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

NCT ID: NCT06935019

Last Updated: 2025-07-11

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: NA
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-05-14
• Study Completion Date: 2028-05-31

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.

Conditions

Genetic Conditions

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

GS-first arm

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.

Group Type: EXPERIMENTAL

Genome sequencing pre-geneticist evaluation

Intervention Type: 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.

Standard-of-care arm

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Genome sequencing pre-geneticist evaluation

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.

Intervention Type: GENETIC

Eligibility Criteria

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.

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital of Eastern Ontario

OTHER

Sponsor Role: collaborator

Toronto Metropolitan University

OTHER

Sponsor Role: collaborator

The Hospital for Sick Children

OTHER

Sponsor Role: lead

Responsible Party

Gregory Costain

Staff Physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Children's Hospital of Eastern Ontario

Ottawa, Ontario, Canada

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

Canada

References

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.

Reference Type: DERIVED

PMID: 40784761 (View on PubMed)

Other Identifiers

CTO5061

Identifier Type: -

Identifier Source: org_study_id