TRIAGE-GS: Towards Reducing Inefficiencies Affecting Genetics Encounters Through Genome Sequencing

Not Applicable

• Conditions: Genetic Conditions

• Registration Number: NCT06935019
• Lead Sponsor: The Hospital for Sick Children

Brief Summary

Individually rare genetic diseases are collectively common, and affect many Canadian families. Making the right diagnosis is both important and challenging. Healthcare providers and families often remain in the dark for too long, limited by the scope and speed of current genetic testing.

The goal of this clinical trial is to learn if performing genome sequencing (a comprehensive genetic test) as soon as a rare genetic disease is suspected is more effective than usual care, where a person waits to see a genetics specialist and then typically gets offered more targeted testing. Researchers will compare a "genome-sequencing first" approach to the standard-of-care in individuals who were referred to the Genetics Clinic at either SickKids or CHEO and recently had their referral accepted by the clinic.

The main questions this clinical trial aims to answer are:

1. Are there more and faster diagnoses with a "genome sequencing first" approach compared to standard-of-care?

2. What do patients, families, and healthcare providers think about a "genome sequencing first" approach compared to standard-of-care?

3. What is the financial impact of a "genome sequencing first" approach compared to standard-of-care on the healthcare system?

Participants will be asked to:

* Let us review their medical records.

* Complete up to 5 questionnaires over the course of the study.

* Give a blood sample for clinical genome sequencing (if in the genome sequencing first group).

This study aims to provide the robust evidence needed to improve care pathways for rare disease diagnosis in Canada. The findings also promise to help translate new genetic technologies into the clinic. Earlier diagnosis is a key first step towards personalized care, targeted treatments, and better outcomes.

Detailed Description

This is a multi-centre, prospective, interventional, open randomized controlled trial that compares patient outcomes generated by clinical whole genome sequencing (GS) initiated at time of referral triage (i.e., prior to evaluation with a medical geneticist) to standard-of-care, where genetic testing is ordered post-evaluation. 200 individuals referred to SickKids or CHEO for suspected undiagnosed rare disease (RD) will be enrolled, along with their biological parents when possible. The purpose of this study is to examine the safety, utility, and feasibility of a "genomics first" diagnostic pathway for RD. The investigators hypothesize that a GS-first pathway will have non-inferior diagnostic yield and lead to a shorter duration of time to RD diagnosis, fewer diagnostics-focused clinic visits, and improved stakeholder satisfaction.

Study Timeline

• Study First Submitted: 2025-03-28
• Study First Submitted QC: 2025-04-11
• Study First Posted: 2025-04-18
• Status Verified: 2025-05
• Study Start: 2025-05-14
• Last Update Submitted: 2025-05-16
• Last Update Posted: 2025-05-21
• Primary Completion: 2026-12
• Study Completion: 2028-05

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

• Referral accepted to the Genetics Clinic at SickKids or CHEO within 7 days of screening for study eligibility.
• Referral is for a patient that is ≤18 years old.
• Reason for referral is a suspected but as-yet-undiagnosed RD
• A genetic aetiology is a possible explanation for the phenotype such that genetic testing is likely to be offered in Genetics Clinic, as determined by the research team.

Exclusion Criteria

• Patient has a known or suspected clinical diagnosis using established criteria of a genetic condition with low locus heterogeneity (e.g., HHT, fCCM, NF1, TSC, others)
• Referral considered "Urgent" using established site criteria.
• Genome-wide sequencing (exome sequencing or GS) or a comprehensive panel that encompasses all genes relevant for the reported phenotype previously completed on a clinical or research basis.
• Patient or family member previously assessed by a medical geneticist within the last 2 years for the same phenotype(s).
• Patient lacks Ontario Health Insurance Plan (OHIP) or comparable coverage (as this will limit options for standard genetic testing).
• Referral is solely to facilitate familial variant testing or for genetic counselling.
• A family member is already enrolled in the study and was referred for the same indication.
• Patient/family does not provide informed consent to participate within 2 weeks of being approached.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Determine the time-to-event (diagnosis or no active follow-up) of a GS-first (pre-geneticist evaluation) outpatient care model for rare disease compared to standard of care.	From date of randomization until the date of the disclosure of diagnosis/plan, up to 18 months.	The primary outcome measure for Aim 1 is a time-to-event variable. The event of interest is "diagnosis or no active follow-up," as measured for each participant from the date of randomization to the date of disclosure of the diagnosis/plan. Selection of a composite event variable was based on input from patients, families, and clinicians regarding the utility of negative GS results in certain scenarios. For example, a negative GS result might lower the index of suspicion for Mendelian disorders of known genetic basis, such that no further testing or short-term follow-up is recommended, or a clinical diagnosis of exclusion is made with confidence.
Compare clinical utility of GS-first to standard of care from the perspectives of care teams.	0-2 weeks after the first results disclosure to the participant/family.	The main outcome for Aim 2 will be differences in C-GUIDE total score, comparing the perceived utility of GS (in the GS-first group) with the first genetic test initiated by the geneticist for participants in the standard-of-care group.
Compare personal utility of GS-first to standard-of-care from the perspectives of patients, families, and care teams.	0-2 weeks after the first results disclosure to the participant/family.	The other main outcome for Aim 2 will be differences in GENE-U total score, comparing the perceived utility of GS (in the GS-first group) with the first genetic test initiated by the geneticist for participants in the standard-of-care group.
Assess cost-effectiveness as the incremental cost per additional case detected for GS-first compared to standard-of-care from a healthcare system payer perspective.	Overall during the study period (up to 18 months).	An incremental cost-effectiveness analysis (CEA) that compares GS-first to standard-of-care per additional positive finding will be undertaken from the perspectives of the healthcare system and society. The economic evaluation will use recommended methods.

Secondary Outcome Measures

Name	Time	Method
Primary diagnostic yield	Overall during the study period (up to 18 months), and within a 6-month time interval from the date of randomization.
Proportion of participants with dual diagnoses	Overall during the study period (up to 18 months).
Proportion of participants with partial genetic diagnoses	Overall during the study period (up to 18 months).
Proportion of participants with potential genetic diagnoses	Overall during the study period (up to 18 months).
Proportion of participants with variants of uncertain significance deemed non-contributory by the clinician	Overall during the study period (up to 18 months).
Proportion of participants with secondary/incidental findings	Overall during the study period (up to 18 months).
Number of new informative HPO terms coded after evaluation by a geneticist (compared with data extracted from collateral records at the time of the referral)	Overall during the study period (up to 18 months).	This can be stratified by the original referral source (i.e., internal referrals from providers at SickKids/CHEO vs. referrals from external providers).
Differences in amount of time/effort required for reporting genome sequencing	Overall during the study period (up to 18 months).	Including time recorded by the analyst, number/type of variants unnecessarily reported due to incomplete phenotypic information, etc.
Number of diagnoses missed by GS in the intervention arm that were later made after geneticist evaluation	Overall during the study period (up to 18 months).	Including variants seen by GS that were not reported based on phenotypic information known prior to geneticist assessment, variants identified on reanalysis using new HPO terms entered post-geneticist assessment, or variant types (e.g., repeat expansions) that were missed by GS due to technical limitations, etc.
Incremental cost per unit improvement in C-GUIDE score	Overall during the study period (up to 18 months).	A secondary analysis under the CEA will examine the incremental cost per unit improvement in C-GUIDE score

Trial Locations

Locations (2)

Children's Hospital of Eastern Ontario; 🇨🇦 Ottawa, Ontario, Canada

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada