Six years' accomplishment of the Initiative on Rare and Undiagnosed Diseases: nationwide project in Japan to discover causes, mechanisms, and cures

Abstract

The 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.

Fig. 1

Initiative on Rare and Undiagnosed Diseases (IRUD) diagnostic and research system. IRUD diagnostic and research system consists of six components indicated by underlines: IRUD Clinical Center (IRUD-CL), IRUD Clinical Specialists Subgroup (IRUD-CSS), IRUD Data Center (IRUD-DC), IRUD Analysis Center (IRUD-AC), IRUD Resource Center (IRUD-RC), and IRUD Coordination Center (IRUD-CC). IRUD-CC manages the IRUD Promoting Board (IRUD-PB), the highest decision-making organization. IRUD-CL manages the IRUD Diagnostic Board (IRUD-DB), which manages the process from the decision on patient entry to establishment of a final diagnosis. IRUD-CL and IRUD-CSS are integrated into IRUD Diagnostic Coordination, in which community clinics/hospitals belonging to the Local Medical Association participate. IRUD-CC also temporally serves as an IRUD-RC

Fig. 2

Sample/information workflow. Initiative on Rare and Clinical Diseases Coordination Center (IRUD-CC) manages a sample/information workflow using a unified identification number system. The workflow utilizes an outsourcing provider to extract genomic DNA samples and establish B lymphoblast cell lines, facilitating the flow of samples and information from IRUD Clinical Centers (IRUD-CLs) to IRUD Analysis Centers (IRUD-ACs) and centralizing information and sample repositories in the IRUD Resource Center (IRUD-RC)

Fig. 3

Location of Initiative on Rare and Clinical Diseases Clinical Center (IRUD-CLs) since fiscal year 2018. Locations of each IRUD-CL are shown in the corresponding numbers. The National Center of Neurology and Psychiatry also operates as an IRUD Coordinating Center (IRUD-CC). The IRUD-CLs operating as IRUD Analysis Center (IRUD-AC) are shown with asterisks, and an IRUD-CL operates as an IRUD Data Center (IRUD-DC) and is indicated with a dagger. Inset: IRUD CLs in Tokyo Metropolis. Univ.: University

Fig. 4

Initiative on Rare and Clinical Diseases (IRUD) diagnostic yield. The cumulative number of pedigrees entered, pedigrees with analysis completed, pedigrees with diagnosis established, and novel genes or disease entities are shown at the surveyed year and month

Fig. 5

Pathogenic variant landscape in the Initiative on Rare and Clinical Diseases (IRUD). a Breakdown of pathogenic variants. Diagnosis was established in 2247of 5136 pedigrees. A total of 1718 pathogenic variants were identified in 657 known aberrated genes, among which 1113 were novel (64.8%). b Overview of the frequencies of pathogenic variants in each gene. The number of novel pathogenic variants (shown in blue) and that of known pathogenic variants (shown in orange) in individual genes were arranged in the order of the total number of pathogenic variants. The most frequent gene was CHD7 with 31 pathogenic variants, whereas 298 of the genes had only one pathogenic variant. Inset: genes identified in >7 pedigrees