Rare Disease Detectives

By definition, rare diseases are individually rare, but they are collectively common across the global population. There are more than 7,000 types of rare disease in existence, meaning the burden on families and healthcare systems is significant. Around 300 million people worldwide have a rare disease, waiting an average of 4–5 years for a diagnosis.  

Aside from great personal cost, research has found the complex diagnostic process for rare diseases has a huge economic impact. In the UK, NHS England has spent more than £3.4 billion over the past ten years on rare disease patient care. Meanwhile, under the private system in the US, the annual cost of rare disease patients is estimated to be $2.2 trillion per year. Despite this great expense, around 60 percent of people still don’t receive a diagnosis.  

Finding the underlying causes of rare diseases presents a significant challenge as the vast majority of conditions are suspected to have complex genetic origins. One of the major contributing factors to breakthroughs in rare disease research is the growing number of international consortia and research partnerships. These efforts bring together the best minds and cutting-edge technologies in genomics today. Investment in such collaborative efforts is critical to unlocking the secrets of rare diseases’ genetic origins, enabling faster and more accurate diagnoses, and improving patient outcomes. 

The diagnostic odyssey
 

Many families start the often years-long diagnostic odyssey with some form of genetic testing. Gene panels, microarrays, and exome sequencing are amongst the chosen methods for investigating the genetic cause of rare disease. However, these technologies do not resolve all cases. 

Gene panel tests look for variants in more than one gene, and can be useful if symptoms are well characterized and specific causative abnormalities are suspected. Microarrays can potentially detect more variants, as well as chromosomal abnormalities, but are biased to only detect known genomic variants. Exome sequencing, which in many countries is the first-line test for suspected genetic disease, is a form of sequencing that captures genetic changes primarily in exonic coding regions. However, many of the variants associated with rare diseases are novel, much longer, or occur in non-coding regions, so often go undetected. These standard testing methodologies may require prior knowledge of which genetic variants to investigate, meaning they are only effective when specific known genes or variants are the suspected cause of disease. If the disease-causing variant is novel, complex, or in a poorly covered region, legacy testing technologies may fall short. 

When exome sequencing doesn’t reveal the cause, the next logical step may be short-read whole genome sequencing (srWGS) to examine the rest of a patient’s genome. This method begins with library preparation that breaks the genome into small fragments, sequences each, then maps variants against the accepted reference genome. This comparison – known as variant calling – helps to identify potential disease-calling variants within a patient’s entire genome. While most of the genome is characterized by srWGS, the technique is more expensive than exome sequencing and only provides a modest increase in solving rare disease (approximately 10 percent). Additionally, certain types of variation like repetitive sequences, which are known to be clinically important to rare diseases, are still challenging to map back to the reference genome using srWGS – imagine a puzzle where all the pieces look the same. 

In short, current testing techniques and interpretational challenges leave families navigating a maze of appointments and enduring uncertainty. In contrast, long-read sequencing, which can capture long stretches of DNA at a time, is revolutionizing the diagnosis of rare disease. This technology can capture genomic variation that other types of genetic testing miss.

Rather than studying rare diseases in silos, a growing number of universities, technology companies, and patient groups are pooling their resources to accelerate research and find answers for families. There is real hope that long-read sequencing will improve diagnostic rates which will ultimately lead to better patient outcomes. 

The undiagnosed hackathon
 

A powerful example of a research consortium in action is the 2024 Undiagnosed Hackathon; initiated by The Wilhelm Foundation and held at Radboud University Medical Center (Radboudumc) in Nijmegen, the Netherlands. More than 120 experts from 28 countries, including doctors, geneticists, bioinformaticians, and AI specialists, collaborated in a 48-hour sprint to aim to diagnose some of 42 families with previously undiagnosed diseases. The results were extraordinary: ten conditions were diagnosed in just two days – a significant breakthrough for families who had been waiting years for answers.

Key to these discoveries was access to advanced genomic technologies at the event, including a type of highly accurate long-read technology called HiFi sequencing. By sequencing the genome in much longer stretches, HiFi enables researchers to accurately call all variant types, including those which are more complex and often misassembled by  traditional tests. Lisenka Vissers of Radboudumc explained at the event, “Unless you use long-reads, there is no test that captures nearly all medically relevant variants. Only with this technique have we gained the way to look at the human genome.” 

In a retrospective clinical study by the Radboudmc team, HiFi sequencing was found to identify 93 percent of pathogenic variants, and led to 8 out of the 10 solves from the event. Events like the hackathon are critical to proving the value of such advanced technologies and encouraging investment from hospitals and research institutions in rare disease research. Events are also key for educating and engaging the rare disease community, from patient groups to scientists. For many participants, such as lab specialists and bioinformaticians, who typically do not have contact with patients, meeting the families added a deeply emotional dimension to their work. Seeing their research in action provided extra motivation, driving the team to relentlessly pursue diagnoses within the 48-hour window. 

The journey ahead – a group road trip?
 

The Hackathon did an amazing job at showcasing the power of cutting-edge technologies and enabling researchers to see the real-life applications of their work. But, at its heart, the event was about building the rare disease community and bringing hope and answers to families left in the dark for years. Radboudmc’s Alexander Hoischen commented on the event, “The beauty of the undiagnosed hackathon is that it will continue and is still growing. We have to bring the latest innovations including long-read sequencing to the patients.” 

Rare disease research is not a solitary endeavor – it’s a shared journey between patients, their families, and all who are committed to solving their condition. No single institution has all the resources or knowledge needed to investigate the complex genetic and biological factors behind rare diseases. By pooling expertise, data, technology, and patient understanding, consortia can accelerate research, improve diagnostic accuracy, and find solutions more efficiently. As the Hackathon proved, advancing rare disease research on a global scale relies on greater collaboration and investment in the field.