Nov 15, 2018 Medical mystery program takes a global approach to disease sleuthing

Japan’s Initiative on Rare and Undiagnosed Diseases is collaborating with similar programs around the world to advance healthcare and science

A key part of global collaboration on rare diseases involves data sharing and information exchange

© Steve Allen/Stockbyte/Getty

When Japan’s Initiative on Rare and Undiagnosed Diseases (IRUD) launched in July 2015, the first task was to build a nationwide network of clinical centres dedicated to tracking the root causes of mysterious medical conditions. Physicians at dozens of large university hospitals stepped up for the job. Multi-disciplinary committees of medical specialists and clinical geneticists were formed to aid in diagnoses. Four analysis centres were created to administer genetic tests, with a data centre established to manage the glut of clinical and genomic records.

It wasn’t long before the initiative was generating diagnoses for hundreds of patients with previously unexplained illnesses. As of March 2018, IRUD members have taken on more than 3,000 cases, analysed in excess of 8,000 DNA samples from patients or their family members, and successfully identified disease-causing mutations for 38 per cent of these individuals.

Now that the national program is up and running, attention has shifted to how best to integrate IRUD’s efforts with similar diagnostic programs happening elsewhere in the world. “We have to engage with other countries to more efficiently and rapidly make discoveries about the genetic underpinnings of undiagnosed diseases,” says IRUD general leader Hidehiro Mizusawa, president of the National Center of Neurology and Psychiatry in Tokyo.

International cooperation is especially important in the rare disease arena because the small numbers of patients affected make it difficult to distinguish between harmful mutations and benign ones, Mizusawa explains. By pooling cases with global stakeholders, Japanese scientists can help contribute to the discovery of new treatments and diagnostic methods; medical advancements that are necessary for the Japan Agency for Medical Research and Development (AMED) to achieve its ambitious goal of delivering personalised treatments for all Japanese patients with rare and intractable diseases, not just those with specifically defined conditions that meet current Nan-byo criteria.

“Patients and their families benefit most from international collaboration,” notes Yoichi Matsubara, executive officer of the National Center for Child Health and Development in Tokyo and project leader for the pediatric arm of IRUD. “By knowing the exact genetic cause of the disease,” he says, “they finally become free from the frustration and the anxiety of their diagnostic odysseys.”

Patients and their families benefit most from international collaboration

IRUD, through its partner organisations and principal leaders, is now a key player in two global alliances: the Undiagnosed Disease Network International (UDNI) and the International Rare Diseases Research Consortium (IRDiRC). Gareth Baynam, director of Western Australia’s Undiagnosed Diseases Program, says that other member organisations now look to the Japanese program for inspiration and guidance. “Their vision to serve the unmet need of those living with rare and undiagnosed diseases, combined with the quality, integrity and speed of their implementation, is truly remarkable,” Baynam says. IRUD, he adds, provides “a unique and powerful change maker with high national and international impact.”

Productive exchange

A key part of global collaboration involves data sharing and information exchange. IRUD leaders had initially reached out to Baynam and others from Australia for help in developing their electronic medical record system. That partnership led IRUD-affiliated scientists to adapt a data storage platform used by the Western Australia program and co-developed by researchers at the Garvan Institute of Medical Research in Sydney. Kenjiro Kosaki and his colleagues from the Keio University School of Medicine modified the tool for the Japanese language and national healthcare system, and in early 2016 the IRUD Exchange was born.

At first, all genetic and clinical records collected on IRUD Exchange were available only to physicians and scientists affiliated with the national initiative. In October 2017, however, IRUD and Western Australia implemented a secure, privacy-preserving mechanism to allow wider sharing of data. Two months later, IRUD joined the global Matchmaker Exchange project and connected its database to a common platform accessible to researchers in the United States, United Kingdom, Canada and elsewhere.

“The search for novel disease genes will need participation from the whole world because we are now looking at very rare diseases,” says Ada Hamosh, a medical geneticist from the Johns Hopkins University School of Medicine and one of the architects of the Matchmaker Exchange. “We are delighted that the Japanese are adding their cases and look forward to more discovery and benefit to patients around the world.”

Many of these cases have led to fruitful collaborations. In 2016, for example, IRUD-affiliated clinicians from Osaka University, Yokohama City University and Yamagata University pooled patient reports with a team from Switzerland and Egypt to reveal how mutations in a gene called PIGG cause intellectual disability and epilepsy1.

Another case involved a Japanese teenager suffering from neurodegeneration and abnormal genitalia. IRUD researchers from Yokohama City University, Gunma University and Hamamatsu University identified mutations in a gene called TOE1, and then worked with a global team to find 11 other families with the same genetic syndrome. Experiments in mice, fish and human cells revealed a link between TOE1 defects and abnormalities in the processing of gene transcripts in the developing brain2.

Think globally

Sometimes, discoveries made through IRUD help expand the scientific understanding of ultrarare gene mutations previously described elsewhere. Such was the case when Kosaki and his Keio colleague Toshiki Takenouchi identified a five-year-old Japanese girl with developmental delays who harboured a mutation in a gene called YY1 — a genetic defect previously reported only once in a young boy from the Netherlands. Kosaki and Takenouchi shared clinical information and photos with their Dutch colleagues, as did clinicians from Switzerland, Norway and the United States. Collectively, this international team outlined the clinical and molecular consequences of YY1 mutations in a paper published in 20173.

In other cases, however, researchers from around the world have added to the collective knowledge about rare diseases that were first found in Japan. Take Takenouchi-Kosaki syndrome, for example. Keio researchers originally described this genetic condition — a disease caused by mutations in a gene called CDC42 — in two unrelated patients with abnormal platelets and intellectual disabilities4,5. A team from Europe and North America recently reported on patients from another 13 unrelated families all with mutations in the same gene6.

“We have to help each other,” Kosaki says. “The diseases we are working on are so rare that we have to collaborate on a global scale.”

The diseases we are working on are so rare that we have to collaborate on a global scale

Christopher Austin, director of the US National Center for Advancing Translational Sciences and chair of the IRDiRC, credits the openness of IRUD scientists for dramatically accelerating global efforts to solve medical mysteries. “In my three years as chair,” he says, “one of the most significant changes to IRDiRC’s effectiveness and productivity has been the addition of Japan to the consortium.” Referencing the literal meaning of Nan-byo — difficult+illness — Austin says, “Japan’s partnership is helping making these medical mysteries less difficult for patients, doctors and researchers.”

The program-affiliated researchers contributing to this research are from the National Center of Neurology and Psychiatry, National Center for Child Health and Development, Keio University School of Medicine, and elsewhere.


  1. Makrythanasis P. et al. American Journal of Human Genetics 98, 615–626 (2016). | Article
  2. Lardelli, R.M. et al. Nature Genetics 49, 457–464 (2017). | Article
  3. Gabriele, M. et al. American Journal of Human Genetics 100, 907–925 (2017). | Article
  4. Takenouchi, T., Kosaki, R., Niizuma, T., Hata, K. & Kosaki, K. American Journal of Human Genetics A 167A, 2822–2825 (2015). | Article
  5. Takenouchi, T., Okamoto, N., Isa, S., Uehara, T. & Kosaki, K. American Journal of Human Genetics A 170A, 852–855 (2016). | Article
  6. Martinelli, S. et al. American Journal of Human Genetics 102, 309–320 (2018). | Article

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