Clinical Genetics Knowledge Sharing System for Congenital Rare Disease Deep Phenotyping Overcoming the "30% limit" of Diagnosis

• Project/Area Number: 18K07850
• 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): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 希少疾患 / 顔貌解析 / 機械学習 / 診断支援 / Face2Gene / ３次元 / ２次元 / ※希少疾患 / 診断補助 / ディープラーニング / 先天形態異常症候群 / 稀少疾患 / 先天性形態異常症候群 / 臨床情報 / 臨床遺伝学 / ゲノム医学

Outline of Final Research Achievements

Face2Gene (https://face2gene.com/), developed by FDNA, Inc. in the U.S., is a machine-learning tool to assist in the diagnosis of congenital morphology syndromes based on facial gestalts. We attempted to evaluate its performance using cases recruited in Japan (49 cases in 26 syndromes) (Mishima et al., J Hum Genet, 2019). As a result, the system successfully presented the top 10 syndromes in 85.7% of the learned syndromes, indicating that the system already has high performance. At the same time, we found that some of the learned syndromes failed to be presented. The reason for this result could be the insufficient number of training cases or the difference in the strength of the effect of racial background.

Academic Significance and Societal Importance of the Research Achievements

Face2Geneは、すでに日本人集団においても高い候補症候群提示能力を持つことが明らかになった。このことは、同システムが臨床遺伝専門医が、本邦における9,000症候群近くが知られる先天形態異常症候群からの診断を絞りこむ上で有用であることを示した。また、先天形態異常症候群の原因である単一遺伝子のバリエーションが顔貌表現型に与える影響は、多くの場合地理的集団による遺伝的バックグラウンドよりも十分に強いものであることが示唆された。

Research Products

• [Journal Article] Progressive Massive Splenomegaly in an Adult Patient with Kabuki Syndrome Complicated with Immune Thrombocytopenic Purpura (2021)
  • Author(s): Mushino Toshiki、Hiroi Takayuki、Yamashita Yusuke、Suzaki Norihiko、Mishima Hiroyuki、Ueno Masaki、Kinoshita Akira、Minami Koichi、Imai Kohsuke、Yoshiura Ko-ichiro、Sonoki Takashi、Tamura Shinobu
  • Journal Title: Internal Medicine Volume: 60 Issue: 12 Pages: 1927-1933
  • DOI: 10.2169/internalmedicine.6694-20
  • NAID: 130008052635
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-06-15
  • Peer Reviewed / Open Access
• [Journal Article] A unique missense variant in the E1A-binding protein P400 gene is implicated in schizophrenia by whole-exome sequencing and mutant mouse models (2021)
  • Author(s): Yoshiro Morimoto, Shinji Ono, Shintaro Yoshida, Hiroyuki Mishima, Akira Kinoshita, Takeshi Tanaka, Yoshihiro Komohara, Naohiro Kurotaki, Tatsuya Kishino, Yuji Okazaki, Hiroki Ozawa, Koh-ichiro Yoshiura, Akira Imamura
  • Journal Title: Translational Psychiatry Volume: 11 Issue: 1 Pages: 132-132
  • DOI: 10.1038/s41398-021-01258-1
  • NAID: 120007000270
  • Peer Reviewed / Open Access
• [Journal Article] Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities (2021)
  • Author(s): Satoh Chisei、Kondoh Tatsuro、Shimizu Hitomi、Kinoshita Akira、Mishima Hiroyuki、Nishimura Gen、Miyazaki Mutsuko、Okano Kunihiko、Kumai Yoshihiko、Yoshiura Koh-ichiro
  • Journal Title: European Journal of Medical Genetics Volume: 64 Issue: 2 Pages: 104125-104125
  • DOI: 10.1016/j.ejmg.2020.104125
  • Peer Reviewed
• [Journal Article] Next-generation sequencing of the whole MEFV gene in Japanese patients with familial Mediterranean fever: a case-control association study (2020)
  • Author(s): Koga T, Sato S, Mishima H, Migita K, Endo Y, Umeda M, Sumiyoshi R, Nonaka F, Fukui S, Kawashiri S-Y, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Ueki Y, Masumoto J, Agematsu K, Yachie A, Yoshiura K-I, Eguchi K, Kawakami A
  • Journal Title: Clin Exp Rheumatol Volume: 38
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac Emerinopathy (2020)
  • Author(s): Ishikawa Taisuke、Ichida Fukiko、Makita Naomasa et al
  • Journal Title: Circulation: Arrhythmia and Electrophysiology Volume: 13 Issue: 10 Pages: 1165-1174
  • DOI: 10.1161/circep.120.008712
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A case of ezetimibe-effective hypercholesterolemia with a novel heterozygous variant in ABCG5 (2020)
  • Author(s): Nakano Y, Komiya C, Shimizu H, Mishima H, Shiba K, Tsujimoto K, Ikeda K, Kashimada K, Dateki S, Yoshiura KI, Ogawa Y, Yamada T.
  • Journal Title: Endocrine Journal Volume: 67 Issue: 11 Pages: 1099-1105
  • DOI: 10.1507/endocrj.ej20-0044
  • NAID: 130007945810
  • Peer Reviewed / Open Access
• [Journal Article] Expression of unfolded protein response markers in the pheochromocytoma with Waardenburg syndrome: a case report (2020)
  • Author(s): Morita Shuhei、Takeshima Ken、Ariyasu Hiroyuki、Furukawa Yasushi、Kishimoto Shohei、Tsuji Tomoya、Uraki Shinsuke、Mishima Hiroyuki、Kinoshita Akira、Takahashi Yuichi、Inaba Hidefumi、Iwakura Hiroshi、Furuta Hiroto、Nishi Masahiro、Doi Asako、Murata Shin-ichi、Yoshiura Koh-ichiro、Akamizu Takashi
  • Journal Title: BMC Endocrine Disorders Volume: 20 Issue: 1 Pages: 90-90
  • DOI: 10.1186/s12902-020-00574-9
  • Peer Reviewed / Open Access
• [Journal Article] AIを用いた先天形態異常症候群の診断 (2020)
  • Author(s): 三嶋博之
  • Journal Title: 月刊泌尿器科 Volume: 13 Pages: 197-202
  • NAID: 40022498432
• [Journal Article] BioHackathon 2015: Semantics of data for life sciences and reproducible research., (2020)
  • Author(s): Vos, Katayama, Mishima et. al
  • Journal Title: F1000Reseaech Volume: - Pages: 136-136
  • DOI: 10.12688/f1000research.18236.1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KAT6B-related disorder in a patient with a novel frameshift variant (c.3925dup) (2019)
  • Author(s): Hamaguchi Yo、Aoki Mikihiro、Watanabe Satoshi、Mishima Hiroyuki、Yoshiura Koh-ichiro、Moriuchi Hiroyuki、Dateki Sumito
  • Journal Title: Human Genome Variation Volume: 6 Issue: 1 Pages: 54-54
  • DOI: 10.1038/s41439-019-0085-3
  • NAID: 120006988337
  • Peer Reviewed / Open Access
• [Journal Article] eterogenous nature of gene expression patterns in BRAF-like papillary thyroid carcinomas with BRAFV600E. (2019)
  • Author(s): Nagayama Y, Mishima H
  • Journal Title: Endocrine Volume: 66 Issue: 3 Pages: 607-613
  • DOI: 10.1007/s12020-019-02063-z
  • Peer Reviewed
• [Journal Article] Target Capture/Next-Generation Sequencing for Nonsyndromic Cleft Lip and Palate in the Japanese Population (2019)
  • Author(s): Shibano Masayasu、Watanabe Akira、Takano Nobuo、Mishima Hiroyuki、Kinoshita Akira、Yoshiura Koh-ichiro、Shibahara Takahiko
  • Journal Title: The Cleft Palate-Craniofacial Journal Volume: 57 Issue: 1 Pages: 80-87
  • DOI: 10.1177/1055665619857650
  • Peer Reviewed
• [Journal Article] Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities (2019)
  • Author(s): Morimoto Y, Yoshida S, Kinoshita A, Satoh C, Mishima H, Yamaguchi N, Matsuda K, Sakaguchi M, Tanaka T, Komohara Y, Imamura A, Ozawa H, Nakashima M, Kurotaki N, Kishino T, Yoshiura K, Ono S
  • Journal Title: Neurology Volume: 92 Issue: 20
  • DOI: 10.1212/wnl.0000000000007505
  • NAID: 120006987711
  • Peer Reviewed / Open Access
• [Journal Article] Genome analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki (2019)
  • Author(s): Taguchi M, Mishima H, Shiozawa Y, Hayashida C, Kinoshita A, Nannya Y, Makishima H, Horai M, Matsuo M, Sato S, Itonaga H, Kato T, Taniguchi H, Imanishi D, Imaizumi Y, Hata T, Takenaka M, Moriuchi Y, Shiraishi Y, Miyano S, Ogawa S, Yoshiura K-i, Miyazaki Y
  • Journal Title: Haematologica Volume: 105 Issue: 2 Pages: 358-365
  • DOI: 10.3324/haematol.2019.219386
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of a novel CCDC22 mutation in a patient with severe Epstein?Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia (2019)
  • Author(s): Yamashita Y, Nishikawa A, Iwahashi Y, Fujimoto M, Sasaki I, Mishima H, Kinoshita A, Hemmi H, Kanazawa N, Ohshima K, Imadome KI, Murata SI、Yoshiura KI, Kaisho T, Sonoki T, Tamura S
  • Journal Title: International Journal of Hematology Volume: 印刷中 Issue: 6 Pages: 744-750
  • DOI: 10.1007/s12185-019-02595-0
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Face2Gene using facial images of patients with congenital dysmorphic syndromes recruited in Japan (2019)
  • Author(s): Mishima Hiroyuki、Suzuki Hisato、Doi Michiko、Miyazaki Mutsuko、Watanabe Satoshi、Matsumoto Tadashi、Morifuji Kanako、Moriuchi Hiroyuki、Yoshiura Koh-ichiro、Kondoh Tatsuro、Kosaki Kenjiro
  • Journal Title: Journal of Human Genetics Volume: 64 Issue: 8 Pages: 789-794
  • DOI: 10.1038/s10038-019-0619-z
  • Peer Reviewed / Open Access
• [Journal Article] Atypical phenotype without fever in a Japanese family with an autosomal dominant transmission of familial Mediterranean fever due to heterozygous MEFV Thr577Asn mutations. (2019)
  • Author(s): Y. Endo, T. Koga, M. Nakashima, H. Mishima, K. Yoshiura, A. Kawakami
  • Journal Title: Clin Exp Rheumatol Volume: in press
  • Peer Reviewed
• [Journal Article] Identification of a homozygous frameshift variant in RFLNA in a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome (2019)
  • Author(s): Shimizu H, Watanabe S, Kinoshita A, Mishima H, Nishimura G, Moriuchi H, Yoshiura K, Dateki S
  • Journal Title: J Hum Genet Volume: 64 Issue: 5 Pages: 467-471
  • DOI: 10.1038/s10038-019-0581-9
  • NAID: 120006987791
  • Peer Reviewed
• [Journal Article] A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency (2019)
  • Author(s): Sumito Dateki, Satoshi Watanabe, Hiroyuki Mishima, Toshihiko Shirakawa, Minoru Morikawa, Eiichi Kinoshita, Koh-ichiro Yoshiura, and Hiroyuki Moriuchi
  • Journal Title: J Hum Genet Volume: 64 Issue: 4 Pages: 341-346
  • DOI: 10.1038/s10038-019-0566-8
  • NAID: 120006987778
  • Peer Reviewed
• [Journal Article] Patients with SATB2-associated syndrome exhibiting multiple odontomas. (2018)
  • Author(s): Kikuiri T, Mishima H, Imura H, Suzuki S, Matsuzawa Y, Nakamura T, Fukumoto S, Yoshimura Y, Watanabe S, Kinoshita A, Yamada T, Shindoh M, Sugita Y, Maeda H, Yawaka Y, Mikoya T, Natsume N, Yoshiura KI.
  • Journal Title: Am J Med Genet A. Volume: 176 Issue: 12 Pages: 2614-2622
  • DOI: 10.1002/ajmg.a.40670
  • Peer Reviewed
• [Journal Article] Identification of a variant associated with early-onset diabetes in the intron of the insulin gene with exome sequencing (2018)
  • Author(s): Matsuno, S., Furuta, H., Kosaka, K., Doi, A., Yorifuji, T., Fukuda, T., Senmaru, T., Uraki, S., Matsutani, N., Furuta, M., Mishima, H., Iwakura, H., Nishi, M., Yoshiura, K., Fukui, M. and Akamizu, T.
  • Journal Title: J Diabetes Investig Volume: Epub ahead of print Issue: 4 Pages: 947-950
  • DOI: 10.1111/jdi.12974
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer. (2018)
  • Author(s): Hidaka H, Higashimoto K, Aoki S, Mishima H, Hayashida C, Maeda T, Koga Y, Yatsuki H, Joh K, Noshiro H, Iwakiri R, Kawaguchi A, Yoshiura KI, Fujimoto K, Soejima H.
  • Journal Title: Clin Epigenetics Volume: 10 Issue: 1 Pages: 150-150
  • DOI: 10.1186/s13148-018-0578-9
  • Peer Reviewed / Open Access
• [Presentation] (SY12-3) 先天性形態異常症候群の顔貌画像による診断補助の現状 (2020)
  • Author(s): 三嶋博之
  • Organizer: 日本人類遺伝学会第 65 回大会
  • Invited
• [Presentation] (OE13-3) PatakaraPlus: The project for individuals with Down Syndrome to develop oral and physical training and evaluation (2020)
  • Author(s): Hiroyuki Mishima, Tetsuro Kitahara, Koh-Ichiro Yoshiura, Tomoko Komatsu, Masaichi Lee, Tatsuro Kondoh
  • Organizer: 日本人類遺伝学会第65回大会
• [Presentation] (P-20) Direct detection of genomic DNA methylation using Nanopore long-read seqiencing technology (2020)
  • Author(s): Hiroyuki Mishima, Yo Hamaguchi, Koh-ichiro Yoshiura
  • Organizer: 放射線災害・医科学研究拠点 第4回シンポジウム
• [Presentation] (P25-9)本邦における先天性形態異常症候群患者の顔貌画像を用いた診断補助システムFace2Geneの評価 (2019)
  • Author(s): 三嶋博之，鈴木寿人，吉浦孝一郎，近藤達郎，小崎健次郎
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] (2605/T) Detection of structural variations in monozygotic twins using Nanopore long-read sequencing technology (2019)
  • Author(s): H. Mishima; S. Yoshida; Y. Morimoto; S. Ono; A. Kinoshita; A. Imamura; H. Ozawa; K.-I. Yoshiura
  • Organizer: American Society of Human Genetics 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] 歯科医学・ゲノム医療・人工知能 (2019)
  • Author(s): 三嶋博之
  • Organizer: 北日本口腔インプラント研究会2019年度第32回北海道地区口腔インプラント臨床コロキウム
  • Invited
• [Presentation] Evaluation of Face2Gene using facial images of patients with congeneital dysmorphic syndromes recruited in Japan (2019)
  • Author(s): Hiroyuki Mishima
  • Organizer: The 30th Fukuoka International Symposium on Pediatric/Maternal-Child Health Research
  • Invited
• [Presentation] Evaluation of Face2Gene using facial images of patients with congenital dysmorphic syndromes recruited in Japan (2019)
  • Author(s): 三嶋博之
  • Organizer: 第59回日本先天異常学会学術＋第13回国際口唇口蓋裂協会世界会議
  • Invited
• [Presentation] 顔貌画像を用いた先天性形態異常症候群の診断補助システムの現状 (2019)
  • Author(s): 三嶋博之
  • Organizer: 第28回日本小児泌尿器科楽器総会・学術集会
  • Invited
• [Presentation] 先天性形態異常症候群の顔貌解析システムFace2Geneの本邦症例に対する性能評価 (2019)
  • Author(s): 三嶋博之
  • Organizer: ROIS-DS-JOINT共同研究集会「希少疾患インフォマティクス：情報保護・情報共有・社会実装」
  • Invited
• [Presentation] 先天性形態異常症候群診断補助システムFace2Geneの本邦症例を用いた性能評価 (2019)
  • Author(s): 三嶋博之，近藤達郎，鈴木寿人，吉浦孝一郎，小崎健次郎
  • Organizer: 第1回日本メディカルAI学会学術集会
• [Presentation] Detection of genomic structural variations in monozygotic twins using Nanopore long-read sequencing technology (2019)
  • Author(s): Hiroyuki Mishima, Shintaro Yoshida, Yoshiro Morimoto, Shinji Ono, Akira Kinoshita, Akira Imamura, Hiroki Ozawa, Koh-ichiro Yoshiura
  • Organizer: 放射線障害・医科学研究拠点 第3回国際シンポジウム
  • Int'l Joint Research
• [Presentation] 患者顔貌画像による先天性形態異常症候群診断補助システムFace2Geneの本邦症例を用いた性能評価 (2019)
  • Author(s): 三嶋博之，鈴木寿人，近藤達郎，吉浦孝一郎，小崎健次郎
  • Organizer: 第41回日本小児遺伝学会学術集会
• [Presentation] 情報共有が可能とする稀少疾患ゲノム解析 (2018)
  • Author(s): 三嶋博之
  • Organizer: 第60回歯科基礎医学会学術大会
  • Invited
• [Presentation] GridIONを使ったヒトゲノム構造バリエーション解析の実際 (2018)
  • Author(s): 三嶋博之
  • Organizer: GridIONを使ったヒトゲノム構造バリエーション解析の実際, オックスフォード・ナノポア現場の会
  • Invited
• [Presentation] 患者顔貌画像による先天性形態異常症候群診断補助システムFace2Geneの本邦症例を用いた性能評価 (2018)
  • Author(s): 三嶋博之，近藤達郎，鈴木寿人，吉浦孝一郎，小崎健次郎
  • Organizer: 日本小児学会長崎地方会
• [Presentation] 低depth全ゲノムシークエンシングによるコピー数バリエーション検出の性能評価 (2018)
  • Author(s): 三嶋博之, 吉浦孝一郎
  • Organizer: 日本人類遺伝学会第63回大会