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写真a

サカモト　マサムネ
坂本　正宗
Masamune Sakamoto
所属
医学研究科 医科学専攻 遺伝学 助教
医学部 医学科
職名
助教
プロフィール

小児科専門医、小児神経専門医、臨床遺伝専門医

外部リンク

学位

  • 博士（医学）（横浜市立大学）

研究キーワード

  • ゲノム

  • 遺伝子

  • 小児神経学

  • 染色体

  • 神経内科学

研究分野

  • ライフサイエンス / 神経内科学

  • ライフサイエンス / 遺伝学

論文

  • Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders

    Yukina Hayashi, Kenta Kajiwara, Seiji Mizuno, Nobuhiko Okamoto, Mei Yan Chan, Tomohide Goto, Seiichi Hayakawa, Mitsuhiro Kato, Chong Ae Kim, Dorit Lev, Lip Hen Moey, Juliet Taylor, Nerine Gregersen, Ifat Nezer-Kaner, Wee Teik Keng, Satoshi Okada, Hitoshi Osaka, Tally Sagie, Yasunari Sakai, Katsuya Tashiro, Patrick Yap, Li Fu, Kazuhiro Iwama, Qiaowei Liang, Naoto Nishimura, Suzuran Saito, Masamune Sakamoto, Yasuhiro Utsuno, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Satoko Miyatake, Takeshi Mizuguchi, Atsushi Fujita, Naomichi Matsumoto

    Journal of Human Genetics   2025年12月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-025-01442-x

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    その他リンク： https://www.nature.com/articles/s10038-025-01442-x

  • Biallelic variants in TNR cause neurodevelopmental disorders with variable expressivity

    Atsuhiro Ozaki, Masamune Sakamoto, Satoko Kumada, Keisuke Hamada, Kazuhiro Ogata, Jun Ikezawa, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of Human Genetics   2025年11月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-025-01431-0

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    その他リンク： https://www.nature.com/articles/s10038-025-01431-0

  • Long-read genomic analyses to elucidate hidden structural variations associated with MECP2 duplication syndrome. 国際誌

    Qiaowei Liang, Yuri Uchiyama, Rie Seyama, Ichiro Kuki, Kazuhiro Haginoya, Toshiyuki Shinozaki, Mitsuhiro Kato, Masamune Sakamoto, Naomi Tsuchida, Eriko Koshimizu, Atsushi Fujita, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of human genetics   2025年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    MECP2 duplication syndrome results from duplication of the MECP2 gene, encoding methyl-CpG-binding protein 2. Structural variations in this region can be detected by short-read next-generation sequencing, but resolving its precise genomic architecture remains challenging because of the involvement of complex and highly repetitive sequences. This study investigated the hidden structural variations using optical genome mapping and targeted long-read nanopore sequencing. We identified 14 breakpoints within the Xq28 regions encompassing MECP2 in four individuals from four families with MECP2 duplication syndrome. Combining the above methods enabled us to identify all the precise breakpoints, except for two inversions embedded within highly repetitive sequences. This also represents the most precise delineation to date of complex structural variants in MECP2 duplication syndrome. Notably, leveraging long nanopore reads (> 75 kb) allowed us to span low-copy repeat regions, including the approximately 72 kb J-group low-copy repeat which was difficult to be resolved, as well as GC-rich segments and dense clusters of short interspersed nuclear elements such as Alu, thus enhancing breakpoint-detection accuracy. We also detected previously underreported rare and complex rearrangement patterns. These findings highlight the power of integrating long-read sequencing with optical genome mapping for the delineation of complex genomic architectures, thus enhancing our understanding of the genomic structure underlying MECP2 duplication syndrome.

    DOI： 10.1038/s10038-025-01419-w

    PubMed

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  • A Case of CACNA1I‐Related Neurodevelopmental Disorder With Dysmorphism and Brain Iron Accumulation: Expanding the Clinical Spectrum

    Ryo Sugiyama, Takashi Saito, Hiroyuki Maki, Noriko Sato, Masamune Sakamoto, Naomichi Matsumoto, Yuji Takahashi, Hidehiro Mizusawa, Hirofumi Komaki

    Clinical Genetics   2025年10月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

    ABSTRACT

    Recently, gain‐ or loss‐of‐function variants in the calcium voltage‐gated channel subunit alpha1I gene ( CACNA1I ) have been shown to cause neurodevelopmental disorders. As only 10 cases have been reported to date, clinical information remains limited. This article describes a patient carrying a previously identified CACNA1I variant (NM_021096.4: c.2579T>A, p.Ile860Asn). Notably, our patient exhibited previously unreported clinical findings resembling those observed in disorders associated with other CACNA1 family members, suggesting that these features may be characteristic of this disorder. Brain MRI revealed previously unreported excess iron accumulation in the globus pallidus and substantia nigra. These findings indicate that this disorder may be part of the spectrum of neurodegeneration with brain iron accumulation.

    DOI： 10.1111/cge.70098

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  • A practical framework for predicting splicing single nucleotide variants in exome sequencing

    Yasuhiro Utsuno, Kohei Hamanaka, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

    NAR Genomics and Bioinformatics   7 ( 4 )   2025年10月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

    Abstract

    Splicing variants significantly contribute to Mendelian disorders, yet predicting their pathogenicity remains challenging. To address this issue, we developed a framework that simplifies the evaluation of pathogenic splicing single nucleotide variants (SNVs) while following ACMG/AMP guidelines and ClinGen recommendations established in 2023. Our system simplifies the 2023 ClinGen criteria by assigning a priority score (ranging from −10 to 14) to SNVs in open reading frame regions. Validation using pathogenic splicing SNVs from the Human Gene Mutation Database and common SNVs from gnomAD demonstrated superior discrimination compared to SpliceAI alone (area under the receiver operating characteristic 0.991 versus 0.983, P = 2.11 × 10⁻23). When applied to 1257 patients with unresolved diagnoses after exome sequencing, our framework identified pathogenic splicing variants in COL2A1, PDHA1, MECP2, and JAKMIP1 and suggested potential candidate disease-causing genes, UBN1 and NFE2L1. This method enhances the detection of splicing variants in exome sequencing.

    DOI： 10.1093/nargab/lqaf180

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  • Genome sequencing provides high diagnostic yield and new etiological insights for intellectual disability and developmental delay

    Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Kazuharu Misawa, Eriko Koshimizu, Yuri Uchiyama, Naomi Tsuchida, Rie Seyama, Masamune Sakamoto, Kazuhiro Iwama, Naoto Nishimura, Yasuhiro Utsuno, Li Fu, Marina Takizawa, Qiaowei Liang, Toshiyuki Itai, Ken Saida, Sachiko Ohori, Shinichi Kameyama, Hiromi Fukuda, Yukina Hayashi, Yuta Inoue, Tomohide Goto, Kazushi Ichikawa, Ichiro Kuki, Masataka Fukuoka, Kiyohiro Kim, Tadashi Shiohama, Konomi Shimoda, Kosuke Otsuka, Yuki Ueda, Kazutoshi Cho, Kotaro Yuge, Nobutada Tachi, Masaki Yoshida, Atsuro Daida, Kyoko Hirasawa, Tomoe Yanagishita, Toshiyuki Yamamoto, Kentaro Shirai, Tammar Fixler Mehr, Aviva Fattal-Valevski, Dorit Lev, Haruna Yokoyama, Emi Iwabuchi, Yoshihiko Saito, Masaki Miura, Kenji Sugai, Akihiko Ishiyama, Masayuki Sasaki, Yoshihiro Watanabe, Jun-ichi Takanashi, Chong Ae Kim, Kenji Yokochi, Jun Tohyama, Tatsuo Mori, Yuishin Izumi, Yuiko Hasegawa, Nobuhiko Okamoto, Takahiro Ikeda, Hitoshi Osaka, Yosuke Kawai, Yosuke Omae, Katsushi Tokunaga, Mitsuhiro Kato, Takeshi Mizuguchi, Naomichi Matsumoto

    npj Genomic Medicine   10 ( 1 )   2025年8月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s41525-025-00521-4

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    その他リンク： https://www.nature.com/articles/s41525-025-00521-4

  • Blended Phenotypes in Individuals With Rare Diseases: A Brazilian Case Series

    Caroline Brandão Piai, Gabriela Yumi Goto Salti, Marcella Cardoso Allegro, Priscila Barbosa Betty, Fernanda de Souza Valente, Isabela Dorneles Pasa, Bruno de Oliveira Stephan, Bianca Domit Werner Linnenkamp, Rachel Sayuri Honjo, Debora Romeo Bertola, Masamune Sakamoto, Yuta Inoue, Ken Saida, Naomi Tsuchida, Noriko Miyake, Naomichi Matsumoto, Chong Ae Kim

    American Journal of Medical Genetics Part A   197 ( 12 )   2025年8月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

    ABSTRACT

    The growing use of whole exome sequencing and whole genome sequencing in clinical practice has revealed the existence of a group of individuals that do not fit into only one molecular diagnosis. These subjects are those in whom pathogenic or likely pathogenic variants occur in more than one gene, creating “blended phenotypes” There are also genes that warrant reporting, even if they are not associated with the primary phenotype, referred to as ‘secondary findings’. In this report, we analyze the prevalence of blended phenotypes in a cohort of 447 individuals who underwent broad genomic sequencing and also present a case series of eight probands who presented multiple diagnoses, generating a mixed phenotype and creating a peculiar clinical situation. In total, 3.86% (8/207) were found to have blended phenotypes, which would have been missed had those individuals not undergone comprehensive genetic testing. We reflect upon the clinical complexity of such cases and explore the consequences of the use of broad sequencing strategies in clinical practice, particularly focusing on the potential to provide a more complete diagnostic scenario. By acknowledging and understanding the complexities of blended phenotypes, clinicians can adopt a more nuanced and tailored approach to patient care.

    DOI： 10.1002/ajmg.a.64209

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  • Recurrent de novo variants in the spliceosomal factor CRNKL1 are associated with severe microcephaly and pontocerebellar hypoplasia with seizures

    Sankalita Ray Das, Rosie Sullivan, Mischa S.G. Ruegg, Julia Horsfield, Jordan Doran, Gemma Poke, Nathalie de Vries, Sarah Duerinckx, Damien Lederer, Muzhirah Haniffa, Wee-Teik Keng, Gaik-Siew Ch’ng, David A. Parry, Andrew P. Jackson, Masamune Sakamoto, Naomichi Matsumoto, Noriko Miyake, Shin Nabatame, Hidetoshi Taniguchi, Emma Wakeling, Katrin Õunap, Pilvi Ilves, Ghayda Mirzaa, Andrew Timms, Emily Pao, Kimberly A. Aldinger, William Dobyns, Axel Bohring, Beate Behre, Daniel G. Calame, James R. Lupski, Juan M. Pascual, Marc Abramowicz, Gregory Gimenez, Louise S. Bicknell

    The American Journal of Human Genetics   112 ( 7 )   1722 - 1732   2025年7月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

    DOI： 10.1016/j.ajhg.2025.05.013

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  • Hemizygous SMARCA1 variants cause X-linked intellectual disability

    Naoto Nishimura, Takeshi Mizuguchi, Keisuke Hamada, Kotaro Yuge, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Yoriko Watanabe, Hitoshi Osaka, Koh-Ichiro Yoshiura, Kazuhiro Ogata, Naomichi Matsumoto

    Journal of Human Genetics   70 ( 7 )   359 - 363   2025年5月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-025-01346-w

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    その他リンク： https://www.nature.com/articles/s10038-025-01346-w

  • Diagnostic utility of single-locus DNA methylation mark in Sotos syndrome developed by nanopore sequencing-based episignature

    Takeshi Mizuguchi, Nobuhiko Okamoto, Taiki Hara, Naoto Nishimura, Masamune Sakamoto, Li Fu, Yuri Uchiyama, Naomi Tsuchida, Kohei Hamanaka, Eriko Koshimizu, Atsushi Fujita, Kazuharu Misawa, Kazuhiko Nakabayashi, Satoko Miyatake, Naomichi Matsumoto

    Clinical Epigenetics   17 ( 1 )   2025年2月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1186/s13148-025-01832-0

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    その他リンク： https://link.springer.com/article/10.1186/s13148-025-01832-0/fulltext.html

  • Clinical and genetic spectrum of patients with IRF2BPL syndrome

    Kazuhiro Iwama, Mitsuhiro Kato, Yuri Uchiyama, Masamune Sakamoto, Ryosuke Miyamoto, Yuishin Izumi, Kei Ohashi, Ayako Hattori, Noboru Yoshida, Yoshiteru Azuma, Akito Watanabe, Chizuru Ikeda, Yuko Shimizu-Motohashi, Shohei Kusabiraki, Eiji Nakagawa, Masayuki Sasaki, Kenji Sugai, Sachiko Ohori, Naomi Tsuchida, Kohei Hamanaka, Eriko Koshimizu, Atsushi Fujita, Mitsuko Nakashima, Satoko Miyatake, Toru Sengoku, Kazuhiro Ogata, Shinji Saitoh, Hirotomo Saitsu, Shuichi Ito, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of Human Genetics   70 ( 4 )   181 - 188   2025年1月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-025-01316-2

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    その他リンク： https://www.nature.com/articles/s10038-025-01316-2

  • Adolescent-onset epilepsy and deterioration associated with CAD deficiency: A case report

    Sebastián Silva, Mónica Rosas, Benjamín Guerra, Marión Muñoz, Atsushi Fujita, Masamune Sakamoto, Naomichi Matsumoto

    Brain and Development   46 ( 7 )   250 - 253   2024年8月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

    DOI： 10.1016/j.braindev.2024.04.001

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  • A family with neuronal intranuclear inclusion disease with focal segmental glomerulosclerosis

    Kazuki Watanabe, Tomoyasu Bunai, Masamune Sakamoto, Sayaka Ishigaki, Takamasa Iwakura, Naro Ohashi, Rie Wakatsuki, Akiyuki Takenouchi, Moriya Iwaizumi, Yoshihiro Hotta, Ken Saida, Eriko Koshimizu, Satoko Miyatake, Hirotomo Saitsu, Naomichi Matsumoto, Tomohiko Nakamura

    Journal of Neurology   271 ( 9 )   6227 - 6237   2024年7月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1007/s00415-024-12593-w

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    その他リンク： https://link.springer.com/article/10.1007/s00415-024-12593-w/fulltext.html

  • A heterozygous germline deletion within USP8 causes severe neurodevelopmental delay with multiorgan abnormalities

    Masamune Sakamoto, Kenji Kurosawa, Koji Tanoue, Kazuhiro Iwama, Fumihiko Ishida, Yoshihiro Watanabe, Nobuhiko Okamoto, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of Human Genetics   69 ( 2 )   85 - 90   2023年11月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-023-01209-2

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    その他リンク： https://www.nature.com/articles/s10038-023-01209-2

  • Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders

    Yasuhiro Utsuno, Keisuke Hamada, Kohei Hamanaka, Keita Miyoshi, Keiji Tsuchimoto, Satoshi Sunada, Toshiyuki Itai, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Satoko Miyatake, Kazuharu Misawa, Takeshi Mizuguchi, Yasuhito Kato, Kuniaki Saito, Kazuhiro Ogata, Naomichi Matsumoto

    Journal of Human Genetics   69 ( 2 )   69 - 77   2023年11月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-023-01206-5

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    その他リンク： https://www.nature.com/articles/s10038-023-01206-5

  • Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration

    Annalisa Vetro, Cristiana Pelorosso, Simona Balestrini, Alessio Masi, Sophie Hambleton, Emanuela Argilli, Valerio Conti, Simone Giubbolini, Rebekah Barrick, Gaber Bergant, Karin Writzl, Emilia K. Bijlsma, Theresa Brunet, Pilar Cacheiro, Davide Mei, Anita Devlin, Mariëtte J.V. Hoffer, Keren Machol, Guido Mannaioni, Masamune Sakamoto, Manoj P. Menezes, Thomas Courtin, Elliott Sherr, Riccardo Parra, Ruth Richardson, Tony Roscioli, Marcello Scala, Celina von Stülpnagel, Damian Smedley, Francesca Pochiero, Francesco Mari, Venkateswaran Ramesh, Valeria Capra, Margherita Mancardi, Boris Keren, Cyiril Mignot, Matteo Lulli, Kendall Parks, Helen Griffin, Melanie Brugger, Vincenzo Nigro, Yuko Hirata, Reiko Koichihara, Borut Peterlin, Yuko Hirata, Ryuto Maki, Yohei Nitta, John C. Ambrose, Prabhu Arumugam, Roel Bevers, Marta Bleda, Freya Boardman-Pretty, Christopher R. Boustred, Helen Brittain, Matthew A. Brown, Mark J. Caulfield, Georgia C. Chan, Adam Giess, John N. Griffin, Angela Hamblin, Shirley Henderson, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Anna Lakey, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Meriel McEntagart, Federico Minneci, Jonathan Mitchell, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Marina B. Pereira, John Pullinger, Tahrima Rahim, Augusto Rendon, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, Mélanie Tanguy, Ana Lisa Taylor Tavares, Ellen R.A. Thomas, Simon R. Thompson, Arianna Tucci, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Annalaura Torella, Jun Tohyama, Reiko Koichihara, Keisuke Hamada, Kazuhiro Ogata, Takashi Suzuki, Atsushi Sugie, Jasper J. van der Smagt, Koen van Gassen, Stephanie Valence, Emma Vittery, Stephen Malone, Mitsuhiro Kato, Naomichi Matsumoto, Gian Michele Ratto, Renzo Guerrini

    The American Journal of Human Genetics   110 ( 8 )   1356 - 1376   2023年8月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

    DOI： 10.1016/j.ajhg.2023.06.008

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  • A case of epilepsy with myoclonic atonic seizures caused by SLC6A1 gene mutation due to balanced chromosomal translocation

    Tatsuo Mori, Masamune Sakamoto, Takahiro Tayama, Aya Goji, Yoshihiro Toda, Atsushi Fujita, Takeshi Mizuguchi, Maki Urushihara, Naomichi Matsumoto

    Brain and Development   45 ( 7 )   395 - 400   2023年8月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

    DOI： 10.1016/j.braindev.2023.03.001

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  • Three KINSSHIP syndrome patients with mosaic and germline AFF3 variants

    Yuta Inoue, Naomi Tsuchida, Nobuhiko Okamoto, Shimakawa Shuichi, Kei Ohashi, Shinji Saitoh, Atsushi Ogawa, Keisuke Hamada, Masamune Sakamoto, Noriko Miyake, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Kazuhiro Ogata, Yuri Uchiyama, Naomichi Matsumoto

    Clinical Genetics   103 ( 5 )   590 - 595   2023年1月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

    Abstract

    AFF3 at 2q11.2 encodes the nuclear transcriptional activator AF4/FMR2 Family Member 3. AFF3 constitutes super elongation complex like 3, which plays a role in promoting the expression of genes involved in neurogenesis and development. The degron motif in AFF3 with nine highly conserved amino acids is recognized by E3 ubiquitin ligase to induce protein degradation. Recently, AFF3 missense variants in this region and variants featuring deletion including this region were identified and shown to cause KINSSHIP syndrome. In this study, we identified two novel and one previously reported missense variants in the degron of AFF3 in three unrelated Japanese patients. Notably, two of these three variants exhibited mosaicism in the examined tissues. This study suggests that mosaic variants also cause KINSSHIP syndrome, showing various phenotypes.

    DOI： 10.1111/cge.14292

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    その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cge.14292

  • A novel homozygous CHMP1A variant arising from segmental uniparental disomy causes pontocerebellar hypoplasia type 8

    Masamune Sakamoto, Toshihide Shiiki, Shuji Matsui, Nobuhiko Okamoto, Eriko Koshimizu, Naomi Tsuchida, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Kazuharu Misawa, Takeshi Mizuguchi, Naomichi Matsumoto

    Journal of Human Genetics   68 ( 4 )   247 - 253   2022年12月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-022-01098-x

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    その他リンク： https://www.nature.com/articles/s10038-022-01098-x

  • Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy

    Masamune Sakamoto, Kazuhiro Iwama, Masayuki Sasaki, Akihiko Ishiyama, Hirofumi Komaki, Takashi Saito, Eri Takeshita, Yuko Shimizu-Motohashi, Kazuhiro Haginoya, Tomoko Kobayashi, Tomohide Goto, Yu Tsuyusaki, Mizue Iai, Kenji Kurosawa, Hitoshi Osaka, Jun Tohyama, Yu Kobayashi, Nobuhiko Okamoto, Yume Suzuki, Satoko Kumada, Kenji Inoue, Hideaki Mashimo, Atsuko Arisaka, Ichiro Kuki, Harumi Saijo, Kenji Yokochi, Mitsuhiro Kato, Yuji Inaba, Yuko Gomi, Shinji Saitoh, Kentaro Shirai, Masafumi Morimoto, Yuishin Izumi, Yoriko Watanabe, Shin-ichiro Nagamitsu, Yasunari Sakai, Shinobu Fukumura, Kazuhiro Muramatsu, Tomomi Ogata, Keitaro Yamada, Keiko Ishigaki, Kyoko Hirasawa, Konomi Shimoda, Manami Akasaka, Kosuke Kohashi, Takafumi Sakakibara, Masashi Ikuno, Noriko Sugino, Takahiro Yonekawa, Semra Gürsoy, Tayfun Cinleti, Chong Ae Kim, Keng Wee Teik, Chan Mei Yan, Muzhirah Haniffa, Chihiro Ohba, Shuuichi Ito, Hirotomo Saitsu, Ken Saida, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Kohei Hamanaka, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Noriko Miyake, Naomichi Matsumoto

    Genetics in Medicine   24 ( 12 )   2453 - 2463   2022年12月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

    DOI： 10.1016/j.gim.2022.08.007

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  • Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants

    Kohei Hamanaka, Noriko Miyake, Takeshi Mizuguchi, Satoko Miyatake, Yuri Uchiyama, Naomi Tsuchida, Futoshi Sekiguchi, Satomi Mitsuhashi, Yoshinori Tsurusaki, Mitsuko Nakashima, Hirotomo Saitsu, Kohei Yamada, Masamune Sakamoto, Hiromi Fukuda, Sachiko Ohori, Ken Saida, Toshiyuki Itai, Yoshiteru Azuma, Eriko Koshimizu, Atsushi Fujita, Biray Erturk, Yoko Hiraki, Gaik-Siew Ch’ng, Mitsuhiro Kato, Nobuhiko Okamoto, Atsushi Takata, Naomichi Matsumoto

    Genome Medicine   14 ( 1 )   2022年4月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    Abstract

    Background

    Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size.

    Methods

    We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns).

    Results

    We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes (GLTSCR1, MARK2, and UBR3). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 × 0.05 = 19)] given their constraints against deleterious variants and extracted 34 “plausible” candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (> 90% true-positive probabilities) candidate genes: HDAC2, SUPT16H, HECTD4, CHD5, XPO1, GSK3B, NLGN2, ADGRB1, CTR9, BRD3, and MARK2.

    Conclusions

    We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes.

    DOI： 10.1186/s13073-022-01042-w

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    その他リンク： https://link.springer.com/article/10.1186/s13073-022-01042-w/fulltext.html

  • Pathogenic variants in the survival of motor neurons complex gene <scp> <i>GEMIN5</i> </scp> cause cerebellar atrophy

    Ken Saida, Junya Tamaoki, Masayuki Sasaki, Muzhirah Haniffa, Eriko Koshimizu, Toru Sengoku, Hiroki Maeda, Masahiro Kikuchi, Haruna Yokoyama, Masamune Sakamoto, Kazuhiro Iwama, Futoshi Sekiguchi, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi, Kazuhiro Ogata, Noriko Miyake, Satoko Miyatake, Makoto Kobayashi, Naomichi Matsumoto

    Clinical Genetics   100 ( 6 )   722 - 730   2021年10月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

    Abstract

    Cerebellar ataxia is a genetically heterogeneous disorder. GEMIN5 encoding an RNA‐binding protein of the survival of motor neuron complex, is essential for small nuclear ribonucleoprotein biogenesis, and it was recently reported that biallelic loss‐of‐function variants cause neurodevelopmental delay, hypotonia, and cerebellar ataxia. Here, whole‐exome analysis revealed compound heterozygous GEMIN5 variants in two individuals from our cohort of 162 patients with cerebellar atrophy/hypoplasia. Three novel truncating variants and one previously reported missense variant were identified: c.2196dupA, p.(Arg733Thrfs*6) and c.1831G &gt; A, p.(Val611Met) in individual 1, and c.3913delG, p.(Ala1305Leufs*14) and c.4496dupA, p.(Tyr1499*) in individual 2. Western blotting analysis using lymphoblastoid cell lines derived from both affected individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for null variants p.(Arg733Thrfs*6) and p.(Ala1305Leufs*14) exhibited complete lethality at 2 weeks and recapitulated a distinct dysplastic phenotype. The phenotypes of affected individuals and the zebrafish mutant models strongly suggest that biallelic loss‐of‐function variants in GEMIN5 cause cerebellar atrophy/hypoplasia.

    DOI： 10.1111/cge.14066

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    その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cge.14066

  • <i>De novo ARF3</i> variants cause neurodevelopmental disorder with brain abnormality

    Masamune Sakamoto, Kazunori Sasaki, Atsushi Sugie, Yohei Nitta, Tetsuaki Kimura, Semra Gürsoy, Tayfun Cinleti, Mizue Iai, Toru Sengoku, Kazuhiro Ogata, Atsushi Suzuki, Nobuhiko Okamoto, Kazuhiro Iwama, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Atsushi Fujita, Kohei Hamanaka, Satoko Miyatake, Takeshi Mizuguchi, Masataka Taguri, Shuuichi Ito, Hidehisa Takahashi, Noriko Miyake, Naomichi Matsumoto

    Human Molecular Genetics   31 ( 1 )   69 - 81   2021年8月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

    Abstract

    An optimal Golgi transport system is important for mammalian cells. The adenosine diphosphate (ADP) ribosylation factors (ARF) are key proteins for regulating cargo sorting at the Golgi network. In this family, ARF3 mainly works at the trans-Golgi network (TGN), and no ARF3-related phenotypes have yet been described in humans. We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A &amp;gt; T (p.Asp67Val) and c.296G &amp;gt; T (p.Arg99Leu). Although the affected individuals presented commonly with developmental delay, epilepsy and brain abnormalities, there were differences in severity, clinical course and brain lesions. In vitro subcellular localization assays revealed that the p.Arg99Leu mutant localized to Golgi apparatus, similar to the wild-type, whereas the p.Asp67Val mutant tended to show a disperse cytosolic pattern together with abnormally dispersed Golgi localization, similar to that observed in a known dominant negative variant (p.Thr31Asn). Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function. Furthermore, in vivo studies revealed that p.Asp67Val transfection led to lethality in flies. In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu. These data indicate that two ARF3 variants, the possibly loss-of-function p.Asp67Val and the gain-of-function p.Arg99Leu, both impair the Golgi transport system. Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu).

    DOI： 10.1093/hmg/ddab224

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    その他リンク： https://academic.oup.com/hmg/article-pdf/31/1/69/41796240/ddab224.pdf

  • Efficient detection of copy‐number variations using exome data: Batch‐ and sex‐based analyses

    Yuri Uchiyama, Daisuke Yamaguchi, Kazuhiro Iwama, Satoko Miyatake, Kohei Hamanaka, Naomi Tsuchida, Hiromi Aoi, Yoshiteru Azuma, Toshiyuki Itai, Ken Saida, Hiromi Fukuda, Futoshi Sekiguchi, Tomohiro Sakaguchi, Ming Lei, Sachiko Ohori, Masamune Sakamoto, Mitsuhiro Kato, Takayoshi Koike, Yukitoshi Takahashi, Koichi Tanda, Yuki Hyodo, Rachel S. Honjo, Debora Romeo Bertola, Chong Ae Kim, Masahide Goto, Tetsuya Okazaki, Hiroyuki Yamada, Yoshihiro Maegaki, Hitoshi Osaka, Lock‐Hock Ngu, Ch'ng G. Siew, Keng W. Teik, Manami Akasaka, Hiroshi Doi, Fumiaki Tanaka, Tomohide Goto, Long Guo, Shiro Ikegawa, Kazuhiro Haginoya, Muzhirah Haniffa, Nozomi Hiraishi, Yoko Hiraki, Satoru Ikemoto, Atsuro Daida, Shin‐ichiro Hamano, Masaki Miura, Akihiko Ishiyama, Osamu Kawano, Akane Kondo, Hiroshi Matsumoto, Nobuhiko Okamoto, Tohru Okanishi, Yukimi Oyoshi, Eri Takeshita, Toshifumi Suzuki, Yoshiyuki Ogawa, Hiroshi Handa, Yayoi Miyazono, Eriko Koshimizu, Atsushi Fujita, Atsushi Takata, Noriko Miyake, Takeshi Mizuguchi, Naomichi Matsumoto

    Human Mutation   42 ( 1 )   50 - 65   2020年11月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

    DOI： 10.1002/humu.24129

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    その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/humu.24129

  • Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy

    Masamune Sakamoto, Kazuhiro Iwama, Futoshi Sekiguchi, Hideaki Mashimo, Satoko Kumada, Keiko Ishigaki, Nobuhiko Okamoto, Mahdiyeh Behnam, Mohsen Ghadami, Eriko Koshimizu, Satoko Miyatake, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Hirotomo Saitsu, Noriko Miyake, Naomichi Matsumoto

    Journal of Human Genetics   66 ( 4 )   401 - 407   2020年10月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-020-00853-2

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    その他リンク： https://www.nature.com/articles/s10038-020-00853-2

  • A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction

    Masamune Sakamoto, Den Kouhei, Muzhirah Haniffa, Sebastián Silva, Mónica Troncoso, Paola Santander, Valeria Schonstedt, Ximena Stecher, Nobuhiko Okamoto, Kohei Hamanaka, Takeshi Mizuguchi, Satomi Mitsuhashi, Noriko Miyake, Naomichi Matsumoto

    Journal of Human Genetics   65 ( 9 )   751 - 757   2020年5月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s10038-020-0765-3

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    その他リンク： http://www.nature.com/articles/s10038-020-0765-3

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