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

NCT06935019 | Enrolling By Invitation

• 1 other identifier: CTO5061
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 2

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:

• 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.

Conditions

Genetic Conditions

Keywords

TRIAGE-GS

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  From date of randomization until the date of the disclosure of diagnosis/plan, up to 18 months.

• Compare clinical utility of GS-first to standard of care from the perspectives of care teams.

  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.

  0-2 weeks after the first results disclosure to the participant/family.

• Compare personal utility of GS-first to standard-of-care from the perspectives of patients, families, and care teams.

  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.

  0-2 weeks after the first results disclosure to the participant/family.

• 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.

  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.

  Overall during the study period (up to 18 months).

Secondary Outcomes (10)

• 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).

Other Outcomes (10)

• Motivations and barriers to study participation

  0-2 weeks post-study enrolment, or offered immediately after declining to participate.

• Sociodemographics

  0-2 weeks post-study enrolment.

• BRIEF Health Literacy Screening Tool

  0-2 weeks post-study enrolment.

Study Arms (2)

GS-first arm

EXPERIMENTAL

The intervention is receiving immediate clinical routine GS, prior to evaluation by a medical geneticist. Pre-test counselling will be done by a research genetic counsellor. Results of GS will be returned during the participant's first visit to Genetics Clinic by their clinical team. Subsequent clinical care (including any other clinically indicated genetic testing or workup) will be arranged by the medical geneticist in clinic.

Genetic: Genome sequencing pre-geneticist evaluation

Standard-of-care arm

NO INTERVENTION

The intervention group will be compared to the standard-of-care group, where evaluation by a medical geneticist in Genetics Clinic is a prerequisite to ordering of genetic testing. Clinical workups and genetic testing are ordered at the discretion of the medical geneticist involved in their clinical care, following evaluation.

Interventions

Genome sequencing pre-geneticist evaluation GENETIC

The intervention is receiving immediate clinical routine GS, prior to evaluation by a medical geneticist. Pre-test counselling will be done by a research genetic counsellor. Results of GS will be returned during the participant's first visit to Genetics Clinic by their clinical team. Subsequent clinical care (including any other clinically indicated genetic testing or workup) will be arranged by the medical geneticist in clinic.

GS-first arm

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Hospital for Sick Children: lead
• Children's Hospital of Eastern Ontario: collaborator
• Toronto Metropolitan University: collaborator
• Ottawa Hospital Research Institute: collaborator

Study Sites (2)

Children's Hospital of Eastern Ontario

Ottawa, Ontario, K1H 5B2, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 0A4, Canada

Location

Related Publications (1)

• Stanley KJ, Chisholm C, Gillespie MK, Caluseriu O, Del Signore N, Elango S, Hartley T, Hewson S, Kim RH, McSheffrey G, Mendoza-Londono R, Sawyer SL, Somerville M, Venkataramanan V, White-Brown A, Telesca S, Shickh S, Marshall CR, Ungar WJ, Hayeems RZ, Bhawra J, Boycott KM, Costain G. TRIAGE-GS: protocol for a randomised controlled trial of a genomics-first approach to rare disease diagnosis for patients awaiting assessment by a clinical geneticist. BMJ Open. 2025 Aug 10;15(8):e107603. doi: 10.1136/bmjopen-2025-107603.

  PMID: 40784761 DERIVED

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Physician

Study Record Dates

• First Submitted: March 28, 2025
• First Posted: April 18, 2025
• Study Start: May 14, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): May 1, 2028
• Last Updated: April 24, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: The data will be made available within 6 months of the study's conclusion, and will remain available for at least 5 years.
• Access Criteria: Accessing the data set will require a signed data transfer agreement.

Locations

CA (2)