pharmaco-resistant cluster seizures similar to PCDH19-related epilepsy (2019)
  • Author(s): Oguni Hirokazu、Nishikawa Aiko、Sato Yu、Otani Yui、Ito Susumu、Nagata Satoru、Kato Mitsuhiro、Hamanaka Kohei、Miyatake Satoko、Matsumoto Naomichi
  • Journal Title: Epilepsy Research Volume: 155 Pages: 106149～106149
  • DOI: 10.1016/j.eplepsyres.2019.06.001
  • Peer Reviewed
• [Journal Article] Primary immunodeficiency with chronic enteropathy and developmental delay in a boy arising from a novel homozygous RIPK1 variant (2019)
  • Author(s): Uchiyama Y, Kim CA, Pastorino AC, Ceroni J, Lima PP, de Barros Dorna M, Honjo RS, Bertola D, Hamanaka K, Fujita A, Mitsuhashi S, Miyatake S, Takata A, Miyake N, Mizuguchi T, Matsumoto N.
  • Journal Title: J Hum Genet Volume: 64 Pages: 955-960
  • DOI: 10.1038/s10038-019-0631-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of mitochondrial DNA variants detection using short- and long-read sequencing (2019)
  • Author(s): Alkanaq AN, Hamanaka K, Sekiguchi F, Taguri M, Takata A, Miyake N, Miyatake S, Mizuguchi T, Matsumoto N.
  • Journal Title: J Hum Genet Volume: 64 Pages: 1107-1116
  • DOI: 10.1038/s10038-019-0654-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hemorrhagic stroke and renovascular hypertension with Grange syndrome arising from a novel pathogenic variant in YY1AP1 (2019)
  • Author(s): Saida K, Kim CA, Ceroni JRM, Bertola DR, Honjo RS, Mitsuhashi S, Takata A, Mizuguchi T, Miyatake S, Miyake N, Matsumoto N.
  • Journal Title: J Hum Genet Volume: 64 Pages: 885-890
  • DOI: 10.1038/s10038-019-0626-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Successful treatment of intractable life-threatening seizures with perampanel in the first case of early myoclonic encephalopathy with a novel de novo SCN1A mutation (2019)
  • Author(s): Ishikawa N, Tateishi Y, Tani H, Kobayashi Y, Itai T, Miyatake S, Kato M, Matsumoto N, Kobayashi M.
  • Journal Title: Seizure Volume: 71 Pages: 20-23
  • DOI: 10.1016/j.seizure.2019.05.024
  • Peer Reviewed
• [Journal Article] Recurrent NUS1 canonical splice donor site mutation in two unrelated individuals with epilepsy, myoclonus, ataxia and scoliosis - a case report (2019)
  • Author(s): Den Kouhei、Kudo Yosuke、Kato Mitsuhiro、Watanabe Kosuke、Doi Hiroshi、Tanaka Fumiaki、Oguni Hirokazu、Miyatake Satoko、Mizuguchi Takeshi、Takata Atsushi、Miyake Noriko、Mitsuhashi Satomi、Matsumoto Naomichi
  • Journal Title: BMC Neurology Volume: 19 Pages: 253-253
  • DOI: 10.1186/s12883-019-1489-x
  • Peer Reviewed / Open Access
• [Journal Article] Malignant Hyperthermia and Cerebral Venous Sinus Thrombosis After Ventriculoperitoneal Shunt in Infant with Schizencephaly and COL4A1 Mutation (2019)
  • Author(s): Watanabe J, Okamoto K, Ohashi T, Natsumeda M, Hasegawa H, Oishi M, Miyatake S, Matsumoto N, Fujii Y.
  • Journal Title: World Neurosurg Volume: 127 Pages: 446-450
  • DOI: 10.1016/j.wneu.2019.04.156
  • Peer Reviewed
• [Journal Article] Single-fiber electromyography-based diagnosis of CACNA1A mutation in children: A potential role of the electrodiagnosis in the era of whole exome sequencing (2019)
  • Author(s): Hirasawa-Inoue A, Ishiyama A, Takeshita E, Shimizu-Motohashi Y, Saito T, Komaki H, Nakagawa E, Yuasa S, Saitsu H, Hamanaka K, Miyatake S, Matsumoto N, Sasaki M.
  • Journal Title: Brain Dev Volume: 41 Pages: 905-909
  • DOI: 10.1016/j.braindev.2019.06.006
  • Peer Reviewed
• [Presentation] 脳小血管病の新たな疾患責任遺伝子 COL4A1/COL4A2 (2019)
  • Author(s): 宮武聡子
  • Organizer: 第37回日本神経治療学会学術集会
• [Presentation] Biallelic COLGALT1 variants as a novel genetic cause of cerebral small vessel disease (2019)
  • Author(s): Satoko Miyatake,Norihisa Koyama, Kenji Yokochi, Kayo Ohmura, Eriko Koshimizu, Yuri Uchiyama, Hiroshi Doi, Hideyuki Takeuchi, Satomi Mitsuhashi, Mitsuko Nakashima, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Hirotomo Saitsu, Naomichi Matsumoto
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] 次世代シーケンサーを用いたコピー数解析 (2019)
  • Author(s): 宮武聡子
  • Organizer: 第26回臨床細胞遺伝学セミナー
  • Invited