Genetic Testing for Rare Genetic Disorders

(GIVE Trial)

Overseen By Seema Lalani, MD

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Baylor College of Medicine

Disqualifiers: Known genetic diseases

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

200 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to transform the current clinical practice paradigm by leveraging an internally designed web-based model of delivery of care called Consultagene to provide remote evaluation and genomic sequencing for improving genetic health of less resourced children with rare disorders living along the Texas-Mexico border.

Do I need to stop my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment Whole Genome Sequencing (WGS) for rare genetic disorders?

Whole Genome Sequencing (WGS) has been shown to improve the diagnosis of rare genetic disorders, with a diagnostic rate of up to 48.5% in some cases, which can lead to more targeted and effective care for patients. ^{1 2 3 4 5}

Is whole genome sequencing (WGS) safe for humans?

Whole genome sequencing (WGS) is generally considered safe for humans as it is a method of analyzing genetic information rather than a treatment that involves physical intervention. It has been used successfully in medical settings to diagnose genetic disorders without reported safety concerns. ^{1 2 6 7 8}

How is whole genome sequencing different from other treatments for rare genetic disorders?

Whole genome sequencing (WGS) is unique because it provides a comprehensive analysis of a person's entire genetic makeup, helping to diagnose rare genetic disorders that are often difficult to identify. Unlike other treatments, WGS can quickly and accurately pinpoint genetic mutations, guiding personalized treatment plans and potentially ending the long search for a diagnosis. ^{1 3 6 8 9}

Research Team

Seema Lalani

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for pediatric patients living in the Rio Grande Valley, Texas, who have rare genetic diseases that remain undiagnosed. Children already diagnosed with a known genetic disease cannot participate.

Inclusion Criteria

Children who live in the Rio Grande Valley, Texas and have rare genetic conditions that have not been diagnosed yet.

Exclusion Criteria

Children with known inherited diseases.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Virtual Evaluation

Participants receive virtual genetics evaluation through the Consultagene platform

4-6 weeks

Virtual visits as needed

Genomic Sequencing

Participants undergo whole genome sequencing and interpretation for rapid genetic diagnoses

4 weeks

Follow-up

Participants are monitored for health outcomes and effectiveness of genetic diagnoses

8 weeks

Treatment Details

Interventions

• Whole genome sequencing (WGS)

Trial Overview The study is testing a web-based model called Consultagene to deliver care and perform Whole Genome Sequencing (WGS) remotely to help identify genetic disorders in children from less resourced areas.

Participant Groups

Group I: WGS arm Experimental Treatment 1 Intervention

All 200 patients recruited will undergo WGS

Whole genome sequencing (WGS) is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Whole Genome Sequencing for:

• Rare genetic disorders
• Congenital anomalies
• Neurodevelopmental disorders

Approved in United States as Whole Genome Sequencing for:

• Unexplained congenital anomalies
• Neurodevelopmental disorders
• Intellectual disability
• Developmental delay

Approved in United Kingdom as Whole Genome Sequencing for:

• Rare genetic disorders
• Congenital anomalies
• Neurodevelopmental disorders
• Cancer

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Findings from Research

Whole-genome sequencing (WGS) has become much faster and cheaper, making it a promising tool for early diagnosis of rare genetic disorders, which affect 3%-5% of newborns.

Despite the potential of WGS to improve diagnosis and treatment, challenges remain in drug development and regulatory approval that hinder the transition to effective therapies for these disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole-genome sequencing holds the key to the success of gene-targeted therapies. Vockley, J., Aartsma-Rus, A., Cohen, JL., et al.[2023]

Whole genome sequencing (WGS) is emerging as a promising first-tier diagnostic tool for identifying rare genetic disorders, but there is a need for standardized practices to ensure its effectiveness.

The Medical Genome Initiative has developed best practice recommendations for interpreting and reporting clinical WGS results, aiming to improve access and quality of this diagnostic test in healthcare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Best practices for the interpretation and reporting of clinical whole genome sequencing. Austin-Tse, CA., Jobanputra, V., Perry, DL., et al.[2022]

Whole genome sequencing (WGS) successfully diagnosed a 7-year-old girl with a severe undiagnosed panvascular artery disease, identifying mutations in the YY1AP1 gene linked to Grange syndrome.

This case highlights the efficacy of WGS in diagnosing rare diseases, achieving a molecular diagnosis where traditional methods failed, and suggests that WGS can expand the understanding of genetic mutations associated with such conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease. Raggio, V., Dell'Oca, N., Simoes, C., et al.[2022]

Whole genome sequencing (WGS) significantly improves the diagnostic yield for suspected genetic disorders in pediatric patients, achieving a 38.6% success rate compared to 37.8% for whole exome sequencing (WES) and only 7.8% for usual care.

The study indicates that WGS is particularly effective for diagnosing Mendelian diseases, suggesting it may be a superior option for targeted genetic diagnosis in children with severe disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole genome sequencing diagnostic yield for paediatric patients with suspected genetic disorders: systematic review, meta-analysis, and GRADE assessment. Nurchis, MC., Altamura, G., Riccardi, MT., et al.[2023]

Whole-genome sequencing (WGS) significantly improved clinical management for acutely ill infants, with 21.1% of those receiving early results experiencing a change in management compared to only 10.3% in the delayed group, indicating a strong effect on treatment decisions.

The study involved 354 infants and showed that WGS not only provided a molecular diagnosis for more patients (31.0% in the early group vs 15.0% in the delayed group) but also has the potential to reduce healthcare disparities by offering equitable diagnostic access.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial. Krantz, ID., Medne, L., Weatherly, JM., et al.[2022]

Whole genome sequencing (WGS) identified pathogenic or likely pathogenic variants in 20% of families with hypertrophic cardiomyopathy (HCM) where previous genetic tests were inconclusive, revealing new genetic causes not detected by standard testing methods.

As a first-line genetic test, WGS was able to find pathogenic variants in 42% of families that had never undergone genetic testing before, demonstrating its effectiveness in diagnosing HCM and improving management for affected families.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy. Bagnall, RD., Ingles, J., Dinger, ME., et al.[2019]

In a pilot program at Children's Hospital of Wisconsin, whole genome sequencing (WGS) was used to diagnose genetic disorders in 22 patients, achieving an initial diagnosis rate of 14%, which increased to 36% after reanalysis.

In 75% of the diagnosed cases, the identified genetic variants influenced treatment decisions or medical monitoring, highlighting the practical impact of WGS in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic. Bick, D., Fraser, PC., Gutzeit, MF., et al.[2020]

Whole-genome sequencing (WGS) is a powerful tool for diagnosing hereditary disorders, especially for patients with undiagnosed conditions, potentially ending their diagnostic journey and improving clinical care.

The clinical WGS test provides high-quality sequencing data and detailed reports that include both primary results and optional secondary findings, allowing for personalized patient care and informed decision-making.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reporting of Clinical Genome Sequencing Results. Song, C., Duzkale, H., Shen, J.[2023]

A comprehensive whole-genome sequencing (WGS) pipeline for diagnosing genetic disorders was developed and validated using 45 samples with known variants, demonstrating its effectiveness in detecting various genetic alterations.

The pipeline includes advanced bioinformatics tools for identifying multiple types of genetic variants, ensuring a robust approach to genetic testing that can improve clinical diagnostics for genetic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Test development, optimization and validation of a WGS pipeline for genetic disorders. Yang, Z., Yang, X., Sun, Y., et al.[2023]

References

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

Whole-genome sequencing holds the key to the success of gene-targeted therapies. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Best practices for the interpretation and reporting of clinical whole genome sequencing. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Whole genome sequencing diagnostic yield for paediatric patients with suspected genetic disorders: systematic review, meta-analysis, and GRADE assessment. [2023]

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

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial. [2022]

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

Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic. [2020]

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

Reporting of Clinical Genome Sequencing Results. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Test development, optimization and validation of a WGS pipeline for genetic disorders. [2023]