Sequencing to diagnose earlier: how biotechnology can help short the rare diseases diagnostic odyssey

There are more than 7,000 known rare diseases that affect more than 300 million people worldwide. In Spain, more than three million people live with a rare disease. With the scale of this challenge, continued efforts are required to accelerate early and accurate diagnosis for patients. ‘Despite all the progress being made, inequalities in access continue to be a key barrier, as the possibility of obtaining a diagnosis can be linked to factors such as geographical location, socio-economic situation and the availability of specialized health infrastructures at the local level. As a result, many patients remain undiagnosed or receive misdiagnoses for years," explains Marco Cappelletti, General Manager MED, Latam & Central Europe at Illumina.

Cappelletti shares in the interview conducted by AseBio on the occasion of World Rare Disease Day, which is celebrated on February 28, that a person living with a rare disease "takes about five years to receive a diagnosis, and 20% of patients wait more than a decade to get an accurate answer”. A tortuous process – known as the "diagnostic odyssey" – that not only delays access to appropriate care and treatments, but also allows the progression of the disease and "places a considerable emotional, social and economic burden on patients, their families and caregivers". In this context, continuing to address inequalities in access to advanced diagnostic technologies and reducing the number of people without a diagnosis "is essential to improve health outcomes and put an end to the diagnostic odyssey that millions of people living with a rare disease continue to face".

Childhood and rare diseases: the urgency of arriving on time

In the paediatric population, early diagnosis is especially crucial, as around 80% of rare diseases are of genetic origin and about 70% manifest in childhood. Detecting them early makes it possible to prevent or slow down their progression, reduce infant mortality and morbidity and facilitate access to appropriate clinical management and targeted therapies, as Cappelletti explains. In addition, it reduces uncertainty and facilitates care planning adapted to the needs of the child and his or her family.

On the contrary, diagnostic delays have a profound impact: 30% of children with a rare disease die before the age of five. Failure to diagnose favours the progression of the disease, can lead to inadequate care circuits and generates a significant emotional, social and economic burden for families.

Biotechnology and genomic sequencing: a new diagnostic era

Biotechnologies have become a key pillar to better understand rare diseases, especially through the genomic sequencing approach. In a context in which most of these pathologies have a genetic origin, tools such as Whole Genome Sequencing (WGS) are set to transform diagnosis and clinical practice, shortening times and improving accuracy.

Early molecular diagnosis and the promotion of genomic neonatal screening are key. In Spain, initiatives such as CRINGENES and GenBorn, and at the European level Screen4Care – within the framework of the International Consortium on Newborn Screening – seek to expand early detection to facilitate earlier and more equitable access to personalised paediatric care and reduce the diagnostic odyssey.

In the specific case of whole genome sequencing, we are talking about a comprehensive tool that allows the human genome to be analysed in its entirety in a single test, unlike more targeted techniques. This facilitates the identification of multiple types of genetic variants responsible for rare diseases and has demonstrated a high diagnostic yield, as well as being cost-effective, especially when incorporated early in the care process. Its impact is particularly relevant in newborns and critically ill paediatric patients, where a rapid diagnosis can be decisive.

In Spain, projects such as Baby Lynx – sponsored by the Carlos III Health Institute and supported by Illumina – are generating evidence on the clinical, diagnostic and economic value of incorporating rapid WGS in neonatal and paediatric intensive care units, with the aim of establishing a national reference model.

From a clinical point of view, WGS allows to increase diagnostic performance, reduce incremental costs, facilitating the early initiation of condition specific management. Compared to sequential approaches based on gene panels or even exome sequencing, WGS, avoiding repeated tests and redundant procedures. Its incorporation "represents a key step to guarantee earlier and more accurate genetic diagnoses" and contributes to ending the diagnostic odyssey. Its incorporation "represents a key step to guarantee earlier and more accurate genetic diagnoses" and contributes to ending the diagnostic odyssey.

In this context, Spain is progressively creating the conditions to translate the benefits of WGS into the standard of care for rare disease patients, even if systematic clinical implementation is not yet in place. Initiatives such as IMPaCT-Genomics, the Undiagnosed Rare Diseases (ENoD) Program, the UNICAS network or the SiGenES project seek to advance coordinated implementation, interoperability and data governance, connecting hospitals with sequencing centers and reinforcing a model in which data travels instead of the patient. However, the use of WGS remains largely concentrated to the research field and has not been consistently embedded within the National Health System’s common portfolio of services, highlighting the need to move from pilots to NHS adoption. The development of harmonised clinical standards and specific funding mechanisms therefore remains a key outstanding step. 

Europe Moving Forward: Financing Models and Access

At the European level, countries such as Denmark, England and Sweden already have regular funding mechanisms for WGS in certain indications while others – like France or Germany - have enabled specific models or pilot programs that facilitate access in rare diseases. These experiences reinforce the viability of their integration, provided that it is accompanied by value-based financing, reinforcement of infrastructures, professional training and active participation of patients.

Today, the main challenges are no longer technological – sequencing times can be less than 24 hours under certain conditions – but organisational and structural: early referral to expert centres, system capacity, training, definition of healthcare circuits and sustained investment in robust data infrastructures that guarantee secure and interoperable management.

Looking ahead, equitable adoption of WGS as a standard of care could reduce diagnostic delays, optimize resources, and improve outcomes at critical stages of child development. Also integrated into neonatal screening programmes, it would allow certain pathologies to be identified from birth and to be acted upon in a timely manner. In addition, the large volumes of data generated not only provide accurate information for each patient, but also drive new scientific discoveries and the development of therapies, in line with the World Health Organization and its recognition of rare diseases as a global public health priority.

In Cappelletti's words, leveraging WGS "can contribute to ending the diagnostic odyssey" and allow patients to receive the right care at the right time, while avoiding inefficiencies arising from lengthy processes and repeated testing. Initiatives such as the WORD Project also point out that its incorporation can increase diagnostic performance and reduce incremental costs, improving the care path.

On this World Rare Disease Day, whole genome sequencing is presented as a tangible example of how biotechnological innovation can change clinical practice: diagnosing earlier not only transforms lives, but also contributes to a more efficient, equitable and sustainable healthcare system. Turning this potential into reality will now depend on a firm commitment to its integration as a standard of care.