Rare DiseasesNCT04586075
UW Undiagnosed Genetic Diseases Program
An observational study of Rare Diseases and Genetic Disease, run by University of Wisconsin, Madison at 1 site in United States.
Trial summary
The primary purpose of this study is to discover new disease genes for rare Mendelian disorders and its secondary purpose include diagnosing people with rare genetic disorders that have not been previously diagnosed through conventional clinical means, learning more about the pathobiology of genetic disorders, and… Read more about this study
- Who is it for?
- Ages Up to 100 years
- Conditions the study is for
- Rare Diseases, Genetic Disease, Undiagnosed Disease
- What is being tested?
- Trio Whole Genome Sequencing and Participant-Specific Research
- How many people
- 1,000 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Jul 2021to Oct 2030
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 100 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Males and females, ages 0-100 years, of all races and ethnicities, with an undiagnosed disease despite thorough evaluation by healthcare providers and having at least one objective finding. Subjects can come from all states of the US, as well as from other countries.
Who may be able to join
- The applicant has a condition that remains undiagnosed despite thorough evaluation by healthcare providers (including clinical genetic testing).
- The applicant has at least one objective finding that is likely to have an identifiable genetic etiology.
- The applicant likely has a currently undescribed/new genetic condition or a known genetic condition associated with a novel gene.
- The applicant/legal guardian agrees to the collection, storage and recurrent sharing of coded information and biomaterials for research and diagnostic purposes both within and outside of the University of Wisconsin-Undiagnosed Diseases Program (UW-UDP)
- The applicant/legal guardian agrees to receive secondary findings from genetic testing.
- The applicant/legal guardian has sufficient proficiency in English to understand the consent.
Who cannot join
- The applicant already has a diagnosis that explains the objective findings.
- A specific diagnosis is suspected and a standard clinical workup performed by the referring/primary care provider would be appropriate.
- The UW-UDP is unlikely to improve on the comprehensive workup the applicant has already received.
- The applicant's symptoms are likely multifactorial or due to a non-genetic cause.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Research Coordinator contact
United States1 site, 1 recruiting
- Recruiting
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin, 53705
Study Coordinator, (608) 263-5877, research@CHGPM.wisc.edu
Bryn Webb, MD
About this study
The primary purpose of this study is to discover new disease genes for rare Mendelian disorders and its secondary purpose include diagnosing people with rare genetic disorders that have not been previously diagnosed through conventional clinical means, learning more about the pathobiology of genetic disorders, and developing novel diagnostic technologies and analytics. 500 participants with undiagnosed and suspected genetic disorders will be recruited.
Read the detailed description
An estimated 10,000 rare Mendelian genetic disorders affect, in aggregate, one in twelve individuals. Importantly, just over half of these diseases have a known genetic cause. This leaves thousands of disease genes waiting to be discovered and millions of affected individuals without a diagnosis. The investigators will address these critical issues in genomic medicine by using genome sequencing and other 'omics technologies to assess patients whose comprehensive clinical workups have failed to yield a diagnosis. The hypothesis is that, when carefully selected, these undiagnosed disease patients will be a rich resource for new disease gene discovery.
This study is the research arm of the UW Undiagnosed Disease program (UW-UDP). The primary objective of this study is to discover new disease genes and expand the known phenotypes of rare Mendelian disorders. The secondary objectives are: a) Diagnose individuals with genetic disorders who have not been diagnosed using conventional clinical means and provide them with actionable knowledge to manage their disorders; b) Improve our understanding of the pathobiology of genetic disorders and the relationships between genomic variation and disease; and c) Develop and trial novel diagnostic technologies and analytics.
These objectives will be achieved through three aims:
Aim 1: Identify candidate disease variants in individuals suspected of an undiagnosed genetic disorder through the use of trio short read genome sequencing and data sharing with the rare disease databases GeneMatcher and MatchMaker Exchange.
Aim2: Further evaluate those individuals not diagnosed in Aim 1 by using novel 'omics technologies and bioinformatics algorithms. These approaches include a) ultra-long read de novo assembly-based genomic sequencing; b) RNA-Seq; c) epigenomics profiling, and d) conformational analysis of chromatin organization.
Aim 3: Provide functional assessments of selected candidate disease genes and genomic variants discovered in Aims 1 and 2 through collaborations with UW and external model organism researchers. These efforts will be facilitated through the use of a UW model organism researcher database that is linked to the Canadian Rare Diseases Models and Mechanisms Network database and an emerging global network of model organism researcher databases.
This research project is closely integrated with the UW-UDP's comprehensive clinical evaluations of undiagnosed patients. The standard clinical care component entails patient referral, collection and pre-visit assessment of medical records, and clinic visits for extensive phenotyping at the beginning of the study and for the return of results at the end of the study. The research workflow includes genome sequencing, data sharing with global disease gene discovery networks, and follow-up studies to determine causality of variants identified by genetic testing. This study will advance understanding of the pathobiology of genetic disease, improve clinical diagnostics, and aid in the diagnosis and management of individuals with previously undiagnosed rare disorders both within Wisconsin and beyond its borders.
- Conditions
- Rare Diseases, Genetic Disease, Undiagnosed Disease
- Being tested
- Trio Whole Genome Sequencing and Participant-Specific Research
- Keywords
- genomics, genome sequencing, undiagnosed disease
- Medical subject headings
- Rare Diseases, Genetic Diseases, Inborn, Undiagnosed Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Trio Whole Genome Sequencing and Participant-Specific ResearchDiagnostic test
The initial evaluation begins with short-read genome sequencing of DNA extracted from blood of affected individual(s) and participating family members (The most common approach will be trio whole genome sequencing, which involves the affected child + their parents).
Additional evaluation may include: functional assessments, animal modeling, reverse phenotyping (may require an interim visit), epigenetic profiling, or clinical database matching through selective sharing of coded patient data with external collaborators (e.g., via Matchmaker Exchange and Phenome Central), long read genome sequencing, de novo genome assembly, RNA sequencing, and novel bioinformatics analyses
| Study group | Role | What they receive |
|---|---|---|
| Undiagnosed Disease Group | Blood or other relevant biological samples obtained from consenting research subjects will be banked and extracted for DNA and RNA. Receives: Diagnostic Test: Trio Whole Genome Sequencing and Participant-Specific Research |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of New Disease Genes Discovered
Measured: up to 5 years
Number of Expanded Disease Gene Phenotypes
Measured: up to 5 years
Secondary outcomes (3)
Number of Participants who are Diagnosed in 5 years
A secondary objective of this study is to diagnose individuals with genetic disorders who have not been diagnosed using conventional clinical means and provide them with actionable knowledge to manage their disorders. This will be measured as the rate of diagnosis over the entire study.
Measured: up to 5 years
Number of Participants Diagnosed per Analytical Technique
A secondary aim of this study is to develop and trial novel diagnostic technologies and analytics. The diagnosis rate per novel analytic technique will be assessed.
Measured: up to 5 years
Diagnostic Rate by Disease Presentation
To improve understanding of the pathobiology of genetic disorders and the relationships between genomic variation and disease, number of participants diagnosed by disease presentation will be reported.
Measured: up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Oct 2020
- Study start16 Jul 2021
- Primary completionOct 2030 (estimated)
- Study completionOct 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Rare DiseasesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 1,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Wisconsin, Madison
- Sponsor type
- University, hospital or other
- Collaborators
- University of Wisconsin Center for Human Genomics and Precision Medicine
- Responsible party
- Sponsor
- Investigators
- Bryn Webb, MD, Principal investigator, University of Wisconsin, Madison
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04586075
- Sponsor's protocol ID
- 2020-0700
- Other IDs
- SMPH, Protocol Version 10/28/2024
- Status last verified
- May 2026
- First submitted
- 6 Oct 2020
- Last updated
- 29 May 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data from the UW-UDP will be shared via PhenomeCentral (https://www.phenomecentral.org) and Matchmaker Exchange (https://www.matchmakerexchange.org/). Data, images, and/or specimens will be shared in compliance with the NIH Genomic Data Sharing Policy and with other clinicians and researchers who may have similar patients and/or specific expertise/assays relevant to the participant's disorder. In this regard, a limited amount of non-PHI containing patient data will be shared with pre-vetted model organism collaborators at UW and elsewhere via our Center's local node of the Rare Diseases Models and Mechanisms Network (http://rdmmn.biotech.wisc.edu). This network facilitates the identification of model organism researchers who are willing and able to functionally assess the pathogenicity of candidate disease gene variants in rare disease patients (see http://www.rare-diseases-catalyst-network.ca for details).
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- UW Undiagnosed Genetic Diseases Program
- ClinicalTrials.gov ID
- NCT04586075
- Acronym / sponsor ID
- 2020-0700
- Conditions
- Rare Diseases, Genetic Disease, Undiagnosed Disease
- Keywords
- genomics, genome sequencing, undiagnosed disease
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 1,000 participants (estimated)
- Lead sponsor
- University of Wisconsin, MadisonUniversity, hospital or other
- Collaborators
- University of Wisconsin Center for Human Genomics and Precision Medicine
- Study start
- 16 Jul 2021 (actual)
- Primary completion
- Oct 2030 (estimated)
- Study completion
- Oct 2030 (estimated)
- First posted
- 14 Oct 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary purpose of this study is to discover new disease genes for rare Mendelian disorders and its secondary purpose include diagnosing people with rare genetic disorders that have not been previously diagnosed through conventional clinical means, learning more about the pathobiology of genetic disorders, and developing novel diagnostic technologies and analytics. 500 participants with undiagnosed and suspected genetic disorders will be recruited.
Detailed description
An estimated 10,000 rare Mendelian genetic disorders affect, in aggregate, one in twelve individuals. Importantly, just over half of these diseases have a known genetic cause. This leaves thousands of disease genes waiting to be discovered and millions of affected individuals without a diagnosis. The investigators will address these critical issues in genomic medicine by using genome sequencing and other 'omics technologies to assess patients whose comprehensive clinical workups have failed to yield a diagnosis. The hypothesis is that, when carefully selected, these undiagnosed disease patients will be a rich resource for new disease gene discovery.
This study is the research arm of the UW Undiagnosed Disease program (UW-UDP). The primary objective of this study is to discover new disease genes and expand the known phenotypes of rare Mendelian disorders. The secondary objectives are: a) Diagnose individuals with genetic disorders who have not been diagnosed using conventional clinical means and provide them with actionable knowledge to manage their disorders; b) Improve our understanding of the pathobiology of genetic disorders and the relationships between genomic variation and disease; and c) Develop and trial novel diagnostic technologies and analytics.
These objectives will be achieved through three aims:
Aim 1: Identify candidate disease variants in individuals suspected of an undiagnosed genetic disorder through the use of trio short read genome sequencing and data sharing with the rare disease databases GeneMatcher and MatchMaker Exchange.
Aim2: Further evaluate those individuals not diagnosed in Aim 1 by using novel 'omics technologies and bioinformatics algorithms. These approaches include a) ultra-long read de novo assembly-based genomic sequencing; b) RNA-Seq; c) epigenomics profiling, and d) conformational analysis of chromatin organization.
Aim 3: Provide functional assessments of selected candidate disease genes and genomic variants discovered in Aims 1 and 2 through collaborations with UW and external model organism researchers. These efforts will be facilitated through the use of a UW model organism researcher database that is linked to the Canadian Rare Diseases Models and Mechanisms Network database and an emerging global network of model organism researcher databases.
This research project is closely integrated with the UW-UDP's comprehensive clinical evaluations of undiagnosed patients. The standard clinical care component entails patient referral, collection and pre-visit assessment of medical records, and clinic visits for extensive phenotyping at the beginning of the study and for the return of results at the end of the study. The research workflow includes genome sequencing, data sharing with global disease gene discovery networks, and follow-up studies to determine causality of variants identified by genetic testing. This study will advance understanding of the pathobiology of genetic disease, improve clinical diagnostics, and aid in the diagnosis and management of individuals with previously undiagnosed rare disorders both within Wisconsin and beyond its borders.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Undiagnosed Disease Group | – | Diagnostic Test: Trio Whole Genome Sequencing and Participant-Specific ResearchBlood or other relevant biological samples obtained from consenting research subjects will be banked and extracted for DNA and RNA. |
Who may qualify
- Ages
- Up to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Males and females, ages 0-100 years, of all races and ethnicities, with an undiagnosed disease despite thorough evaluation by healthcare providers and having at least one objective finding. Subjects can come from all states of the US, as well as from other countries.
Key inclusion criteria (6 listed)
- The applicant has a condition that remains undiagnosed despite thorough evaluation by healthcare providers (including clinical genetic testing).
- The applicant has at least one objective finding that is likely to have an identifiable genetic etiology.
- The applicant likely has a currently undescribed/new genetic condition or a known genetic condition associated with a novel gene.
- The applicant/legal guardian agrees to the collection, storage and recurrent sharing of coded information and biomaterials for research and diagnostic purposes both within and outside of the University of Wisconsin-Undiagnosed Diseases Program (UW-UDP)
- The applicant/legal guardian agrees to receive secondary findings from genetic testing.
Key exclusion criteria (4 listed)
- The applicant already has a diagnosis that explains the objective findings.
- A specific diagnosis is suspected and a standard clinical workup performed by the referring/primary care provider would be appropriate.
- The UW-UDP is unlikely to improve on the comprehensive workup the applicant has already received.
- The applicant's symptoms are likely multifactorial or due to a non-genetic cause.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Trio Whole Genome Sequencing and Participant-Specific ResearchThe initial evaluation begins with short-read genome sequencing of DNA extracted from blood of affected individual(s) and participating family members (The most common approach will be trio whole genome sequencing, which involves the affected child + their parents). Additional evaluation may include: functional assessments, animal modeling, reverse phenotyping (may require an interim visit), epigenetic profiling, or clinical database matching through selective sharing of coded patient data with external collaborators (e.g., via Matchmaker Exchange and Phenome Central), long read genome sequencing, de novo genome assembly, RNA sequencing, and novel bioinformatics analyses | Diagnostic test | Undiagnosed Disease Group |
Primary outcome
Number of New Disease Genes Discovered
Time frame: up to 5 years
Number of Expanded Disease Gene Phenotypes
Time frame: up to 5 years
3 secondary outcomes
Number of Participants who are Diagnosed in 5 years
Time frame: up to 5 years
Number of Participants Diagnosed per Analytical Technique
Time frame: up to 5 years
Diagnostic Rate by Disease Presentation
Time frame: up to 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2026.
- Individual participant dataSharing planned: Yes. Data from the UW-UDP will be shared via PhenomeCentral (https://www.phenomecentral.org) and Matchmaker Exchange (https://www.matchmakerexchange.org/). Data, images, and/or specimens will be shared in compliance with the NIH Genomic Data Sharing Policy and with other clinicians and researchers who may have similar patients and/or specific expertise/assays relevant to the participant's disorder. In this regard, a limited amount of non-PHI containing patient data will be shared with pre-vetted model organism collaborators at UW and elsewhere via our Center's local node of the Rare Diseases Models and Mechanisms Network (http://rdmmn.biotech.wisc.edu). This network facilitates the identification of model organism researchers who are willing and able to functionally assess the pathogenicity of candidate disease gene variants in rare disease patients (see http://www.rare-diseases-catalyst-network.ca for details).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Research Coordinator contact
Bryn Webb, MD principal investigator
University of Wisconsin, Madison
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Rare Diseases and Genetic Disease, run by University of Wisconsin, Madison at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Research Coordinator ((608) 263-5877), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of New Disease Genes Discovered (time frame: up to 5 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2026.