Implementation of 3-D Facial Image-based Diagnosis Assistance of Ultrarare Congenital Malformation Syndromes

• Project/Area Number: 21K07800
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagasaki University
• Principal Investigator: Mishima Hiroyuki 長崎大学, 原爆後障害医療研究所, 助教 (10513319)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 顔貌解析 / ３次元モデリング / バイオインフォマティクス / ダウン症候群 / 単一遺伝子病 / 染色体起因疾患 / 希少疾患 / 難病 / 未診断疾患 / 顔貌 / ３次元 / 診断支援 / 機械学習 / Face2Gene / Cliniface

Outline of Research at the Start

本研究の目的は、情報密度の高い３次元顔貌情報の導入による、学習症例数が限られた極めてまれな先天形態異常症候群における診断補助の実現である。そのために本研究は、（１）申請者が導入済みの３次元カメラを用いた日本人３次元顔貌データ収集と、（２）顔貌計測値の定義詳細まで含めた情報共有のための基盤技術の確立、（３）顔貌計測値と３次元曲面形状の機械学習による診断補助技術の開発を行う。

Outline of Final Research Achievements

To date, three-dimensional facial imaging has been performed on 43 cases at 59 different time points. For some cases, longitudinal changes could be tracked with an interval of approximately six months or more. The breakdown of cases includes 38 cases of Down syndrome and five cases of other monogenic or chromosomal disorders. In addition, as a control group, three-dimensional facial imaging was performed on seven individuals at 10 different time points. These data were used to set measurement points and obtain anthropometric facial measurements using the Cliniface software. The data from this Japanese cohort significantly diverged from the reference values obtained from Caucasian cohorts, indicating the necessity of establishing reference values specifically for the Japanese population.

Academic Significance and Societal Importance of the Research Achievements

臨床診断が難しい先天形態異常症候群の確定診断には、とくに大きな手がかりとなる顔貌特徴とが重要である。研究代表者は、２次元顔貌解析技術 Face2Gene が本邦症例でもすでに高い性能を持つが、極めてまれな症候群の診断補助には能力不足であることを報告した。本研究の目的は、情報密度の高い３次元顔貌情報の導入による、学習症例数が限られた極めてまれな先天形態異常症候群における診断補助の実現である。
この研究の成果は、今後さらに規模を拡大した国内の３次元顔貌情報の収集と共有、あるいは国際的な情報共有による超希少疾患の診断能力の向上へむけた先駆けとなるものである。

Research Products

• [Journal Article] Proto-oncogene mutations in middle ear cholesteatoma contribute to its pathogenesis (2023)
  • Author(s): Satoh Chisei、Yoshiura Koh-ichiro、Mishima Hiroyuki、Yoshida Haruo、Takahashi Haruo、Kumai Yoshihiko
  • Journal Title: BMC Medical Genomics Volume: 16 Issue: 1 Pages: 238-238
  • DOI: 10.1186/s12920-023-01640-6
  • Peer Reviewed / Open Access
• [Journal Article] Four conserved amino acids on human papillomavirus E6 predict clinical high‐risk types (2023)
  • Author(s): Niiya Akari、Hamaguchi Yo、Mishima Hiroyuki、Miura Shoko、Komatsu Nahoko、Nagata Koh、Hasegawa Yuri、Miura Kiyonori、Yoshiura Koh‐ichiro
  • Journal Title: Journal of Medical Virology Volume: 95 Issue: 8 Pages: 106844-106844
  • DOI: 10.1002/jmv.29049
  • Peer Reviewed
• [Journal Article] Disrupted CaV1.2 selectivity causes overlapping long QT and Brugada syndrome phenotypes in the CACNA1C-E1115K iPS cell model (2023)
  • Author(s): Kashiwa A、Makiyama T、Kohjitani H、Maurissen T L、Ishikawa T、Yamamoto Y、Wuriyanghai Y、Gao J、Huang H、Imamura T、Aizawa T、Nishikawa M、Chonabayashi K、Mishima H、Ohno S、Toyoda F、Sato S、Yoshiura K、Takahashi K、Yoshida Y、Woltjen K、Horie M、Makita N、Kimura T
  • Journal Title: Heart Rhythm Volume: 20 Issue: 1 Pages: 89-99
  • DOI: 10.1016/j.hrthm.2022.08.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intestinal Mucosa-Associated Lymphoid Tissue Lymphoma Transforming into Diffuse Large B-Cell Lymphoma in a Young Adult Patient with Neurofibromatosis Type 1: A Case Report (2022)
  • Author(s): Kosako Hideki、Yamashita Yusuke、Tanaka Ken、Mishima Hiroyuki、Iwamoto Ryuta、Kinoshita Akira、Murata Shin-ichi、Ohshima Koichi、Yoshiura Koh-ichiro、Sonoki Takashi、Tamura Shinobu
  • Journal Title: Medicina Volume: 58 Issue: 12 Pages: 1830-1830
  • DOI: 10.3390/medicina58121830
  • Peer Reviewed / Open Access
• [Journal Article] Targeted deep sequencing analyses of long QT syndrome in a Japanese population (2022)
  • Author(s): NagataY、WatanabeR、EichhornC、OhnoS、AibaT、IshikawaT、NakanoY、AizawaY、HayashiKi、MurakoshiN、NakajimaT、YagiharaN、MishimaH、SudoT、HiguchiC、TakahashiA、SekineA、MakiyamaT、TanakaY、WatanabeA、TachibanaM、MoritaH、YoshiuraK-i、TsunodaT、WatanabeH、KurabayashiM、NogamiA、KiharaY、HorieM、ShimizuW、MakitaN、TanakaT
  • Journal Title: PLOS ONE Volume: 17 Issue: 12 Pages: e0277242-e0277242
  • DOI: 10.1371/journal.pone.0277242
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AIによる先天異常症候群の診断支援 （特集・小児外科を取り巻く最新テクノロジー） (2022)
  • Author(s): 三嶋博之
  • Journal Title: 小児外科 Volume: 54 Pages: 1018-1021
• [Journal Article] Identification of unique DNA methylation sites in Kabuki syndrome using whole genome bisulfite sequencing and targeted hybridization capture followed by enzymatic methylation sequencing (2022)
  • Author(s): Hamaguchi Yo、Mishima Hiroyuki、Kawai Tomoko、Saitoh Shinji、Hata Kenichiro、Kinoshita Akira、Yoshiura Koh-ichiro
  • Journal Title: Journal of Human Genetics Volume: 67 Issue: 12 Pages: 711-720
  • DOI: 10.1038/s10038-022-01083-4
  • Peer Reviewed
• [Journal Article] Anti‐desmoglein 1 antibody‐positive mother and antibody‐negative child with Darier's disease (2022)
  • Author(s): Kawaguchi Ami、Matsuda Mitsuhiro、Koga Hiroshi、Ohata Chika、Hamada Takahiro、Mishima Hiroyuki、Yoshiura Koh‐ichiro、Jinnin Masatoshi、Minami Hironori、Kanazawa Nobuo
  • Journal Title: The Journal of Dermatology Volume: 50 Issue: 2 Pages: 250-253
  • DOI: 10.1111/1346-8138.16568
  • Peer Reviewed / Open Access
• [Journal Article] Alvocidib inhibits IRF4 expression via super‐enhancer suppression and adult T‐cell leukemia/lymphoma cell growth (2022)
  • Author(s): Sakamoto Hikaru、Ando Koji、Imaizumi Yoshitaka、Mishima Hiroyuki、Kinoshita Akira、Kobayashi Yuji、Kitanosono Hideaki、Kato Takeharu、Sawayama Yasushi、Sato Shinya、Hata Tomoko、Nakashima Masahiro、Yoshiura Koh‐Ichiro、Miyazaki Yasushi
  • Journal Title: Cancer Science Volume: 113 Issue: 12 Pages: 4092-4103
  • DOI: 10.1111/cas.15550
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant hypomethylation at imprinted differentially methylated regions is involved in biparental placental mesenchymal dysplasia (2022)
  • Author(s): Aoki Saori、Higashimoto Ken、Hidaka Hidenori、Ohtsuka Yasufumi、Aoki Shigehisa、Mishima Hiroyuki、Yoshiura Koh-ichiro、Nakabayashi Kazuhiko、Hata Kenichiro、Yatsuki Hitomi、Hara Satoshi、Ohba Takashi、Katabuchi Hidetaka、Soejima Hidenobu
  • Journal Title: Clinical Epigenetics Volume: 14 Issue: 1 Pages: 64-64
  • DOI: 10.1186/s13148-022-01280-0
  • Peer Reviewed / Open Access
• [Journal Article] gnomAD (第８章疾患に関するゲノムやバリアントを調べる） (2022)
  • Author(s): 三嶋博之
  • Journal Title: 実験医学増刊・バイオDBとウェブツール ラボで使える最新70選 Volume: 40 Pages: 2894-2897
• [Journal Article] gnomAD（特集: ゲノム医療におけるデータベース―使い方とコツ） (2022)
  • Author(s): 三嶋博之
  • Journal Title: 遺伝子医学 Volume: 12 Pages: 60-64
• [Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency (2021)
  • Author(s): Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 0-0
  • DOI: 10.1038/s41467-021-27085-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BCS1L mutations produce Fanconi syndrome with developmental disability (2021)
  • Author(s): Kanako Kojima-Ishii、Sakakibara Nana、Murayama Kei、Nagatani Koji、Murata Satoshi、Otake Akira、Koga Yasutoshi、Suzuki Hisato、Uehara Tomoko、Kosaki Kenjiro、Yoshiura Koh-ichiro、Mishima Hiroyuki、Ichimiya Yuko、Mushimoto Yuichi、Horinouchi Tomoko、Nagano China、Yamamura Tomohiko、Iijima Kazumoto、Nozu Kandai
  • Journal Title: Journal of Human Genetics Volume: 67 Issue: 3 Pages: 143-148
  • DOI: 10.1038/s10038-021-00984-0
  • Peer Reviewed
• [Journal Article] A Patient with Kabuki Syndrome Mutation Presenting with Very Severe Aplastic Anemia (2021)
  • Author(s): Tamura Shinobu、Kosako Hideki、Furuya Yoshiaki、Yamashita Yusuke、Mushino Toshiki、Mishima Hiroyuki、Kinoshita Akira、Nishikawa Akinori、Yoshiura Ko-Ichiro、Sonoki Takashi
  • Journal Title: Acta Haematologica Volume: 145 Issue: 1 Pages: 89-96
  • DOI: 10.1159/000518227
  • Peer Reviewed
• [Journal Article] <i>Itpr1</i> regulates the formation of anterior eye segment tissues derived from neural crest cells (2021)
  • Author(s): Kinoshita Akira、Ohyama Kaname、Tanimura Susumu、Matsuda Katsuya、Kishino Tatsuya、Negishi Yutaka、Asahina Naoko、Shiraishi Hideaki、Hosoki Kana、Tomiwa Kiyotaka、Ishihara Naoko、Mishima Hiroyuki、Mori Ryoichi、Nakashima Masahiro、Saitoh Shinji、Yoshiura Koh-ichiro
  • Journal Title: Development Volume: 148 Issue: 16 Pages: 188755-188755
  • DOI: 10.1242/dev.188755
  • Peer Reviewed / Open Access
• [Journal Article] Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome. (2021)
  • Author(s): Ishikawa T, Kimoto H, Mishima H, Yamagata K, Ogata S, Aizawa Y, Hayashi K, Morita H, Nakajima T, Nakano Y, Nagase S, Murakoshi N, Kowase S, Ohkubo K, Aiba T, Morimoto S, Ohno S, Kamakura S, Nogami A, Takagi M, Karakachoff M, Dina C, Schott JJ, Yoshiura KI, Horie M, Shimizu W, Nishimura K, Kusano K, Makita N.
  • Journal Title: Eur Heart J. Volume: 42(29) Issue: 29 Pages: 2854-2863
  • DOI: 10.1093/eurheartj/ehab254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bile extracellular vesicles from end-stage liver disease patients show altered microRNA content (2021)
  • Author(s): Nakashiki Suguru、Miuma Satoshi、Mishima Hiroyuki、Masumoto Hiroshi、Hidaka Masaaki、Soyama Akihiko、Kanda Yasuko、Fukushima Masanori、Haraguchi Masafumi、Sasaki Ryu、Miyaaki Hisamitsu、Ichikawa Tatsuki、Takatsuki Mitsuhisa、Eguchi Susumu、Yoshiura Koh-ichiro、Nakao Kazuhiko
  • Journal Title: Hepatology International Volume: 15 Issue: 3 Pages: 821-830
  • DOI: 10.1007/s12072-021-10196-5
  • Peer Reviewed
• [Journal Article] Multifaceted array‐based keloidal gene expression profiling reveals specific MDFI upregulation in keloid lesions (2021)
  • Author(s): Asai M.、Koike Y.、Kuwatsuka Y.、Yagi Y.、Kashiyama K.、Tanaka K.、Mishima H.、Yoshiura K.、Utani A.、Murota H.
  • Journal Title: Clinical and Experimental Dermatology Volume: 46 Issue: 7 Pages: 1255-1261
  • DOI: 10.1111/ced.14698
  • Peer Reviewed
• [Journal Article] ヒトゲノムデータの利活用の実際（特集・みんなのバイオDX） (2021)
  • Author(s): 三嶋博之
  • Journal Title: 実験医学 Volume: 39 Pages: 3014-3017
• [Presentation] 「パタカラプラス」の自動評価 (2024)
  • Author(s): 三嶋博之
  • Organizer: 第36回日本ダウン症療育研究会
  • Invited
• [Presentation] (O-15) T2T完全長ヒト参照ゲノムを用いた全ゲノムシークエンシングのためのアノテーションワークフローの開発 (2023)
  • Author(s): 三嶋博之, 吉浦孝一郞
  • Organizer: 第30回日本遺伝子診療学会大会・第8回クリニカルバイオバンク学会シンポジウム合同学術集会
• [Presentation] 希少疾患ゲノム解析における最近の潮流 (2022)
  • Author(s): 三嶋博之
  • Organizer: ポストコッホ生態研究集会＠長崎大学
  • Invited
• [Presentation] 先天性形態異常症候群の診断補助システムの現状 (2021)
  • Author(s): 三嶋博之
  • Organizer: 第58回日本小児外科学会学術集会
  • Invited