Rare Disease Genomic Testing: How Do We Make Access Equitable and Timely?

The most recent event from PET (the Progress Educational Trust) brought together five experts to discuss rare disease genomic testing in the UK. What is it? How does it work? Who can benefit from it? And how can we make it accessible to them?

Several of the speakers had previously contributed to a position statement exploring these questions, as well as writing an accompanying comment piece for BioNews (see BioNews 1264). The event provided them with an opportunity to elaborate on their thoughts and address the latest developments.

The event was chaired by Sarah Norcross, director of PET. She began by emphasising that 'rare' diseases are so common, collectively, that they affect as many as one in seventeen people.

The first speaker was Dr Sarah Wynn, chief executive of Unique, a charity that supports people affected by rare chromosome and gene disorders. She explained how important diagnosis is for families, and how long it can take to obtain one (if indeed a diagnosis is ever obtained). It means finally finding a long-awaited answer, which can then inform treatment as well as other big decisions like reproductive planning.

Dr Wynn described the difficulties and intricacies of genomic testing for rare diseases. Test results and diagnoses can be confusing, and families with rare conditions can feel isolated and unsure what to do. She explained that in a surprisingly large number of cases, a definitive diagnosis cannot be made – for example, when tests reveal something unusual in a child's genome, but it is unclear whether or how it relates to the child's symptoms. This is known as a 'variant of uncertain significance', or VUS.

The second speaker – Miranda Durkie, head of rare disease at the North East and Yorkshire Genomic Laboratory Hub – provided a laboratory perspective on genomic testing. Whole genome sequencing (WGS) is the most complex and comprehensive test currently offered. Interpreting the resulting data can involve clinical scientists sorting through 3-5 million variants in a person's genome, and sometimes this takes more than seven hours per case. All of this work may, or may not, uncover one or two causative variants in a genome. This labour-intensive process is one of the reasons why there can be backlogs in labs and long wait times for results.

Durkie argued that the key question was how to speed up this process, without compromising its accuracy. Since 2022, there have been significant improvements, but this has varied by region and work is still needed to standardise turnaround times. Streamlining the process involves upskilling technicians, implementing measures such as stopping analysis once the likely variant is found, and using AI tools such as the software 'Emedgene' (which has helped to reduce the number of variants for analysis by 61 percent).

The third speaker was Emma Baple, who is professor of genomic medicine at the University of Exeter, as well as lead for genetics and genomics at the NIHR Exeter Biomedical Research Centre and medical director of the NHS South West Genomic Laboratory Hub.

Professor Baple's talk focused on undiagnosed patients, and how providing them with diagnoses will require partnerships and innovation in both academia and industry. Encouragingly, innovation in this area means that those who were previously tested can benefit from new discoveries. Stored genetic data can be retested for newly discovered genetic variants, increasing the overall diagnostic yield.

However, Professor Baple explained that equity issues come into play, as the majority of publicly available genomic variant data is from people of European ancestry (see BioNews 1194, 1207, 1293, 1297 and 1302). The lack of data from people of other ancestries means that there is increased potential for missed or misdiagnosis, and an impaired ability to interpret genomic variation in patients from more diverse and underrepresented ethnic backgrounds.

The fourth speaker – Dr Ellen Thomas, chief medical officer at Genomics England – spoke about the importance of good infrastructure underpinning genomic testing programmes, using the best and most standardised systems. She reiterated the need for a close working relationship between practice and research, and echoed Professor Baple on the potential benefits of retesting. Between 2022 and 2025, 500 new potential diagnoses came out of NHS laboratories, which would not have been picked up in previous tests.

Dr Thomas also talked about the NHS-embedded Generation Study, which is obtaining consent from parents to sequence the whole genomes of 100,000 newborns, in order to evaluate the utility and feasibility of using this approach to look for a large number of rare conditions at birth (see BioNews 1172, 1210, 1259, 1261 and 1297). She explained that equity of access is one of the four core principles guiding the study, accompanied by thoroughgoing consultation of the public and professionals (see BioNews 1122, 1127, 1129, 1133, 1137 and 1262).

The final speaker, Adam Clatworthy, reminded us that every piece of data represents a real person and a family. He told the story of his family's diagnostic odyssey, looking for explanations for the symptoms of his daughter Lola (who died at the age of two) and his son Alfie. Finally, both children were diagnosed with an extremely rare disease, as yet poorly understood, that involves irregularities in the Creld1 gene.

Clatworthy spoke about how, with a severely ill child and no answers, parents exist in survival mode. They have to become 'FBI agents', reading and researching everything available. He also mentioned the importance of the internet, as it was via a Facebook communication from another affected family that he first heard of Creld1.

Clatworthy spoke about the broader importance of community for families affected by rare diseases. He establlished the charity CRELD1 Warriors for people affected by Creld1-related diseases, to promote research and to help people and families who would otherwise feel isolated. Clatworthy also became vice-chair for rare conditions at Genomics England's Participant Panel, which provides independent oversight and advice from a patient perspective.

The five presentations were followed by a lively Q&A, during which a very engaged audience asked questions of the panel. These included queries about the practicalities of genetic and genomic tests, and reasons why the present state of affairs remains inequitable. One attendee asked who cares for those without a diagnosis, and the speakers mentioned the vital role played by the UK's SWAN (Syndromes Without A Name) support network, which is led by Genetic Alliance UK.

Dr Thomas mentioned the need for community advocates to help explain what tests are available and encourage people to seek them out, as well as the importance of listening to the concerns of underserved communities. Dr Wynn mentioned the work of the NHS Race and Health Observatory, which tackles race-related inequities in health and social care.

The event was incredibly effective in communicating how NHS genomic testing works for patients and families with rare diseases, how the process is being improved with the implementation of new approaches, and the importance of improving the timeliness, accessibility and and equitability of these services.

As a concluding example of what success looks like, Clatworthy discussed the recent case of baby Freddie – an infant participating in the Generation Study, whose rare eye cancer was picked up presymptomatically and whose eyesight can therefore hopefully be preserved by early treatment (see BioNews 1311 and 1312). 'That's the future we'd love to see,' said Clatworthy.

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PET is grateful to the NIHR Exeter Biomedical Research Centre for supporting this event.