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Page 323 Casas-Alba et al. J Transl Genet Genom 2022;6:322-32 https://dx.doi.org/10.20517/jtgg.2022.03

Keywords: Data sharing, epigenomics, exome sequencing, genome sequencing, rare diseases, transcriptomics,
undiagnosed diseases

INTRODUCTION
In this review, we summarize the latest international recommendations and guidelines to classify
undiagnosed patients as well as present the current diagnostic workflows. We depict the advanced
sequencing techniques revolutionizing genetic diagnostic practices, the future of multiple omics
technologies (such as epigenomics, transcriptomics, proteomics, and metabolomics), and the use of in silico
prediction of variant pathogenicity and functional genomics.

Rare diseases (RDs) are very numerous (more than 6000), with many of them being ultra-rare. In the
European Union (EU), the definition of RDs was established in the EU Regulation on orphan medicinal
products (1999) as life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000
[1]
individuals . The American Orphan Drug Act (1983) defined RDs as disorders affecting fewer than 200,000
individuals in the United States (US) . Nguengang et al. calculated that 71.9% of RDs are genetic (including
[2]
[3]
all diseases known or suspected to be familial), and 69.9% are exclusively pediatric onset . Currently, the
estimated prevalence of RDs is at least 3.5%-5.9%, which equates to 263-446 million individuals
[3]
worldwide . Moreover, RDs pose an economic burden as direct medical costs per patient are estimated to
be around 3-5 times higher than controls of the same age without RDs .
[4]
[5]
The high frequency with which RDs remain undiagnosed is a major challenge, as reflected in one of the
International Rare Diseases Research Consortium (IRDiRC) goals for 2017-2027, which encourages to
achieve a diagnosis of patients within one year if their disorder is known in the medical literature . The
[6]
term diagnostic odyssey refers to the time between when a potential RD is noted until the final diagnosis is
made, while diagnostic impasse refers to the difficulty in achieving a diagnosis after performing all currently
available procedures. The diagnostic deficit is usually associated with patients with complex phenotypes, the
lack of genotype/phenotype correlation, or the lack of certainty of the clinical impact of a given genetic
variant. Diagnosis in RD patients not only provides answers for patients and families but also has a potential
clinical impact, which includes gaining knowledge on the natural history of disease and prognosis,
providing genetic counseling, guiding personalized treatments, offering patient support networks, enabling
participation in research studies, informing reproductive choices, and impacting the health of relatives .
[7]

Many but not all patients with an undiagnosed disease have an RD . Undiagnosed and rare diseases
[8]
(URDs) are conditions that elude diagnosis by a referring specialist or center of expertise for a long time
and despite extensive state-of-the-art investigations . Graessner et al. estimated that around 50% of patients
[9]
with RDs remain undiagnosed even in advanced expert clinical settings where genome sequencing
techniques are applied routinely . Available investigations vary in each socioeconomic context, and there is
[5]
not a consensus list of laboratory and ancillary tests to be performed before concluding that a patient is
undiagnosed. Our ability to diagnose URDs is limited by our incomplete knowledge of the natural history
and clinical expression of the disease, the genotype/phenotype correlations, the full mutational spectrum
associated with all RDs, and the number of unique RDs that have yet to be discovered . The IRDiRC
[10]
Solving the Unsolved Task Force proposes to classify URD patients into specific subsets with significant
[10]
utility for optimizing diagnostic strategies [Table 1] . However, in many cases, it is more important to take
into account the potential explanations for the diagnostic deficit before undergoing follow-up tests. In these
cases, we can use an alternative classification system [Table 2].