Genome Sequencing for Inherited Disorders

(TRIAGE-GS Trial)

Enrolling by invitation at 1 trial location

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: The Hospital for Sick Children

Disqualifiers: Clinical diagnosis, Urgent referral, Previous sequencing, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: Up to 18 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether immediate genome sequencing (analyzing a person's complete set of DNA) diagnoses rare genetic diseases faster and more accurately than the usual method, which involves waiting to see a genetics specialist first. Researchers compare this "genome sequencing first" approach to the standard process to determine if it leads to quicker answers and assess perceptions of it. They also evaluate if this new approach is cost-effective for the healthcare system. For children recently referred to the Genetics Clinic at SickKids or CHEO for a suspected but undiagnosed rare genetic disease, this study might be suitable. Participants will allow a review of their medical records, answer questionnaires, and possibly provide a blood sample for genetic testing. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could revolutionize genetic disease diagnosis.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It seems focused on genetic testing rather than medication changes.

What prior data suggests that genome sequencing is safe for diagnosing rare genetic diseases?

Research has shown that genome sequencing is generally safe and well-tolerated for diagnosing rare genetic diseases. This method examines a person's entire genetic information without causing harm. For instance, a large study with over 490,000 participants found that genome sequencing safely identifies genetic differences by providing a complete view of the human genome.

Overall, genome sequencing is considered a safe way to find genetic conditions. However, like any medical test, it may involve minor risks, such as discomfort from drawing blood. The procedure itself remains safe because it involves analyzing the blood sample in a lab. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the genome sequencing approach for inherited disorders because it offers a faster and more direct path to diagnosis compared to the standard method. Unlike traditional approaches where a medical geneticist must first evaluate a patient before ordering tests, the genome sequencing-first method provides immediate genetic insights. This allows for quicker identification of genetic disorders, potentially leading to faster, more tailored treatment plans. Additionally, pre-test counseling by a genetic counselor ensures that patients and families are well-informed throughout the process.

What evidence suggests that genome sequencing is effective for diagnosing rare genetic diseases?

Research has shown that genome sequencing can diagnose rare genetic diseases more quickly and accurately. In studies involving children in intensive care, 37% received a genetic diagnosis through rapid genome sequencing, and 26% of these cases experienced changes in treatment following the diagnosis. In this trial, participants in the GS-first arm will receive immediate clinical routine genome sequencing, potentially leading to faster diagnosis and influencing subsequent clinical care. Real-world evidence indicates that early genome sequencing can expedite the diagnosis of childhood developmental and seizure disorders while also reducing costs. Whole-genome sequencing provides a comprehensive view of a person's genes, revealing genetic differences that other methods might miss. Overall, early genome sequencing is believed to enhance the diagnosis and care of rare genetic conditions. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals suspected of having a rare genetic disease, who have been recently referred to and accepted by the Genetics Clinic at SickKids or CHEO. Participants will allow their medical records to be reviewed, complete questionnaires, and provide a blood sample if they're in the genome sequencing group.

Inclusion Criteria

I have been referred to the Genetics Clinic at SickKids or CHEO within a week for screening.

I am referred for a suspected but undiagnosed rare disease.

My condition might have a genetic cause.

Exclusion Criteria

Referral considered 'Urgent' using established site criteria

A family member is already enrolled in the study and was referred for the same indication

I have a diagnosed genetic condition with specific criteria.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-test Counselling

Pre-test counselling will be done by a research genetic counsellor for participants in the GS-first arm.

0-2 weeks

1 visit (in-person or virtual)

Treatment

Participants in the GS-first arm receive immediate clinical routine genome sequencing, while the standard-of-care arm follows usual geneticist evaluation and testing.

Up to 18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including the disclosure of results and subsequent clinical care.

Up to 18 months

Multiple visits (in-person or virtual) as needed

What Are the Treatments Tested in This Trial?

Interventions

• Genome sequencing

Trial Overview The study compares two approaches: 'genome sequencing first' versus standard care where patients wait for a genetics specialist's evaluation. It aims to determine which method leads to more rapid and accurate diagnoses, assesses patient/provider opinions on both methods, and evaluates financial impact on healthcare.

How Is the Trial Designed?

Group I: GS-first arm Experimental Treatment 1 Intervention

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 II: Standard-of-care arm Active Control 1 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.

Who Is Running the Clinical Trial?

The Hospital for Sick Children

Lead Sponsor

Trials

724

Recruited

6,969,000+

Children's Hospital of Eastern Ontario

Collaborator

Trials

134

Recruited

61,000+

Toronto Metropolitan University

Collaborator

Trials

95

Recruited

19,300+

Published Research Related to This Trial

Next-generation sequencing (NGS) technologies allow for a more comprehensive approach to genetic diagnosis, moving from a traditional gene-by-gene method to broader techniques like diagnostic gene panel sequencing (DPS), diagnostic exome sequencing (DES), and diagnostic genome sequencing (DGS).

These NGS methods can be cost-effective for diagnosing rare genetic disorders with high variability, and they have the potential to identify new disease-related genes that were not previously associated with human diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in the Clinical Application of Next-Generation Sequencing. Ki, CS.[2021]

In a study of 48,118 participants from four clinical trials on acute coronary syndromes, 50% reported adverse events within a year, with 14.4% classified as serious adverse events (SAEs) and 85.6% as nonserious adverse events (AEs).

The reporting of adverse events peaked shortly after hospital discharge and was influenced by factors such as chronic obstructive pulmonary disease and heart failure, while participants from Eastern Europe and Asia reported fewer SAEs, highlighting the need for improved adverse event collection methods in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled analysis of adverse event collection from 4 acute coronary syndrome trials. Zimerman, A., Lopes, RD., Stebbins, AL., et al.[2016]

Human genomic sequencing can provide valuable insights for diagnosis, prognosis, and treatment across various medical fields, but its widespread use is limited by a lack of evidence showing improved patient outcomes in those without specific testing indications.

The paper reviews clinical outcome studies in genomic medicine, highlighting the challenges of generating robust evidence to support the integration of next-generation sequencing into standard patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building evidence and measuring clinical outcomes for genomic medicine. Peterson, JF., Roden, DM., Orlando, LA., et al.[2020]

The definition of an adverse drug event (ADE) should be tailored to the specific purpose of the evaluation, with stricter definitions needed for scientific studies and more flexible ones for clinical use.

Postmarketing safety data for drugs is limited at launch, but can be supplemented through systems like the FDA's Spontaneous Reporting System and targeted research projects, emphasizing the importance of robust epidemiological evidence for regulatory actions like drug recalls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug events: identification and attribution. Rogers, AS.[2022]

Genome-wide sequencing, including exome or whole genome sequencing, is recommended for patients suspected of having Mendelian diseases when conventional tests fail to identify the cause.

This approach is effective in pinpointing specific genetic causes of serious diseases, which can significantly enhance clinical care and patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controversy and debate on clinical genomics sequencing-paper 2: clinical genome-wide sequencing: don't throw out the baby with the bathwater! Adam, S., Friedman, JM.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1098360024000029

Real-world diagnostic outcomes and cost-effectiveness of ... Using real-world data, we found earlier access to ES may yield more rapid genetic diagnosis of childhood developmental and seizure disorders and cost savings.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10899612/

Rapid genomic sequencing for genetic disease diagnosis and ... In 44 studies of children in ICUs with diseases of unknown etiology, 37% received a genetic diagnosis, 26% had consequent changes in management, ...

3. genomemedicine.biomedcentral.com genomemedicine.biomedcentral.com/articles/10.1186/s13073-024-01301-y

Genome sequencing as a generic diagnostic strategy for rare ... We assessed whether genome sequencing (GS) can replace these existing workflows aimed at germline genetic diagnosis for rare disease.

4. nature.com nature.com/articles/s41586-025-09272-9

Whole-genome sequencing of 490640 UK Biobank ... Whole-genome sequencing provides an unbiased and complete view of the human genome and enables the discovery of genetic variation without ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2814303

Cost-Effectiveness of Whole-Genome vs Whole-Exome ... Our data suggest that WGS is cost-effective for diagnosing infants with potential genetic disorders at a WTP threshold of €30 000 to €50 000 (US ...

6. bmcmedgenomics.biomedcentral.com bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01795-w

Whole genome sequencing in clinical practice Whole genome sequencing (WGS) is becoming the preferred method for molecular genetic diagnosis of rare and unknown diseases and for ...

7. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2804586

Perspectives of Rare Disease Experts on Newborn ... In this survey study of 238 rare disease experts, 87.9% agreed that genomic sequencing for monogenic treatable conditions should be available to all newborns.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4113721/

Genomic Sequencing: Assessing The Health Care System ... New genomic sequencing technologies enable the high-speed analysis of multiple genes simultaneously, including all of those in a person's genome.

9. hca.wa.gov hca.wa.gov/assets/program/WGS-final-report-2024.pdf

Whole Genome Sequencing: Final Evidence Report This evidence report is based on research conducted by the RTI–University of North Carolina. Evidence-based Practice Center through a ...