Why Rare Diseases Still Go Undiagnosed

Rare diseases are defined as conditions affecting fewer than 200,000 people in the US or less than 1 in 2,000 in Europe.1-2 While each disease is individually rare, collectively, they represent a substantial global health burden, affecting an estimated 300 million people worldwide.3

Despite advances in medical technology, many rare diseases continue to evade diagnosis due to a range of factors that must be thoroughly considered and addressed.

With approximately 7,000 rare diseases identified to date, their recognition and diagnosis remain significantly challenging.2

A key factor contributing to missed or delayed diagnoses is the limited awareness among physicians, largely due to the insufficient representation of rare diseases in medical education and training.4

Additionally, many rare diseases present with nonspecific, variable, or overlapping symptoms that mimic more common disorders, increasing the risk of misdiagnosis. In time-constrained clinical settings, such presentations are often attributed to more familiar conditions, leading to delays in further investigation.5

This complexity, combined with the limited familiarity many physicians have with rare diseases, often results in prolonged diagnostic pathways for patients. This process frequently involves multiple referrals and evaluations, and in some cases, it can even take up to five years to reach an accurate diagnosis, significantly impacting patient outcomes.6

Limited access to genetic testing is another key factor contributing to the underdiagnosis of rare diseases, as the majority (80%) of these conditions have a genetic origin.7

Despite rapid advancements in genomic technologies, such tests remain inaccessible in many settings, particularly in low-resource environments or healthcare systems where they are not routinely integrated.

This contributes to delays in diagnosis and treatment, further exacerbating existing healthcare inequities and imposing substantial socioeconomic burdens on those affected.8,9

In addition, data silos and underreporting contribute to the challenge of diagnosing rare diseases. Medical data is often fragmented across different institutions, regions, or countries, preventing the comprehensive sharing and analysis of patient information.9

This lack of centralized, interoperable data hinders the recognition of rare disease patterns, delays the validation of clinical presentations, and limits the ability to identify emerging rare diseases, thereby impeding effective diagnosis and treatment.

Advancements in technology, global collaborations, and patient advocacy are transforming the approach to diagnosing and treating rare diseases, offering potential new solutions to ongoing challenges.

Genome sequencing, particularly through next-generation sequencing (NGS) technologies, allows for a comprehensive analysis of genetic mutations associated with rare conditions, uncovering genetic diversity often overlooked by traditional methods and improving both diagnosis and management.10

AI tools, specifically deep learning and machine learning, are increasingly being utilized to enhance the diagnostic process of rare diseases.

Machine learning algorithms are capable of processing extensive genomic and clinical datasets, identifying patterns and potential disease-associated mutations that might otherwise remain undetected. Furthermore, these AI-driven systems facilitate the integration of genetic, clinical, and phenotypic data, thereby improving the accuracy and efficiency of diagnosis.10

Cross-border research collaborations have become a critical strategy in addressing the challenges of diagnosing and treating rare diseases. A coordinated global approach is essential for advancing research and improving patient outcomes.

Given the low prevalence of individual conditions, international partnerships, such as the Undiagnosed Diseases Network International (UDNI), which comprises over 161 members from 55 countries, are becoming more crucial.9

This is just one example of the important collaborations that facilitate the creation of global registries, biobanks, and databases, thereby enhancing diagnostic accuracy and aiding the identification of new biomarkers and therapeutic targets.

Through the sharing of expertise and resources, these collaborations expedite the development of innovative treatments and streamline regulatory pathways.9

Furthermore, patient advocacy groups work collaboratively to raise awareness, provide critical resources, and advocate for policy changes that improve diagnostic processes and access to care.

For example, the US-based National Organization for Rare Disorders (NORD) advocates for improved research, education, patient support, and public policy related to rare diseases.1

Orphanet, established in France by the INSERM (French National Institute for Health and Medical Research), provides valuable medico-scientific resources that bridge the gap between medical professionals, researchers, and the patient advocacy community.11

By facilitating collaboration among patients, healthcare providers, researchers, and policymakers, patient advocacy efforts help drive initiatives that promote earlier diagnosis, enhance treatment options, and support research funding.12

Rare diseases, by definition, exhibit low prevalence, resulting in limited data, insufficient awareness, and considerable challenges in diagnosis and treatment. This scarcity of resources impedes research and the development of effective therapies.

As global recognition of rare diseases increases, international collaboration becomes paramount in addressing these critical gaps in proper management.

Achieving faster and more accurate diagnosis of rare diseases requires a comprehensive strategy that prioritizes increasing awareness among healthcare providers and the public while promoting innovation and investment in integrated diagnostic techniques.

The strategy must also facilitate the broader adoption of standardized genetic testing and advanced biomarker identification to enhance screening quality, as well as expedite the availability of novel therapies.

It is imperative to recognize that while each rare disease affects a relatively small number of individuals, their collective impact on global health is far-reaching. As Orphanet states:11

“Rare diseases are rare, but rare disease patients are numerous.”

Food and Drug Administration (FDA). (2024). Rare Diseases at FDA. [Online]. Available at: https://www.fda.gov/patients/rare-diseases-fda (Accessed on 5 April 2025)

Orphanet. (2025). About rare diseases. [Online]. Available at: https://www.orpha.net/en/other-information/about-rare-diseases (Accessed on 5 April 2025)

The Lancet Global Health. (2024). The landscape for rare diseases in 2024. Lancet Global Health, 12(3):e341. doi: 10.1016/S2214-109X(24)00056-1

Walkowiak, D., & Domaradzki, J. (2021). Are rare diseases overlooked by medical education? Awareness of rare diseases among physicians in Poland: an explanatory study. Orphanet Journal of Rare Diseases, 16, 400. doi: 10.1186/s13023-021-02023-9

Benito-Lozano, J., Arias-Merino, G., Gómez-Martínez, M., Ancochea-Díaz, A., Aparicio-García, A., Posada de la Paz, M., & Alonso-Ferreira, V. (2022). Diagnostic Process in Rare Diseases: Determinants Associated with Diagnostic Delay. International Journal of Environmental Research and Public Health, 19(11):6456. doi: 10.3390/ijerph19116456

Faye, F., Crocione, C., de Peña, R.A., Bellagambi, S., Peñaloza, L.E., Hunter, A., Jensen, L., Oosterwijk, C., Schoeters, E., de Vicente, D., Faivre, L., Wilbur, M., Le Cam, Y., & Dubief, J. (2024). Time to diagnosis and determinants of diagnostic delays of people living with a rare disease: results of a Rare Barometer retrospective patient survey. European Journal of Human Genetics, 32:1116–1126. doi: 10.1038/s41431-024-01604-z

Gürkan, H., & Satkın N.B. (2025). The Importance of Genetic Diagnosis in Rare Diseases. Balkan Medical Journal, 42(2):92-93. doi: 10.4274/balkanmedj.galenos.2025.2025-270125.

Chung, C.C.Y, Ng, N.Y.T., Ng, Y.N.C., Lui, A.C.Y., Fung, J.L.F., Chan, M.C.Y., Wong, W.H.S., Lee, S.L., Knapp, M., & Chung, B.H.Y., (2023). Socio-economic costs of rare diseases and the risk of financial hardship: a cross-sectional study. The Lancet Regional Health – Western Pacific, 34:100711. doi: 10.1016/j.lanwpc.2023.100711

Palmer, E.E., Cederroth, H., Cederroth, M., Delgado-Vega, A.M., Roberts, N., Taylan, F., Nordgren, A., & Botto, L.D. (2024). Equity in action: The Diagnostic Working Group of The Undiagnosed Diseases Network International. npj Genomic Medicine, 9, 37. doi: 10.1038/s41525-024-00422-y

Choon, Y.W., Choon, Y.F., Nasarudin, N.A., Al Jasmi, F., Remli, M.A., Alkayali, M.H., & Mohamad, M.S. (2024). Artificial intelligence and database for NGS-based diagnosis in rare disease. Frontiers in Genetics, 14:1258083. doi: 10.3389/fgene.2023.1258083

Orphanet. (2025). Knowledge on rare diseases and orphan drugs. [Online]. Available at: https://www.orpha.net/ (Accessed on 5 April 2025)

Rare Diseases - Clinical Research Network. (n.d.). About the Coalition of Patient Advocacy Groups (CPAG). [Online]. Available at: https://www.rarediseasesnetwork.org/patient-advocacy-groups/cpag (Accessed on 5 April 2025)