In Europe a disease is defined as rare when it affects less than 1 person per 2.000 . The term “rare disease” comprehends neurological, metabolic and rheumatological disorders, certain types of cancer, immune deficiencies and autoinflammatory diseases.
To date, over 6.000 rare diseases are known  and most of them are “orphans”, meaning that they don’t have a market large enough to gather support and resources to sustain research and discover treatments.
The Diagnostic Odyssey
However, there is an upstream problem called “diagnostic odyssey”: Rare Disease (RD) patients have to wait a long time before being correctly diagnosed. In fact, according to a survey carried out in 17 European countries, 25% of RD patients experienced a diagnostic delay of 5 to 30 years . This can be explained by the partial adoption of techniques to address missing heritability (WGS, epigenomics, transcriptomics), by the lack of knowledge on genes or disease mechanism, requiring years of research to be revealed. All these factors lead to the lack of a diagnosis or to a misdiagnosis .
To make matters worse, the COVID-19 pandemic has further exacerbated challenges in patients receiving a timely diagnosis. This was caused by the hospitals’ overcrowding that happened during the pandemic: the mandatory need to treat such a large number of sick people at the same time has stuck the health system, causing a delay for all the other clinical circumstances, including RD diagnosis.
Normally, the diagnostic process is based on clinical practices, such as physical examination, personal and family history, laboratory tests and imaging studies. However, because these pathologies are characterized by a broad diversity of symptoms (often common), there are certain difficulties in diagnosis. Patients are moved from practitioner to practitioner, undergo a myriad of diagnostic tests and run into many incorrect diagnostics, before eventually obtaining the correct one. With a delayed diagnosis, or no diagnosis, the patients aren’t properly managed by the healthcare system. It’s very distressing for the patient and highly costly for the system. 
Getting a rapid and accurate diagnosis is of vital importance for RD patients. In agreement with the England Rare Disease Action Plan, an accurate and timely diagnosis can facilitate access to treatment, provide a possible prognosis and enable connections with a supportive community .
Considering that this exhausting journey lasts for an average of 7-8 years, the consequences are quite intuitive: late and wrong diagnosis delays the beginning of treatments and besides worsening a patient's clinical status, they can cause significant psychological distress to the patient and families. Furthermore, people living with rare diseases often face a lifetime of complex care, leading to a profound impact on their education, physical mobility and financial stability .
The financial burden is not only charged to patients but also to the health system: according to a survey performed in England in 2018, rare disease patients, while undiagnosed or misdiagnosed, have cost the National Health System in excess of £3.4 billion . In the US, the estimated costs for suspected pediatric genetic diseases are between $4.6 billion and $17.5 billion, accounting for approximately 12% to 47% of the national bill for pediatric inpatient care .
Reaching an early and accurate diagnosis
To date, to enable a timely and accurate diagnosis, two goals should be reached.
The first one is the improvement of the community's awareness of rare diseases. Every year, on 28th February ( 29th in lap years) the Rare Disease Day is celebrated. The purpose is to turn the light on the 300 million people worldwide living with these pathologies by sharing their stories and sensibilize the community to the themes of RD and diagnostic odyssey .
Furthermore, in 2013 the web-based platform GeneMatcher was created to connect researchers, clinicians (but also health care providers, patients and families) and other organizations and stakeholders (for example pharmaceutical industry) with interest in the same genes, variants or phenotypes .
These are great starting points to increase RD awareness, but It is also fundamental to connect patients through networks, with national and international organizations such as EURODIS-Rare Disease Europe .
The second instrument is the development of diagnostic tools based on genetics, to sustain clinician’s work and shorten the odyssey. This need is based on the fact that most rare diseases are caused by one or more gene mutations, so the key to diagnosis is to first identify the mutated gene (or genes) . In this perspective NGS techniques (such as WES) provide a quick, powerful, and low-cost genetic analysis , significantly increasing the diagnostic yield of RD. However, for more than a half of RD, the causative mutated genes are yet to be discovered , and this is one of the reasons why many patients remain undiagnosed.
For those cases we have to mention the Telomere-2-Telomere project whose value is giving a complete human genome reference sequence to compare to a patient’s sequence in order to find new mutations in the coding and non-coding genome.
Even Newborn screening plays a significant role in diagnosing rare diseases early, offering opportunities for treatment, management and support, even before symptoms develop. This is fundamental considering that 75% of rare diseases affect children and more than 30% of them die before their fifth birthday .
The application of genomic technologies has the potential to transform patients’ lives, providing quick and accurate diagnoses, and matching patients to the most effective medications (if existing) and interventions. However, to obtain the odyssey’s shortening, focusing only on genetic tools is not enough, in fact, as it was previously said, sequencing data collected needs to be shared between clinicians, patient and organization, in order to build a solid worldwide network and to raise awareness on RD.
This should simplify data communications and lead to an earlier and accurate diagnosis for RD patients, in order to be beneficial for their social life, education, mental health and financial status, and giving them the chance to live a healthy life.
Written by Martina Cattaneo