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Casas-Alba et al. J Transl Genet Genom 2022;6:322-32 Journal of Translational
DOI: 10.20517/jtgg.2022.03
Genetics and Genomics

Review Open Access

Diagnostic strategies in patients with undiagnosed
and rare diseases

3,4
1
3
1,2
Dídac Casas-Alba , Janet Hoenicka 1,3,4 , Alba Vilanova-Adell , Lourdes Vega-Hanna , Jordi Pijuan ,
Francesc Palau 1,2,3,4,5,6
1
Department of Genetic Medicine, Pediatric Institute of Rare Diseases (IPER), Hospital Sant Joan de Déu, Esplugues de Llobregat
08950, Spain.
2
European Reference Network, ERN ITHACA, Esplugues de Llobregat 08950, Spain.
3
Laboratory of Neurogenetics and Genomic Medicine, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat 08950,
Spain.
4
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid 28029, Spain.
5
Clinic Institute of Medicine and Dermatology (ICMiD), Hospital Clínic, Barcelona 08036, Spain.
6
Division of Pediatrics, University of Barcelona School of Medicine and Health Sciences, Esplugues de Llobregat 08950, Spain.
Correspondence to: Prof./Dr. Francesc Palau, Department of Genetic Medicine, Hospital Sant Joan de Déu, Passeig Sant Joan de
Déu 2, Esplugues de Llobregat 08950, Barcelona, Spain. E-mail: francesc.palau@sjd.es
How to cite this article: Casas-Alba D, Hoenicka J, Vilanova-Adell A, Vega-Hanna L, Pijuan J, Palau F. Diagnostic strategies in
patients with undiagnosed and rare diseases. J Transl Genet Genom 2022;6:322-32. https://dx.doi.org/10.20517/jtgg.2022.03
Received: 17 Jan 2022 First Decision: 5 May 2022 Revised: 23 May 2022 Accepted: 7 Jun 2022 Published: 4 Jul 2022
Academic Editors: Bridget Bax, Andrea L. Gropman Copy Editor: Fangling Lan Production Editor: Fangling Lan

Abstract
Rare diseases are life-threatening or chronically debilitating conditions affecting millions of people worldwide. In
many instances, the patients experience a delay in their diagnosis or remain undiagnosed despite extensive
investigations carried out by specialists. There are several explanations to account for this phenomenon including
the socioeconomic context and the lack of an established consensus for diagnostic testing. Nonetheless, the
widespread use of genetic and genomic tests in the past decades has had a major impact on clinical reasoning
paradigms, and new troves of data are constantly being generated and analyzed. This requires constantly updating
tools to match the discovery rate and allow reanalysis. In this review, we summarize the latest international
recommendations and guidelines to address the problem of diagnostic deficit as well as present the current
diagnostic workflows. Increasing access to exome and genome sequencing technologies and biological validation,
gaining insight into the interpretation of multi-omics datasets, and fostering data sharing would reduce the long
diagnostic odyssey and diagnostic gap.

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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