Rare Disease Day, observed every year at the end of February, is the annual recognition of the impact of rare diseases on the lives of so many families and caregivers around the world. It aims to raise awareness, give thanks and create change for all those affected. Although individually rare, these conditions are collectively quite common, affecting approximately 6 per cent of the population.² However, being rare means these diseases are often not as well known individually and don’t get the same recognition as more common diseases.

Moreover, compared to other diseases, rare diseases disproportionately affect children, who often have less of a voice in society. These conditions are typically severe, with more than 30 per cent of children living with a rare disease dying before their fifth birthday.² As a result, rare disease families are often consumed with caring for their loved ones.

Rare Disease Day is a rare opportunity for people living with these conditions, their families and caregivers to be seen and heard.

Around 72 per cent of rare diseases have a genetic origin.¹ A genetic diagnosis is the foundation of good clinical care – giving options for therapy, tailored clinical management, access to support services and opportunities to participate in research studies. Through our pioneering work on studying DNA, the Sanger Institute has proudly contributed to diagnosing and furthering rare disease research in multiple ways. These include:

• Making the biggest single contribution to the reference human genome sequence and ensuring its open access. This has and continues to be used in every genetic diagnostic test to identify rare disease-causing variants in people living with rare conditions.

• Generating comprehensive databases of genetic variation worldwide. This has allowed easier identification of rare disease-causing variants.

• Trialling cutting-edge genomic technologies to demonstrate their utility for making genetic diagnoses.

• Undertaking large genetic studies of thousands of people with undiagnosed rare diseases, such as the Deciphering Developmental Disorders (DDD) Study, to identify over 100 new rare genetic diseases.

• Designing improved genetic techniques and tests to increase the proportion of patients that can be diagnosed.

• Developing and openly sharing software to better identify rare disease-causing variants from genetic data.

• Establishing a secure web portal called DECIPHER to allow rare disease families around the world to share limited amounts of their clinical and genetic data, anonymously and responsibly. This enables researchers to identify novel rare diseases, irrespective of whether people with the same condition live in the same country.

• Spinning out a company called Congenica to allow the lessons we have learnt from our research studies in how to sift through vast volumes of genetic data to drive sustainable diagnostic services in healthcare systems around the world.

• Using innovative genome editing technologies, such as CRISPR, to profile the biological impact of every single possible genetic variant in a rare disease gene, well in advance of ever seeing it in a patient, with the goal of fast-tracking the diagnostic process.

One of the main challenges is that each rare disease, by definition, is rare in the population. This can make it more challenging at every step along a patient’s journey – from diagnosis to treatment.

Identifying the underlying genetic cause of a particular disease requires large samples, and some rare conditions only affect very few people across the world. This also presents a challenge when finding sufficient individuals with the same condition to participate in clinical trials for new therapies.

It is even more challenging to motivate pharmaceutical companies to develop drugs for specific rare diseases that may only benefit a small number of patients. As a result, there is a fundamental mismatch between the need to find new therapies, and the amount of effort being expended to find them.

To date, approximately 95 per cent of rare diseases do not yet have treatments.³

New genomic technologies have been critical for driving a revolution in rare disease diagnosis. Twenty years ago, patients were diagnosed by testing single disease genes at a time, one after another. In retrospect, this was an incredibly slow and costly way of diagnosing people with rare diseases and was heavily dependent on clinical expertise in recognising the subtle, discriminating features of individual rare diseases. Because of this dependence on specialist clinical expertise, it was much harder to perform genetic diagnostics in countries with limited resources and infrastructure.

Today, using the latest technologies, all 20,000 genes in the human genome can be sequenced at the same time, and these approaches are becoming more readily accessible to patients around the world.

In addition, there have been advances in technologies for studying other biological molecules, such as proteins, RNA and metabolites, which are now giving us insights into the molecular mechanisms of disease. These technologies are already showing great potential, in addition to DNA evidence, for making genetic diagnoses.

Finally, new technologies for editing the genetic code are allowing the detailed biology of particular rare diseases to be much more readily studied in experimental models. This will hopefully pave the way for identifying potential drug targets.

It has been incredibly gratifying to see the clinical uptake of new genomic technologies over recent years. Most notably in the UK, this has been driven by Genomics England, working closely in partnership with the NHS. It is only right that people living with rare diseases are diagnosed rapidly within their healthcare system, rather than reliant on research studies and researchers. As a result, Sanger has been able to move to more of a supporting role with regard to generating genetic data. This can allow us to focus on:

• Championing and demonstrating the immense value of making clinically-generated, anonymised genetic data available to researchers.

• Developing novel analytical approaches to increase the proportion of patients that receive a genetic diagnosis.

• Trying to understand why rare genetic diseases often vary considerably in severity among people with the same disease.

• Scaling up genome editing technologies to profile the biological impact of every single genetic variant in all rare disease genes in order to speed up diagnosis and reduce disparities between ethnicities. The Atlas of Variant Effects (AVE), an international collaboration between the Sanger Institute and other institutes, aims to assess the effects of all variants in our genome. This Atlas will not only speed up diagnosis but will also give us insights into the different types of disease-causing variants as well as empower drug development efforts.

I am proud to reflect on how the Wellcome Sanger Institute has contributed to rare disease research over the past 20 years, and I look forward to seeing how our insights can start to provide an impact beyond just diagnosis and into the development of new therapies. Nevertheless, such progress cannot be made alone, it will continue to require a collaborative effort among researchers, policymakers, clinicians, industry and the patient community. With this approach, there is greater hope to drive innovation forward and ultimately improve the lives of people living with rare diseases around the world.