Genome Sequencing for Inherited Disorders

(TRIAGE-GS Trial)

Recruiting 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

200 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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 data supports the effectiveness of the treatment Genome sequencing for inherited disorders?

Genome sequencing, especially next-generation sequencing (NGS), is effective in diagnosing rare inherited disorders by quickly identifying genetic mutations. It has been shown to be a cost-effective approach for diagnosing conditions with genetic diversity, like glycogen storage disease and primary immunodeficiency, and can even discover new genes linked to diseases. ^{1 2 3 4 5}

Is genome sequencing for inherited disorders safe for humans?

The safety of genome sequencing in humans is generally well-regarded, as it is a diagnostic tool rather than a treatment. It involves analyzing your DNA to understand genetic conditions, and while it is non-invasive, it is important to discuss any concerns with your healthcare provider. ^{6 7 8 9 10}

How does genome sequencing differ from other treatments for inherited disorders?

Genome sequencing is unique because it identifies the specific genetic mutations causing inherited disorders, which can lead to more accurate and personalized diagnosis and treatment plans. Unlike traditional treatments that may address symptoms, genome sequencing targets the root genetic cause, offering a more precise approach to managing these conditions. ^{11 12 13 14 15}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Building evidence and measuring clinical outcomes for genomic medicine. [2020]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

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

3. Switzerland pubmed.ncbi.nlm.nih.gov

Validation of Ion TorrentTM Inherited Disease Panel with the PGMTM Sequencing Platform for Rapid and Comprehensive Mutation Detection. [2022]

4. United States 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! [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Implementation, Evolution, and Laboratory Performance of Methods-Based Proficiency Testing for Next-Generation Sequencing Detection of Germline Sequence Variants. [2023]

6. New Zealand pubmed.ncbi.nlm.nih.gov

A Comparison Study of Algorithms to Detect Drug-Adverse Event Associations: Frequentist, Bayesian, and Machine-Learning Approaches. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Adverse drug events: identification and attribution. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Variation in detected adverse events using trigger tools: A systematic review and meta-analysis. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Pooled analysis of adverse event collection from 4 acute coronary syndrome trials. [2016]

10. Canada pubmed.ncbi.nlm.nih.gov

Population Analysis of Adverse Events in Different Age Groups Using Big Clinical Trials Data. [2020]

11. China pubmed.ncbi.nlm.nih.gov

[Exome sequencing: an efficient strategy for identifying the causative genes of monogenic disorders]. [2011]

12. India pubmed.ncbi.nlm.nih.gov

Current scenario of the genetic testing for rare neurological disorders exploiting next generation sequencing. [2021]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Delivery of a clinical genomics service. [2018]

14. United States pubmed.ncbi.nlm.nih.gov

Implementation of Exome Sequencing to Identify Rare Genetic Diseases. [2023]

15. England pubmed.ncbi.nlm.nih.gov

Next-generation sequencing for mitochondrial disorders. [2021]