Table 2 Inclusion and exclusion criteria for Undiagnosed Diseases Programs (UDPs)
From: International Undiagnosed Diseases Programs (UDPs): components and outcomes
UDP | Inclusion criteria | Exclusion criteria |
|---|---|---|
Age or age of onset | ||
Italy [30] | Either pediatric or adult patients | Â |
Japan [34] | Patient undiagnosed for six months or longer (not necessary for infants) | Patient undiagnosed for less than six months |
Spain [28] | Undiagnosed ‘for a long time’ |  |
Sweden [33] | Both pediatric and adult patients | Â |
Australia (WA) [22] | ‘Generally’ at least 6 months old |  |
Prior investigations or lack of diagnosis | ||
Belgium [31] | Prior evaluation in routine diagnostic setting | Â |
Canada [25] | Appropriate investigations (based on standard of care for the respective province/territory) | Appropriate investigations incomplete |
Italy [30] | Extensive/thorough investigations: biochemical (e.g., enzymes, electrolytes, antibodies), imaging (e.g., ultrasound, MRI), neuropsychological and neurological tests (e.g., NCS), biological samples (i.e., biopsy), genetic (i.e., karyotype, CMA, targeted single-gene, gene-panel sequencing) | A clear clinical diagnosis or definitive molecular diagnosis Previous investigation requirements incomplete |
Korea [27] | Undiagnosed after appropriate tests conducted by experts or a diagnostic journey of more than 5 years despite regular checkups at secondary/tertiary centers | Â |
South Africa [29] | Still undiagnosed at time of recruitment In-depth clinical information available | Â |
Spain [28] | Undiagnosed despite extensive clinical investigations by specialists of the Spanish National Health System | Â |
Sweden [33] | Thorough phenotyping and clinical investigations, including biochemical testing, imaging, neurophysiological and neuropsychiatric evaluation, and histopathologic tissue studies | Appropriate investigations incomplete |
UK [32] | Undiagnosed following standard care in the NHS, which included either no diagnostic tests (because none were available) or approved diagnostic tests | Prior whole genome sequencing A genetic diagnosis |
US [71] | Undiagnosed despite evaluation by at least two specialists who assessed the patient for the objective finding(s) | A diagnosis explaining objective findings A diagnosis suggested on record review |
Australia (Victoria) [26] | Appropriate investigations complete, including standard-resolution CMA and singleton ES Phenotypically relevant genomic lesions not tractable by ES excluded (e.g. FMR1 triplet repeat analysis, methylation studies) | Appropriate investigations incomplete |
Australia (WA) [22] | Known to the public health system, specifically the children’s hospital and the multi-disciplinary UDP-WA team of clinicians Have typically had multiple specialist assessments and hospital admissions |  |
Likelihood of genetic cause | ||
Canada [25] | Suspected monogenic cause | Molecular diagnosis or compelling VUS |
Japan [34] | Likely genetic etiology based on direct/indirect evidence or objective sign(s) that cannot be reduced to a single organ | Â |
Singapore [24] | Likely genetic disorder (based on abnormal antenatal ultrasound, multiple congenital anomalies and developmental delay) | A known genetic diagnosis, either after clinical assessment or investigations (such as karyotype or chromosomal microarray) |
South Africa [29] | Suspected rare monogenic disorder amenable to diagnosis by ES | Â |
UK [32] | Likely monogenic or oligogenic | Â |
Australia (Victoria) [26] | Likely monogenic based on phenotype | Â |
Australia (WA) [22] | Undiagnosed despite clinical factors supporting the possibility of obtaining a diagnosis with current approaches (e.g., multiple affected family members, consanguinity, highly unique phenotypic combinations, facial dysmorphism, growth disturbances) | Â |
Nature of condition | ||
Belgium [31] | At least one objectifiable disease sign | Â |
Japan [34] | Symptoms affect daily life | Â |
Korea [27] | Suspected to have a medically actionable disease with rapid deterioration and an irreversible clinical course | Â |
UK [32] | Have a rare disease (defined in the UK as a disorder affecting ≤ 1 in 2000 persons) |  |
US [71] | One or more objective findings pertinent to the phenotype for which a UDN application was submitted | Reported symptoms with no relevant objective findings |
Australia (WA) [22] | Have chronic, complex, and typically multisystem diseases | Â |
Other | ||
Canada [25] | Assessment by member of Care4Rare Canada consortium Consented to Care4Rare Research Ethics Board-approved protocol Available samples, follow-up possible Family member data available (deep-phenotype, samples) | Â |
Italy [30] | ‘Familiar or sporadic cases, ethnic isolates’ |  |
South Africa [29] | Consent to be part of the program | Â |
Spain [28] | Consent provided (to store biological materials in BioNER (a consented biorepository), and share de-identified clinical data and samples with the UDNI and other networks | Â |
US [71] | Consent provided (to store and share information and biomaterials in an identified fashion amongst the UDN centers, and in a de-identified fashion to research sites beyond the network) | Unwillingness to share data |
Australia (Victoria) [26] | Additional family members for sequencing were available if appropriate | Â |
Sweden [33] | Informed consent and pedigree available | No informed consent |