Diagnosing rare diseases shouldn’t be so hard

Contributing lab leader: Will Greene

When our son was born in late 2021 with a low birth weight and various signs of a potentially serious neuromuscular disorder, my wife and I wanted to know as soon as possible what, if anything, was wrong. Five weeks later, after a seemingly endless series of tests and specialist consultations, our son was diagnosed with Prader-Willi syndrome, a rare and serious genetic disease with limited treatment options and no cure.1

In almost every respect, that five-week journey to diagnosis—a process that is often referred to as the ‘diagnostic odyssey’—was by far the most heart-wrenching period of my life. In some ways, though, I was lucky. For many patients and caregivers diagnosing rare diseases can last for years, cost staggering amounts of money, and take a profound emotional toll on everyone involved.

A disease is defined as ‘rare’ in the European Union if it impacts fewer than 1 in 2,000 people, but many rare diseases are rarer than that. Some ‘ultra-rare’ conditions may impact only a small handful of people around the world. Due to low patient numbers, these diseases are not widely known or understood by clinicians. As a result, signs and symptoms might be attributed to other causes or overlooked completely, resulting in missed opportunities for early intervention that can improve outcomes and sometimes save lives.  

Even when caregivers, patients or clinicians have clinical suspicion of a rare disease, high-quality diagnostics are not readily available in many places. More than 10,000 rare diseases have been characterised in the medical literature, and the latest diagnostic technologies can identify many of them in a matter of days, or even hours.2 Subtyping is also becoming more precise and cost-effective. But healthcare systems in many countries are not always ready to implement or pay for these technologies, so patients may struggle to access them. 

Rare diseases are individually rare, but collectively common, impacting more than 300 million people around the world. Given the large global burden of these diseases, it is unfortunate and increasingly unconscionable that so many people lack access to high-quality diagnostics to aid diagnosing rare diseases. The clinical lab community has an important role to play in changing this situation for the better. 

Article highlights:

  • It often takes years for rare disease patients and their caregivers to achieve a diagnosis.
  • Newborn screening systems and novel sequencing technologies can shorten the diagnostic odyssey, improve patient outcomes and reduce healthcare costs.
  • As more treatments for genetic diseases are approved, the lab community must advocate for better access to rare disease diagnostics.
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The power of newborn screening in diagnosing rare diseases

One approach to diagnosing rare disease is via newborn bloodspot screening (NBS), a process that involves taking a few drops of blood from a newborn infant within the first few days of life and running the samples through a series of tests. Most NBS panels are heavily reliant on tandem mass spectrometry, a diagnostic technology that enables the identification of analytes associated with various congenital disorders, but other methods are also sometimes used. 

In most advanced countries today, the vast majority of newborns access NBS through state-sponsored, population-level programmes. These programmes typically focus on conditions that may not show any clinical signs or symptoms at birth, and for which disease-modifying interventions are available. They operate quietly in the background, with many parents not even knowing that they exist unless they get a call about a positive result. 

But here’s the rub: the largest NBS panels cover roughly 60 conditions, or less than 1% of the total number of rare diseases that are known. In many countries, NBS panels are even smaller than that, covering perhaps only a dozen or even just a few conditions. Many lower-income countries don’t do NBS at all.

In the quest to expand newborn screening panels, most NBS labs are focused on making incremental improvements, with tests being added cautiously and one at a time. NBS labs in Australia, for example, are currently starting to test for spinal muscular atrophy (SMA), a rare neurodegenerative condition that is severely debilitating and often fatal. As SMA medicines become more accessible, other countries in the Asia Pacific region are likely to soon follow.

The addition of SMA to NBS panels allows clinicians to proactively identify patients and initiate treatments that promise to slow disease progression, according to Dr Michelle Farrar, a paediatric neurologist and clinical academic researcher based in Sydney, Australia. “What we learned was that every day counts,” she said in a Q&A with Lab Insights. “Does newborn screening for SMA lead to improved outcomes? The answer is clearly, adamantly, and unequivocally yes.” 

Arguably, the same can be said for many other rare genetic diseases. So why aren’t we moving faster to expand NBS panels in order to improve diagnosing rare diseases and other conditions?

If only it were so simple

Expanding NBS panels is not necessarily a straightforward process. Adding new conditions typically requires evidence of clinical utility and cost effectiveness; advocacy from clinicians and patient groups; additional funding that may or may not be readily available; and often years of effort. Even after health policy makers give the green light to a new test, NBS labs may need to do the work of procuring new equipment, running the necessary validation processes, and updating workflows.

Then there’s the question of what to do when rare disease patients are identified. Many argue that it’s not enough to simply deliver a life-changing diagnosis and stop there. Follow-on services that help caregivers and patients to manage the condition should be available and accessible, and healthcare systems need to be sufficiently briefed to make sure they can direct families appropriately. All this takes time and resources that often aren’t available. 

Determining what to include in NBS panels can also be tricky. Some believe that it makes no sense to test for conditions that lack effective treatment, particularly in the case of conditions where children may develop more or less normally for the first few years before their health begins to deteriorate. If nothing can be done, the thinking goes, why impose fear and heartache on caregivers before it is absolutely necessary?  

I see things differently. Even in the absence of an effective treatment, caregivers have plenty of options for improving their chances of a positive outcome. They can join patient advocacy groups and enrol in clinical trials to drive development of new treatments. They can undergo further testing to assess recurrence risk and take precautions to avoid having additional children with the same disease. And they can make financial and other life planning decisions that ensure they are well prepared for the challenges that lay ahead.

Ultimately, though, the decision of whether and how to test for rare diseases is a deeply personal one, and parents should always have the option to opt-in or opt-out of the testing process if they so desire. But those like me who would rather know more than less, NBS should not be limited merely to conditions that have no treatments. 

The potential of genome sequencing in diagnosing rare diseases

In light of all the challenges, healthcare systems tend to move slowly in expanding their NBS panels. But if we continue adding conditions one at a time and at the current rate of approximately one every year or so, it will literally take millennia before we’ve covered even half of the universe of rare genetic diseases. We need a better way. 

Fortunately, novel genomic techniques, including whole genome sequencing (WGS) technologies that can quickly and cost-effectively interrogate the entire genome, hold promise to change the game. Around the world, many advanced healthcare systems are actively exploring their utility for newborn screening, as well as for rapid diagnosis of children who land in neonatal and paediatric intensive care units for unknown reasons.

WGS poses many of the same bioethical and technological challenges that NBS labs face when making more incremental changes, but at a much larger scale. Depending on how it is implemented, WGS could conceivably identify thousands of conditions, including some that have a wide spectrum of possible outcomes or completely unknown significance for caregivers. Many healthcare systems and most patients simply aren’t ready to deal with that much information and uncertainty.

Even so, some see the implementation of WGS for NBS as necessary and inevitable. “The system we have is too conservative and it’s time to move to a new paradigm,” said Dr Phil Reilly, a clinical geneticist and biotech venture capitalist with deep experience in the rare disease diagnostics space, in a Q&A with Lab Insights. “Whole genome sequencing of newborns is going to be a routine part of newborn care in the relatively near future.” 

It is still early days, but research on this topic is flourishing globally. At Murdoch Children’s Research Institute in Australia, for example, researchers are actively exploring innovative NBS technologies. This includes the recently-funded BabyScreen+ project, which will trial a WGS model that covers several hundred conditions, as well as research on a low-cost diagnostic method called EpiGNs, which uses a combination of DNA methylation testing and genomic workflows to expand NBS panels.

The jury is still out on when and how methods like these will become routine for NBS. Moreover, some countries will have greater success in adapting them than others due to financial, cultural and technological factors. But no matter how you cut it, genomic approaches to detecting rare genetic diseases are certain to gain traction in many parts of the world, and soon.

Implications for clinical labs

So what does this all mean for clinical labs? For starters, the growing array of diagnostic modalities present exciting opportunities for healthcare systems to drive earlier identification and treatment of rare genetic diseases. For the public sector, this holds potential to improve population health and reduce costs. For private firms, it means entirely new lines of diagnostic business

Getting insurers to pay for these services may be a challenge in the near term, but with evidence mounting that early identification of rare diseases can reduce costs by guiding appropriate care and offsetting unnecessary healthcare expenditures, the case for reimbursement will become increasingly strong. Meanwhile, patient advocacy groups will continue to lobby for expanded NBS panels and pressure governments to improve coverage of rare disease diagnostics.

In some countries, such changes may seem far off. I currently live in Singapore, and out here, virtually all employer-provided health insurance policies have gaping exclusions for congenital disease care, from diagnostics to treatments and everything in between. Public sector coverage for rare disease care is also limited, and in such a system, some people will understandably opt to avoid testing altogether, given both the steep out-of-pocket costs of the tests and also the fact that a positive diagnosis may result in loss of coverage. 

This is not acceptable. Call me idealistic, but I strongly believe that every person should have access to high-quality diagnostics that can support the early identification of a rare genetic disease, as well as follow-up services and adequate insurance to cover them. Expanding access to NBS testing, including eventually via WGS or other novel approaches, is an important step towards this broader goal. 

Amid all the excitement about WGS and other emerging technologies that can support diagnosing rare diseases, NBS labs will still need to do the day-to-day work of managing operations effectively and adding new tests incrementally. Expanding an NBS panel by even one condition can involve considerable effort, requiring staff to learn new workflows without compromising the integrity of their existing operations. 

At the same time, the lab community has an important role to play in advising governments, insurers, industry and patient groups about the importance of early diagnosis, as well as setting appropriate expectations for what can be done with existing technology and how much it will cost. Without their input, healthcare systems may continue to drag their feet, resulting in missed opportunities to treat patients and save lives.

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  1. Greene. (2022). Article available from [Accessed March 2023]
  2. RareX. (2022). Report available from [Accessed March 2023]