Advanced diagnosis for patients with rare conditions

This week, results from the 100,000 Genomes Project showed that whole genome sequencing improves the diagnosis of rare diseases and shortens diagnostic journeys for patients.

Dr Antony Smith, who leads LifeArc’s assay development and diagnostics division, reflects on the opportunities of whole genome sequencing for rare diseases.

This study is good news for many patients and their families affected with a rare illness – opening the door to getting a precise genetic diagnosis that can finally explain the cause of their condition. Having a diagnosis can be a huge psychological milestone for some patients. Improved diagnosis will help ensure they can receive effective, personalised treatment and access to improved genetic counselling.

Rare diseases are defined as conditions that affect less than 1 in 2,000 people. But collectively, these illnesses affect a large number of individuals and families. An estimated 3.5 million people are living with a rare condition in the UK. Around three-quarters of these illnesses affect children. Most are lifelong conditions, and some are progressive, gradually worsening over time. In some cases, these illnesses can be life-threatening.

But some rare conditions are notoriously hard to diagnose. Many families will experience years, or even decades of appointments without getting any answers. Not knowing the cause of their illness can be incredibly difficult, preventing access to potential treatments, information about the condition or access to the relevant support groups.

Advances in genomic testing

In recent years, rapid advances in the speed and cost of DNA sequencing technologies have led to many disease-causing genes being identified, particularly for rare conditions. This has led to an accurate diagnosis for more families.

But unfortunately, for many patients, the exact cause of their condition still cannot be identified using standard genomic testing methods that usually focus only on certain genes or key portions of their DNA. In these cases, it may be necessary to sequence their whole genome to achieve a diagnosis.

The 100,000 genomes project, which started in 2012, was set up to sequence whole genomes from many NHS patients and their families affected by a rare disease, or cancer. The project would also make the case for a new genomic medicine service – which would transform the way people are cared for and bringing advanced diagnosis and personalised treatment for patients who need them.

This pilot study focused on rare diseases, analysing the genes of 4,660 people from 2,183 families in the study. It found that whole genome sequencing led to a new diagnosis for 25% of the participants. Of these, 14% were found in regions of the genome that would have been missed by conventional testing methods.

Identifying the precise genetic cause of patient’s illness can enable care providers to provide tailored advice or medications – many of which may work better if they are given earlier. This could offer opportunities to prevent their condition or slow down its progression so that symptoms are less severe, and improve their quality of life.

For around a quarter of those taking part in the study who received a diagnosis, this led to more focused clinical care, which included further family screening, dietary change, supplementation with vitamins and/or minerals, and other therapies.

Hope for patients

These results are a major step forward for patients with rare diseases, demonstrating the power of whole genome sequencing to improve the likelihood of finding out what is causing their condition.

But identifying the precise genetic cause of an illness is only the first step in realising the potential of precision medicine. For many patients, even when it is possible to identify the disease, there will be no effective treatments currently available to offer them. While 7,000 rare diseases have so far been identified, only 400 so far have licensed treatments. As many are life-threatening conditions, there is an urgent need to find effective new therapies that can prevent or correct these illnesses.

Developing treatments for rare diseases is challenging, due to small patient populations and the high costs of research. In this arena, whole genome sequencing has the potential to be a game-changer for progressing our collective understanding of the causes of rare diseases that will facilitate the development of new treatments.

We are exploring ways to collaborate, fund and build alliances, and work out how our data science teams can improve our understanding of this area of research. We hope that our work in rare diseases will help to shed light on how whole genome sequencing can help patients.

The ability to identify more patients with a rare condition, combined with building our knowledge of its precise genetic causes, offers exciting opportunities to accelerate the search for new treatments and test these in clinical trials. These will include repurposing existing medicines or the development of cutting-edge new treatments, such as gene and cell therapies.

Looking to the future

We welcome the latest results from this fantastic initiative, which represent a significant step forward to the goal of precision medicine. We hope this proof-of-concept will help accelerate the rollout of whole genome sequencing across the NHS and around the world, giving more patients with rare diseases the chance of receiving an accurate diagnosis. This will ensure they can gain access to the right support and eligibility for treatments that will provide the best chance of a successful outcome.

But there still remain significant challenges around bringing the wider opportunities of whole genome sequencing to fruition.

This includes urgently addressing legitimate ethical concerns around the collection, storage and sharing of genetic data for analysis. Building infrastructure with appropriate reassurances and controls in place will be crucial.

And of course, there are challenges in implementing genetic testing on this scale in the UK. A huge amount of policy work will be needed to realise the potential of this technology and bring it to the clinic.

It’s also important to highlight that this is a still relatively small study – and 75% of participants thought to have a rare disease were left without a diagnosis. The next step will involve expanding the approach to include even larger and more diverse cohorts, which will uncover more of the genetic drivers behind a wide range of rare – and more common – conditions that are more complex than a single mutation. This knowledge, in turn, will accelerate the delivery of personalised medicine and earlier intervention.