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

TRIAGE-GS: A Randomized Controlled Trial of a Genomics-first Approach to Rare Disease Diagnosis

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.

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.

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.