Six years’ accomplishment of the Initiative on Rare and Undiagnosed Diseases: nationwide project in Japan to discover causes, mechanisms, and cures
Authors: Takahashi Yuji , Date Hidetoshi , Oi Hideki , Adachi Takeya , Imanishi Noriaki , Kimura En , Takizawa Hotake , Kosugi Shinji , Matsumoto Naomichi , Kosaki Kenjiro , Matsubara Yoichi ,   IRUD Consortium, Ando Yukio , Anzai Toshihisa , Ariga Tadashi , Fukushima Yoshimitsu , Furusawa Yoshihiko , Ganaha Akira , Goto Yuichi , Hata Kenichiro , Honda Masataka , Iijima Kazumoto , Ikka Tsunakuni , Imoto Issei , Kaname Tadashi , Kobayashi Masao , Kojima Seiji , Kurahashi Hiroki , Kure Shigeo , Kurosawa Kenji , Maegaki Yoshihiro , Makita Yoshio , Morio Tomohiro , Narita Ichiei , Nomura Fumio , Ogata Tsutomu , Ozono Keiichi , Oka Akira , Okamoto Nobuhiko , Saitoh Shinji , Sakurai Akihiro , Takada Fumio , Takahashi Tsutomu , Tamaoka Akira , Umezawa Akihiro , Yachie Akihiro , Yoshiura Kouichiro , Chinen Yasutsugu , Eguchi Mariko , Fujio Keishi , Hosoda Kiminori , Ichikawa Tomohiko , Kawarai Toshitaka , Kosho Tomoki , Masuno Mitsuo , Nakamura Akie , Nakane Takaya , Ogi Tomoo , Okada Satoshi , Sakata Yasushi , Seto Toshiyuki , Takahashi Yoshiyuki , Takano Tadao , Ueda Mitsuharu , Yagasaki Hideaki , Yamamoto Toshiyuki , Watanabe Atsushi , Hotta Yoshihiro , Kubo Akiharu , Maruyama Hirofumi , Moriyama Keiji , Nanba Eiji , Sakai Norio , Sekijima Yoshiki , Shimosegawa Toru , Takeuchi Tsutomu , Usami Shinichi , Yamamoto Kazuhiko , Mizusawa Hidehiro 
Published: March 2022

AbstractThe identification of causative genetic variants for hereditary diseases has revolutionized clinical medicine and an extensive collaborative framework with international cooperation has become a global trend to understand rare disorders. The Initiative on Rare and Undiagnosed Diseases (IRUD) was established in Japan to provide accurate diagnosis, discover causes, and ultimately provide cures for rare and undiagnosed diseases. The fundamental IRUD system consists of three pillars: IRUD diagnostic coordination, analysis centers (IRUD-ACs), and a data center (IRUD-DC). IRUD diagnostic coordination consists of clinical centers (IRUD-CLs) and clinical specialty subgroups (IRUD-CSSs). In addition, the IRUD coordinating center (IRUD-CC) manages the entire IRUD system and temporarily operates the IRUD resource center (IRUD-RC). By the end of March 2021, 6301 pedigrees consisting of 18,136 individuals were registered in the IRUD. The whole-exome sequencing method was completed in 5136 pedigrees, and a final diagnosis was established in 2247 pedigrees (43.8%). The total number of aberrated genes and pathogenic variants was 657 and 1718, among which 1113 (64.8%) were novel. In addition, 39 novel disease entities or phenotypes with 41 aberrated genes were identified. The 6-year endeavor of IRUD has been an overwhelming success, establishing an all-Japan comprehensive diagnostic and research system covering all geographic areas and clinical specialties/subspecialties. IRUD has accurately diagnosed diseases, identified novel aberrated genes or disease entities, discovered many candidate genes, and enriched phenotypic and pathogenic variant databases. Further promotion of the IRUD is essential for determining causes and developing cures for rare and undiagnosed diseases.