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Undiagnosed rare diseases

New Content ItemEdited by David Adams

In medicine, the diagnosis of a patient’s condition is the touchstone which allows the basis of prognosis. It allows health professionals to offer the most appropriate treatment and develop a therapeutic plan and adequate management over time. In many cases, patients affected by rare diseases present non-specific clinical manifestations that progress insidiously over time with a significant degree of complexity. This leads many patients to remain undiagnosed for a long time, bringing about a diagnostic odyssey consisting of multiple laboratory or imaging tests (sometimes invasive), visits to different health professionals, and risks of receiving erroneous diagnoses. The term “undiagnosed disease” has emerged as a concept and category which helps properly guide the patient's management within the health system and reduce the time to obtain a correct diagnosis. This new series from Orphanet Journal of Rare Diseases will delve into the questions which need to be answered, in order to better the lives of those with these conditions.

People with undiagnosed diseases have some unique challenges relative to people with other types of chronic disease. Encounters with the medical system are beset with communication difficulties caused by a lack of clear definition concerning medical signs and symptoms. Prognosis and treatment are imprecise. A recurring conflict between risk and diagnostic aggressiveness is present. Patients and family members are often anxious about having inadequately pursued a treatable diagnosis not recognized during past evaluations. Finally, in depth efforts to re-interpret medical test results considering new literature is difficult to maintain consistently over long periods of time.

Undiagnosed diseases can indicate different clinical assumptions: 

  • delayed diagnosis- the diagnosis is delayed although it can be obtained by relatively simple or common means in clinical practice; in such a case, the patient may not have been referred to the appropriate clinician or team
  • complex diagnosis- with a non-orientative phenotype, insufficient biomarkers, and non-conclusive genomic profiles; the patient requires specific equipment and contact with a center of expertise or a reference network

  • Diagnostic impasse- despite the fact that all available investigations have been carried out in the clinical environment of experts, the patient and physicians may be facing a new, undescribed disorder. 

There are many symptoms and signs that can be the first manifestations of a disease, without the etiological diagnosis being evident after the first ancillary tests. Such cases include hypotonia at birth or infancy as the early manifestation of Prader-Willi syndrome or congenital myopathy, interstitial lung disease as a manifestation of chronic granulomatous disease, or adult or infant sudden death as the first consequence of cardiomyopathies or genetic heart channelopathies. 

The purpose of the call is to request scientific and medical care proposals that address the open question about the undiagnosed disease.

Some areas we are looking for authors to address include:

- What is the value of a diagnosis to the integral management of the patient?
- The importance of utilizing individual approaches in treating patients with undiagnosed diseases
- Functional studies- we are looking for submissions which address some combination of the general problems of following up on clinically-generated variants of unknown significance, funding mechanisms for such work, and matching clinicians and researchers.
- What are the best approaches to utilize data-sharing tools to solve rare and undiagnosed disease cases?
- What is the best way to optimize communication between busy clinicians and researchers around diagnostic hypotheses requiring research-level investigation?
- The resources required for studying undiagnosed diseases are often beyond what is available for routine medical care. Record review, literature review, and re-analysis of data and clinician-researcher collaborations are time-intensive activities. What is the best way to support these activities?

This collection of articles has not been sponsored and articles have undergone the journal’s standard peer-review process.

Please find out more about our journal and its policies, here. Submission guidelines can be found here, and please submit to the series via our submission system (there will be a field for which you can indicate if you are submitting to this series).

  1. The ‘diagnostic odyssey’ is a common challenge faced by patients living with rare diseases and poses a significant burden for patients, their families and carers, and the healthcare system. The diagnosis of ra...

    Authors: Mariam Al-Attar, Sondra Butterworth and Lucy McKay
    Citation: Orphanet Journal of Rare Diseases 2024 19:172
  2. Precise data about ATTR-CM incidence rates at national level are scarce. Consequently, this study aimed to estimate the annual incidence and survival of transthyretin amyloid cardiomyopathy (ATTR-CM) in France...

    Authors: Thibaud Damy, Guillaume Bourel, Michel Slama, Vincent Algalarrondo, Olivier Lairez, Pauline Fournier, Jérôme Costa, Françoise Pelcot, Agnès Farrugia, Isabelle Durand Zaleski, Hervé Lilliu, Caroline Rault, Mathilde Bartoli, Stéphane Fievez, Anna Granghaud, Jeremie Rudant…
    Citation: Orphanet Journal of Rare Diseases 2023 18:345
  3. Systemic amyloidosis is caused by the deposition of misfolded protein aggregates in tissues, leading to progressive organ dysfunction and death. Epidemiological studies originate predominantly from high-income...

    Authors: Roberta Shcolnik Szor, Fabio Fernandes, Angelina Maria Martins Lino, Leonardo Oliveira Mendonça, Fernanda Salles Seguro, Valkercyo Araujo Feitosa, Jussara Bianchi Castelli, Lecticia Barbosa Jorge, Lucas Bassolli de Oliveira Alves, Precil Diego Miranda de Menezes Neves, Evandro de Oliveira Souza, Livia Barreira Cavalcante, Denise Malheiros, Jorge Kalil, Gracia Aparecida Martinez and Vanderson Rocha
    Citation: Orphanet Journal of Rare Diseases 2022 17:425
  4. Alström syndrome (ALMS) is a rare autosomal recessive genetic disorder that is caused by homozygous or compound heterozygous mutation in the ALMS1 gene. Dilated cardiomyopathy (DCM) is one of the well-recognized ...

    Authors: Savas Dedeoglu, Elif Dede, Funda Oztunc, Asuman Gedikbasi, Gozde Yesil and Reyhan Dedeoglu
    Citation: Orphanet Journal of Rare Diseases 2022 17:359
  5. Skeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be ...

    Authors: Lian Liu, Liying Sun, Yujun Chen, Muchuan Wang, Chenxi Yu, Yingzhao Huang, Sen Zhao, Huakang Du, Shaoke Chen, Xin Fan, Wen Tian, Zhihong Wu, Guixing Qiu, Terry Jianguo Zhang and Nan Wu
    Citation: Orphanet Journal of Rare Diseases 2022 17:139
  6. Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have li...

    Authors: Dorian M. Cheff, Alysson R. Muotri, Brent R. Stockwell, Edward E. Schmidt, Qitao Ran, Reena V. Kartha, Simon C. Johnson, Plavi Mittal, Elias S. J. Arnér, Kristen M. Wigby, Matthew D. Hall and Sanath Kumar Ramesh
    Citation: Orphanet Journal of Rare Diseases 2021 16:446
  7. With the advent of whole exome (ES) and genome sequencing (GS) as tools for disease gene discovery, rare variant filtering, prioritization and data sharing have become essential components of the search for di...

    Authors: Elizabeth Wohler, Renan Martin, Sean Griffith, Eliete da S. Rodrigues, Corina Antonescu, Jennifer E. Posey, Zeynep Coban-Akdemir, Shalini N. Jhangiani, Kimberly F. Doheny, James R. Lupski, David Valle, Ada Hamosh and Nara Sobreira
    Citation: Orphanet Journal of Rare Diseases 2021 16:365
  8. Although clinician, researcher, and patient resources for matchmaking exist, finding similar patients remains an obstacle for rare disease diagnosis. The goals of this study were to develop and test the effect...

    Authors: Kimberly LeBlanc, Emily G. Kelley, Anna Nagy, Jorick Bater, Tala Berro, Molly A. McGuinness, Courtney Studwell and Matthew Might
    Citation: Orphanet Journal of Rare Diseases 2021 16:210
  9. Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and disease...

    Authors: Dustin Baldridge, Michael F. Wangler, Angela N. Bowman, Shinya Yamamoto, Tim Schedl, Stephen C. Pak, John H. Postlethwait, Jimann Shin, Lilianna Solnica-Krezel, Hugo J. Bellen and Monte Westerfield
    Citation: Orphanet Journal of Rare Diseases 2021 16:206