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Session


Keywords: Exome sequencing; Identification of disease genes; Genetic testing; Mendelian disorder

Authors:
Y. Takahashi 1; H. Date 1; H. Oi 2; S. Kosugi 3; N. Matsumoto 4; K. Kosaki 5; Y. Matsubara 6; H. Mizusawa 7; IRUD. Consortium 8

Affiliations:
1) Department of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan; 2) Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan; 3) Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Kyoto, Japan; 4) Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 5) Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan; 6) National Center for Child Health and Development, Tokyo, Japan; 7) National Center of Neurology and Psychiatry, Tokyo, Japan; 8) Agency for Medical Research and Development. Japan


Background
IRUD was launched in 2015 as a nation-wide project in Japan to construct a comprehensive medical and research system for establishing diagnosis, discovering causes and ultimately providing cures for rare and undiagnosed diseases, supported by Agency for Medical Research and Development (AMED). IRUD covers the entire geographic areas and the whole fields of specialties, taking advantage of the health care system in Japan. IRUD has been motivated by a global trend to tackle undiagnosed diseases through international collaborative networks, leveraging the phenotypic and genetic data by extensive data-sharing to solve so-called ‘N-of-1’ problems.

Purpose
To demonstrate the accomplishment of the three-years’ effort of IRUD project illustrating the landscape of rare and undiagnosed diseases in Japan.

Methods
IRUD consists of the four pillars: a coordinating center (IRUD-CC) to orchestrate the whole system and strengthen the governance, clinical centers?IRUD-C?to operate diagnostic committees which take charge of the process from the decision for recruitment to the establishment of final diagnosis, analysis centers?IRUD-AC? to conduct whole exome sequencing analysis and a data center (IRUD-DC) to implement data-sharing platform, IRUD Exchange. Phenotypic data described in Human Phenotype Ontology and candidate genes are registered in IRUD Exchange, which architecture is compatible to international data-sharing platform, MatchMaker Exchange. Resources including DNA samples and cell lines are deposited in a resource center (IRUD-RC) and prepared for further utilization.

Results
Thirty-seven clinical centers, 5 analysis centers, 1 data center and 1 coordinating center have been established. Until the end of July 2018, 3356 pedigrees including 9524 individuals have been enrolled in IRUD. WES has been completed in 2756 pedigrees and final diagnosis has been established in 1027 pedigrees (36.9%). Novel genes or new disease entities have been discovered in 18 pedigrees through extensive data-sharing.

Conclusion
IRUD has realized a nation-wide comprehensive diagnosis network for rare and undiagnosed diseases and succeeded in establishing diagnosis, identifying novel causative genes and new disease entities through extensive data-sharing and accomplishing resource repository. Extensive international collaboration would play an essential role in elucidating causes and ultimately providing cures for such rare and undiagnosed diseases.