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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. 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

    Content type: Research

    Published on:

  2. 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

    Content type: Research

    Published on:

  3. 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

    Content type: Position statement

    Published on: