Scientific progress is often viewed as an unqualified good: faster sequencing, cheaper tests, and cutting-edge genomics tools seem to promise quicker diagnoses and personalised treatments. But for families living with some rare genetic conditions, those advances are quietly creating a dangerous blind spot.
We spoke to Allison Watson (CEO, Ring20 Research & Support UK CIO) about her 20-year journey following her son’s diagnosis of a rare form of epilepsy, and the often-overlooked reality that scientific progress doesn’t benefit all patients equally.
Allison’s son David was diagnosed at the age of eight with ring chromosome 20 syndrome (or r(20), for short), an ultra-rare chromosomal disorder that causes severe epilepsy, and for which there are no recommended treatments.
Figure 1: A diagram showing the chromosomal alteration that causes r(20).
“I believe they call it ‘nano-rare’, as, according to the medical literature, there are only 200 diagnosed cases. So, we established Ring 20 Research and Support UK, a UK based charity supporting all families with ring chromosome 20 syndrome in the world, and we support well over 60% of reported individuals and families.”
But despite unprecedented evolution in the genomics world, diagnoses of r(20) and other chromosomal disorders are now on the decline – and not because there are truly fewer cases.
“We’ve actually produced a graph that shows direct diagnostic decline in the last 10+ years,” Allison says. “And we believe that’s a direct consequence of next generation sequencing being used as the preferred tool.”
The problem is not a lack of technology, but the wrong technology being prioritised as the field evolves. “There’s a belief that we can see so much more, and we can diagnose single gene disorders a lot faster with these new advanced technologies. And that is true, and I’m seeing that very much in other rare conditions and other rare epilepsies. I am seeing diagnostic rates dramatically increase,” Allison says. “But you cannot diagnose a structural variant like a ring chromosome using whole genome or exome sequencing. These tools look in very fine detail at genes, but they don’t show you changes in chromosome structure.” To see a ring chromosome, labs need to use tools such as karyotyping: microscopic analysis of chromosomes that many health systems now view as obsolete, being low resolution and time-consuming.
“It’s made me begin to wonder if it’s not just r(20). What other complex chromosomal disorders, large CNVs, may potentially be in diagnostic decline? There are many people that present with complex, apparently rare disorders that can’t be diagnosed. Is this because we’re looking with the wrong technologies?” she asks.
“For us, technological advancement has actually made things go backwards. If people aren’t being diagnosed, awareness declines. Knowledge declines. And then research interest declines. We get pushed further and further into the shadows.”
So, what needs to change?
First, Allison believes diagnostics must stop being one-size-fits-all. “We need to use all the tools in our toolkit,” she says. “Start at lower resolution when appropriate, then drill down. Sometimes we’re trying to be too detailed, and it’s holding us back.”
“I would absolutely advocate that we don’t throw old technologies away while they still have utility,” she says. “We need to modernise them.” One promising avenue is digital karyotyping, which uses automation and image recognition to analyse chromosomes more efficiently. “We need to bring it to the 21st century,” Allison states.
She also points to emerging genomic tools that may bridge the gap between old and new. Long-read sequencing technologies can read much larger sections of DNA and may reveal structural abnormalities missed by short-read sequencing, in addition to optical genome mapping, which is a powerful tool to visualise large genome changes. “Different technologies tell us different things,” Allison says.
“I’m sure there are other opportunities out there, and I would love to hear from anybody that has any ideas about other technologies or opportunities that could help to solve this.”
Equally important is listening to patients and their families. “We are affected by the same disorder every day, and we build up a huge knowledge about symptomology and so can very succinctly pull together red flags,” she says. “A medical professional may only see one individual in their lifetime with that disorder.” The solution, according to Allison, is collaboration. “Why can we not work together? Because there’s huge potential out there, and we need that to use that experience and all of the tools in our toolkit to advance things even faster than we’re doing today.”
Allison’s understanding of genomics and rare disease has evolved significantly over the last 20 years. “What I have learned along the way is there’s not an answer to everything, and we have to keep an open mind, we have to keep talking, we have to collaborate, and we have to not take no for an answer,” she says. “We have to look beyond what we think we know today and unlock the potential.”
“People say they want a cure for a condition. I am realistic enough to say I would actually just like a treatment that’s more effective and that improves quality of life, so individuals like my son can lead a better life day-to-day in the near future.”
Her central message is simple, and urgent. “I want people to think of genomics beyond single gene variation,” Allison says. “Often there might be multiple genes, or larger changes. And it’s important to keep an open mind about that.”
