Solving the unsolvable: a revolutionary new model for diagnosing rare diseases
Written by Emma Bishop, RARE Revolution insider
Interview with Helene Cederroth, founder and CEO, Wilhelm Foundation
Estimated reading time: 9 minutes
Where traditional medical approaches have failed, one pioneering initiative is transforming the landscape of undiagnosed diseases. The Undiagnosed Hackathon is international collaboration at its best, bringing together experts in genetics, bioinformatics and research from across the globe to solve the seemingly unsolvable. Breaking down professional barriers and placing families at the heart of medical investigations, this innovative approach has already secured diagnoses for multiple families, replacing years of uncertainty with hope
Breaking down silos to tackle complex undiagnosed conditions
With the number of rare diseases worldwide quoted between 6000 and 10,000, it can take, on average, five years for someone with a rare disease to receive a diagnosis.1 However, so many exceed this average, with some people never receiving an answer. There are currently 350 million people, globally, living with an undiagnosed disease.2 It is this group that the Wilhelm Foundation, founded by Mikk and Helene Cederroth, aim urgently to address. As Helene explains, “genome sequencing can provide answers for 40% of people living with an undiagnosed disease.3 That means 60% don’t receive a diagnosis and we need to change that. We need to focus on the 60% that we can’t solve.”
Like so much in the rare space, the Cederroths felt new, outside-the-box approaches were needed to address this overwhelming statistic. In his role as a CTO (chief technology officer) Mikk was familiar with hackathons—events where people gather to find solutions to a problem, in a short space of time, typical in the world of IT. Mikk and Helene had the idea of applying this model to the undiagnosed space, assembling clinicians, bioinformaticians, geneticists and molecular biologists, as opposed to software developers, to tackle some of the most complex, unsolved disease cases.
Partnering with Prof Ann Nordgren from Karolinska Institute in Sweden, the first Undiagnosed Hackathon was held in June 2023. 95 medical professionals from 28 countries came together to collaborate, with the aim of providing diagnoses for selected individuals with undiagnosed diseases. The decision was made to remove professional titles from name tags, to encourage equal partnership and authentic communication between participants. Despite some initial reluctance this was embraced which Helene says was a great success. Country names will also be removed at the next Undiagnosed Hackathon.
The human impact
It was important from the outset that as well as medical professionals, families with the undiagnosed diseases were present to help participants understand the personal impact and to give a human context to the samples and data being analysed in the lab. “We discovered that many bioinformaticians had never met an undiagnosed family before, and they were overwhelmed seeing the families—some with very sick children and with siblings running around the room. It brought some of them to tears because they saw for the first time who they were trying to help. It was so touching,” recalls Helene.
Phenotyping is an integral part of the Undiagnosed Hackathon and why it is so important to integrate the families into the process. By spending time with the families, the teams gain a unique perspective with the chance to observe and fully consider all aspects, however small, that might build up to a bigger picture and aid a diagnosis. “When you see a doctor or specialist you only have about 10 to 15 minutes, less in some countries, and so you focus on the most severe symptoms. You don’t have time to mention the smaller, maybe less significant symptoms, that could be important for a diagnosis,” says Helene.
The impact of working this way is also hugely significant for the families who have lived with such uncertainty and fear. Helene tells of a mother with four children—two with a severe disease and two unaffected. “This mother said, ‘there were 95 people all looking at my children and asking questions which was the best feeling.’ Many of the families with undiagnosed diseases feel left behind by the healthcare system so the fact her family was being seen and listened to was just wonderful.”
A long-awaited diagnosis
At the first Undiagnosed Hackathon in 2023 four families received a diagnosis out of the attending 11, in just two days. A second Undiagnosed Hackathon was held at Radboud University Medical Center, Nijmegen, Netherlands, in June 2024. Of the 26 families attending, 10 received a diagnosis, again in just 48 hours, some having waited their whole lives for answers. A further nine, while receiving no definite diagnosis, had promising results that were followed up after the event.
Helene recalls the story of a little girl from Turkey who attended the second Undiagnosed Hackathon. She had severe blisters on her body, making walking almost impossible and robbing her of her hair, along with eye findings and short stature. After nine years of living with uncertainty, she finally received a diagnosis. Her condition is most prevalent in Brazil and Portugal and previously thought unlikely to occur in Turkey, but because of the global collaboration the disease was recognised by international partners, putting an end to her search for answers.
The effects of this innovative collaboration do not stop when the Undiagnosed Hackathon stops. As Helene explains, the little girl for Turkey had no relatives from either Brazil or Portugal, confirming that her disease does occur outside these countries. Participants can take this learning back to their own countries to inform future diagnoses. “It shows that international collaboration is so necessary. She was the first one in Turkey to be diagnosed, but there will possibly be more.”
Being heard
As someone who has lost three children to an undiagnosed disease, Helene knows all too well the desire for answers, to be heard and believed. She empathises with families, who even though there is no treatment for their, or their child’s condition, take solace in the fact they now know what the condition is and how to manage it.
Helene expands further to say it is not uncommon in the search for a diagnosis for the focus to shift to the parents, the mother in particular, especially when a child is failing to thrive, with no obvious explanation. She connected with a family who were suspected of not feeding their child adequately, which escalated to having a social worker monitor how and what they were feeding their child. “Mothers are often suspected as having Munchausen by proxy [when a parent or carer exaggerates or deliberately causes symptoms of illness in a child], when they have a child with an undiagnosed disease. And so when they receive a diagnosis, even if there is no treatment, they are so grateful.”
The Undiagnosed Hackathon 2025
The next Undiagnosed Hackathon will take place at Mayo Clinic in the US, on 22-24 September 2025, once again bringing together clinicians, bioinformaticians, molecular biologists, scientists, developers, AI specialists and more. “It is very important to us that we find new ways to solve undiagnosed diseases, and so we are including more AI specialists this year.”
With the number of confirmed diagnoses more than doubling from the first to the second event, learning is taken from each Undiagnosed Hackathon to grow and build on this unique event. For the third Undiagnosed Hackathon the focus will primarily be on long read sequencing, which can now be fully examined at Mayo Clinic. Specialists from Mayo Clinic will also conduct face to face or virtual meetings with the families prior to the event to begin the investigation.
With innovative thinking needed to tackle the problem of millions of people living with undiagnosed conditions, the Wilhelm Foundation have created a revolutionary model of working, in just three years, that can be replicated globally. In fact, following the success of the previous two Undiagnosed Hackathons, the Karolinska Institute have now changed the way they work, recognising the importance of including multiple disciplines in the diagnostic process and breaking down existing silos. “Karolinska are now integrating bioinformaticians into the diagnostic process, whereas previously they were working in silos, in different parts of the hospital, in isolation.”
Helene’s hope is that other countries will conduct their own national Undiagnosed Hackathons, particularly in low- to middle-income countries—to break down existing barriers and encourage authentic collaboration, with families at the centre of the process, to provide much needed answers to those living in perpetual uncertainty.
“It’s not a competition. It’s about building trust and working together to solve these undiagnosed diseases and to find new ways of working where we haven’t succeeded before.”
References
[1] https://www.eurordis.org/information-support/what-is-a-rare-disease/
[2] Nguengang Wakap, S., Lambert, D.M., Olry, A. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 28, 165–173 (2020). https://doi.org/10.1038/s41431-019-0508-0
[3] Whole genome sequencing diagnostic yield for paediatric patients with suspected genetic disorders: systematic review, meta-analysis, and GRADE assessment DOI: https://doi.org/10.1186/s13690-023-01112-4
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