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Table 1. Clinical groupings and diagnostic strategies for patients with undiagnosed and rare diseases (adapted from the IRDiRC
solving the Unsolved Task Force [10] )

Clinical groupings Recommended diagnostic strategies
Patients with clinically recognizable disorders
No causative variant after an appropriate highly Explore new tests and computational tools (e.g., RNAseq might be useful in patients with
sensitive test (e.g., single-gene disorders such as suspected neurofibromatosis type 1 and negative conventional tests)
neurofibromatosis type 1)
No identified causative variant in the context of Get large datasets of patients, detailed phenotypic and genomic information, and share
genetic heterogeneity (e.g., retinitis pigmentosa) data (data sharing of patients with a similar phenotype can help in the identification of
disease-causing variants in yet-to-be-discovered disease genes)
Unsolved but recognizable disorder (e.g., VACTERL
association) Explore new tests and computational tools
Patients without clinically recognizable disorders
Patients with syndromes without a name (SWAN), Exome or genome sequencing as first-line tests
which are not recognizable as a previously described
disorder

The widespread use of genetic tests in the clinical setting has had a great impact on the paradigms of clinical
reasoning in the field of clinical genetics. Classical linear reasoning, in which phenotype assessment leads to
a clinical suspicion that is further confirmed or refuted by genetic testing, has increasingly been replaced by
circular reasoning, where both phenotype and genotype are assessed in parallel [14,15] . Moreover, some
diagnoses are only considered after the identification of a specific genetic variant. However, considering
phenotype assessment and clinical suspicion is still an essential piece of the diagnostic process.

THE GENOMIC SCENARIO: EXOME AND GENOME SEQUENCING
Exome and genome sequencing (ES and GS, respectively) are now recommended by the American College
of Medical Genetics and Genomics (ACMG) to be considered as first- or second-tier tests (after
chromosomal microarray (CMA) or focused gene testing) for patients with congenital anomalies (CA),
developmental delay (DD), or intellectual disability (ID) . Only patients with clinical presentations
[16]
suggestive of a specific diagnosis should undergo targeted testing first . This may include patients with
[16]
suspicion of a chromosomal disorder, a diagnosis in which sequencing may not be diagnostic (e.g., fragile X
syndrome), or known family history of a disorder . This recommendation supersedes the previous advice
[16]
to perform CMA as first-line tests in patients with CA and DD/ID (setting aside patients with autism
spectrum disorder without other delays) .
[17]

The recent change in recommendations is due to the high diagnostic yield of ES and GS. The Ontario
Health Technology Assessment reported a diagnostic yield of 43% for GS and 34% for ES (not
differentiating between the trio and singleton testing), compared with the diagnostic yield of 21% for
standard genetic testing (which typically included CMA, candidate single-gene testing, or large gene panel
testing) . Although GS, by definition, captures more comprehensively all types of variants in testing, ES is
[18]
expected to be used for a long time in clinical genetics given the lower cost, focused approach, and reduced
[19]
burden on downstream analysis compared to GS . When performing ES and GS, best practice includes trio
testing if available to help contextualize rare variants, but they also can be effectively performed as singleton
[16]
testing, with diagnostic yield being slightly reduced .
Although first-line ES or GS has still not been established as standard clinical practice in all settings, the
increased use of ES in the past decade has had a significant impact in the field of URDs. If a patient remains
undiagnosed after performing ES, it is essential to know the limitations of ES to continue with the
diagnostic process [Table 3]. In addition to recommending ES/GS as first-tier tests (or second-tier tests in
certain cases), the ACMG suggests a diagnostic algorithm for the evaluation of patients with GDD/ID if ES