UW ISeqU: Clinical Impact of Whole-genome Sequencing in Adults

The goal of this study is to learn how clinical whole genome sequencing can help identify diagnoses and guide medical care in adults. The study is based on the hypothesis that genome sequencing will identify a genetic explanation in some adults whose condition has not previously been diagnosed and that some results will change medical care. The main questions it aims to answer are:

• How often does genome sequencing identify a genetic diagnosis that explains or contributes to a participant's symptoms?
• How do genetic results affect medical care and decision-making?
• Is genome sequencing feasible and acceptable to adult patients and families?
• Are there differences in access to genetic testing or diagnosis across different groups of patients?

Participants will:

• Provide a blood sample (often collected during routine care) or cheek swab for genetic testing
• Allow researchers to review their medical records
• Receive genetic results that will also be shared with their medical team
• May be asked to complete a brief survey or interview about their experience

Researchers will follow participants over time to understand how genetic testing impacts diagnosis and care.

Study Overview

• Status: Enrolling by invitation
• Conditions: Critical Illness; Hereditary Diseases
• Intervention / Treatment: Genetic: Genome sequencing

Detailed Description

This is a prospective observational cohort study evaluating the use of clinical whole genome sequencing in adults with unexplained medical conditions, atypical disease courses, or clinical presentations for which a genetic contribution is suspected. Participants will be identified at the University of Washington Medicine sites (UW Montlake and Harborview Medical Center). The study is intended to characterize how genome sequencing can be incorporated into adult clinical care. Participation is voluntary and does not replace standard diagnostic evaluation or treatment.

Potential participants will be identified through review of hospital admissions and referrals from treating clinicians or specialty services. Informed consent may be completed in person, by telephone, or by secure videoconference. When a hospitalized participant is unable to provide consent because of illness or impaired decision-making capacity, consent may be obtained from a legally authorized representative in accordance with applicable requirements. During consent, participants will indicate whether they wish to receive ACMG medically actionable secondary findings and whether they agree to future contact.

After enrollment, the study team will collect clinical and phenotypic information relevant to genomic interpretation. Information may include the participant's presenting symptoms, medical and family history, prior diagnostic testing, medications, hospital course, and subsequent clinical care. Data will be obtained from participant or family interview, review of the electronic health record, and communication with the treating team. Clinical information from before and after sequencing will be collected to support interpretation and to evaluate the downstream effects of genomic findings.

The only physical procedure is collection of a biospecimen for genomic testing. Research blood collection will be coordinated with a clinically indicated blood draw to avoid an additional venipuncture. Alternatively, a buccal swab may be used.

A close biological relative may also be enrolled as a genetic comparator when this would assist in genetic interpretation. Comparator participation is optional. Comparators will provide a buccal specimen and limited identifying information needed for laboratory testing. Their medical records will not be reviewed.

Whole-genome sequencing will be performed and interpreted by GeneDx, a CLIA-certified laboratory. Variants will be classified using current ACMG/AMP standards. Findings will be assessed in relation to the participant's phenotype and may be categorized as diagnostic, contributory, secondary, or non-contributory. Variants of uncertain significance may be reported when considered relevant by the clinical laboratory.

Participants may choose whether to receive medically actionable secondary findings in genes recommended by the ACMG. Comparator analysis will generally be limited to variants relevant to interpretation of the enrolled participant. A comparator may receive a result when a clinically significant variant identified in the participant is also present in the comparator or when the comparator has separately chosen to receive an eligible secondary finding.

Clinically relevant results will be returned by a genetic counselor or clinical geneticist by telephone, secure video visit, or in person. Results will be communicated to the clinical team and will be made available in the medical record. When appropriate, participants may be advised to discuss additional evaluation, surveillance, treatment, or family testing with their clinicians or to seek consultation with a medical genetics referral. Clinical care resulting from a genomic finding, including laboratory testing, imaging, specialist referral, or treatment, is not provided as a study procedure.

In addition to the clinical laboratory analysis, genomic and clinical data may be used for exploratory research. These analyses may include pharmacogenomic assessment, evaluation of gene-disease relationships, or other studies of disease mechanisms and treatment response. Exploratory research findings will not be returned clinically.

The study team will review participants' medical records for up to 3 years after enrollment to evaluate the downstream clinical effects of sequencing, including changes in diagnosis, treatment, surveillance, referrals, and family counseling. Participants may also be invited to complete a brief survey or interview about their experience with genetic testing and result disclosure. Participants who agree to future contact may be contacted if clinically important new information or a meaningful reinterpretation of their genomic findings becomes available.

Clinical and genomic data will be stored using coded study identifiers on secure systems. The linkage between study identifiers and participant identities will be maintained separately, with access restricted to authorized study personnel. Genomic data may be retained for future reanalysis as scientific knowledge changes. Individual genetic variants may be submitted in de-identified form to public variant databases such as ClinVar; raw genomic data and medical records will not be included in those submissions.

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

University of Washington - Montlake Campus or Harborview Medical Center Seattle, WA, USA

Description

Inclusion Criteria:

• Person has a medical condition that does not yet have a clear explanation
• Enough medical information is available within the UW Medicine system to evaluate the person's condition and interpret genetic test results
• A blood sample or cheek-swab sample can be collected for genetic testing
• The person does not already have a confirmed genetic diagnosis that fully explains their current medical condition
• The person, or their legally authorized representative when applicable, is willing and able to provide informed consent.

Exclusion Criteria:

• The current illness has a clear non-genetic explanation, such as a traumatic injury, confirmed overdose or intoxication, or an infection that fully explains the illness
• The person previously had genetic testing specifically for the current condition or symptoms, including prior whole-exome or whole-genome sequencing
• The person is currently incarcerated.
• The person has had a donor stem cell, bone marrow transplant or active blood cancer that makes a sample unsuitable for testing their inherited genetic information

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adults Undergoing Clinical Genome Sequencing; Adults with unexplained medical conditions or clinical presentations who undergo clinical genome sequencing and longitudinal follow-up	Genetic: Genome sequencing; Clinical whole-genome sequencing of blood or buccal DNA, with optional family comparator analysis and return of clinical results

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic Yield of Clinical Genome Sequencing	Number and percentage of participants with one or more definitive or possible diagnostic findings on clinical genome sequencing. This will be further stratified as secondary outcome measures by clinical and demographic characteristics.	Through study completion, an average of 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Short-term and long-term changes in medical management	Number and percentage of participants with a change in medical management attributable to the genome sequencing result. Changes may include initiation, discontinuation, or modification of medication or treatment; additional diagnostic testing; changes in monitoring or surveillance; inpatient consultation; outpatient referral; transition to comfort-focused care; or testing and evaluation of biological relatives.	At 6 months after testing and at 3 years after testing

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: GeneDx
• Investigators: Principal Investigator: Evonne McArthur, MD, PhD, University of Washington; Study Director: Danny E Miller, MD, PhD, University of Washington

Publications and helpful links

Helpful Links

• Public homepage for study details and updates

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2026
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): July 1, 2032

Study Registration Dates

• First Submitted: July 14, 2026
• First Submitted That Met QC Criteria: July 17, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 17, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: genetic; genome sequencing; undiagnosed disease; rapid whole genome sequencing; adult genetics; critical illness genetics
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Undiagnosed Diseases; Critical Illness; Genetic Diseases, Inborn
• Other Study ID Numbers: STUDY00025204; RG1126449 (Other Identifier: UW Clinical Trials Office)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be made publicly available because the dataset includes sensitive clinical and genomic information. Aggregate study results may be shared through publications and presentations, and de-identified individual genetic variants may be submitted to public variant databases.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No