UW Undiagnosed Genetic Diseases Program

Study Overview
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Brief Summary
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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 over approximately 5 years time.

Detailed Description
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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.

Official Title
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UW Undiagnosed Genetic Diseases Program

Conditions
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Rare Diseases, Genetic Disease, Undiagnosed Disease

Intervention / Treatment
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* Diagnostic Test: Trio Whole Genome Sequencing and Participant-Specific Research


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Undiagnosed Disease Group<br>Blood or other relevant biological samples obtained from consenting research subjects will be banked and extracted for DNA and RNA. | Diagnostic Test: Trio Whole Genome Sequencing and Participant-Specific Research<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of New Disease Genes Discovered |  | up to 5 years | 
| Number of Expanded Disease Gene Phenotypes |  | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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genomics, genome sequencing, undiagnosed disease