Genome Sequencing for Genetic Disorders

(BeginNGS Trial)

Overseen By Lauren Olsen, MSN

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Rady Pediatric Genomics & Systems Medicine Institute

Disqualifiers: Mother under 18, Wards of state, Non-US address, Ill neonates, Others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

10000 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify whether participants need to stop taking their current medications. However, since the trial involves newborns, it is unlikely that they would be on any medications.

What data supports the effectiveness of the treatment BeginNGS for genetic disorders?

Research shows that rapid whole-genome sequencing (rWGS) used in newborn screening can identify genetic disorders early, allowing for timely interventions. In a study, rWGS identified 87% of previously diagnosed cases and found additional cases not detected by conventional methods, suggesting that early treatment could prevent or reduce symptoms in many children. ^{1 2 3 4 5}

Is genome sequencing for genetic disorders safe for humans?

The research articles focus on identifying and managing adverse events in neonatal and pediatric care, but they do not provide specific safety data for genome sequencing treatments like BeginNGS or Newborn Genome Sequencing. ^{6 7 8 9 10}

How is the treatment BeginNGS different from other treatments for genetic disorders?

BeginNGS, or Newborn Genome Sequencing, is unique because it uses rapid whole-genome sequencing to identify genetic disorders in newborns before symptoms appear, allowing for early intervention. This approach is more comprehensive than traditional newborn screening, which typically tests for a limited number of conditions. ^{2 5 11 12 13}

What is the purpose of this trial?

The goal of this clinical trial is to test a new method for newborn screening using whole genome sequencing, called BeginNGS. Parents will be approached to provide informed consent to enroll their newborns in prenatal, postnatal, and outpatient settings. The main questions this study aims to answer are: What is the utility of BeginNGS as compared to state newborn screening? What is the acceptability and feasibility of BeginNGS as compared to state newborn screening? What is the cost effectiveness of BeginNGS as compared to state newborn screening? Enrolled newborns will have a blood sample taken and will receive the BeginNGS test. Newborns will have also had the state newborn screening test.

Research Team

Stephen Kingsmore, MD DSc

Principal Investigator

Rady Children's Institute for Genomic Medicine

Rebecca Reimers, MD MPH

Principal Investigator

Rady Children's Institute for Genomic Medicine

Eligibility Criteria

This trial is for newborns whose parents consent to enroll them. It's designed to compare a new whole genome sequencing test, BeginNGS, with the standard state newborn screening tests.

Inclusion Criteria

Parents must have identified a primary care provider (or group)

My baby is less than 28 days old.

Exclusion Criteria

My mother was under 18 when I was born.

My newborn is under state care.

Neonates whose parent/legal guardian is unable to provide consent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Enrollment and Testing

Enrolled newborns will have a blood sample taken and will receive the BeginNGS test in addition to the state newborn screening test.

1-2 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after testing, including confirmatory testing and analysis of outcomes.

5 years

Periodic follow-up visits

Data Analysis and Reporting

Analysis of utility, acceptability, feasibility, and cost effectiveness of BeginNGS compared to standard NBS.

Ongoing throughout the study

Treatment Details

Interventions

• BeginNGS

Trial Overview The BeginNGS Test is being studied to see how useful it is compared to traditional screenings for genetic disorders in newborns. The study will assess its acceptability, feasibility, and cost-effectiveness.

Participant Groups

Group I: Enrollees Experimental Treatment 1 Intervention

Enrolled infants will receive the BeginNGS test in addition to the state newborn screen.

BeginNGS is already approved in United States for the following indications:

Approved in United States as BeginNGS for:

• Newborn screening for severe childhood genetic diseases

Who Is Running the Clinical Trial?

Rady Pediatric Genomics & Systems Medicine Institute

Lead Sponsor

Trials

10

Recruited

214,000+

Findings from Research

In a study involving 159 newborns, genomic sequencing (nGS) identified a risk of childhood-onset diseases in 9.4% of infants, none of which were predicted based on their clinical or family histories, highlighting the potential of nGS to uncover hidden health risks.

The study also found that nGS could reveal actionable adult-onset disease risks in 3.5% of newborns and carrier status for recessive diseases in 88%, demonstrating its effectiveness in detecting conditions not identified by standard newborn screening methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Ceyhan-Birsoy, O., Murry, JB., Machini, K., et al.[2022]

Rapid whole-genome sequencing (rWGS) for newborn screening (NBS) can identify a wide range of genetic disorders, with a high sensitivity of 88.8% and a negative predictive value of 99.6%, making it a promising tool for early diagnosis and intervention.

In a simulated study involving over 454,000 subjects, rWGS could have potentially prevented symptoms in critically ill newborns by diagnosing conditions that conventional NBS missed, highlighting its effectiveness in improving outcomes for genetic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases. Kingsmore, SF., Smith, LD., Kunard, CM., et al.[2023]

A targeted next-generation sequencing panel (NBDx) was developed to confirm diagnoses in newborns, showing a high analytical sensitivity of 99.8% for known mutation hotspots across 126 genes related to newborn diseases.

The NBDx panel allows for rapid processing of multiple cases (8 to 20) within 105 hours, demonstrating its practicality for second-tier confirmation in clinical settings and potential for broader DNA-based screening in newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of DNA confirmatory and high-risk diagnostic testing for newborns using targeted next-generation DNA sequencing. Bhattacharjee, A., Sokolsky, T., Wyman, SK., et al.[2023]

There is a pressing need to expand newborn screening (NBS) using rapid whole genome sequencing (rWGS) to identify over 400 genetic disorders, which could significantly improve early diagnosis and treatment options for newborns.

The BeginNGS consortium aims to create a self-learning healthcare system that not only screens for genetic diseases but also confirms diagnoses and facilitates effective treatments, while also accelerating the development of orphan drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dispatches from Biotech beginning BeginNGS: Rapid newborn genome sequencing to end the diagnostic and therapeutic odyssey. Kingsmore, SF.[2023]

A significant majority (87.9%) of rare disease experts support the use of newborn genome sequencing (NBSeq) to identify treatable monogenic disorders in all newborns, highlighting its potential to improve early detection and treatment.

Experts recommended including 25 specific genes associated with treatable conditions in NBSeq, with 42 gene-disease pairs endorsed by at least 80% of respondents, indicating a strong consensus on which conditions should be prioritized for screening.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives of Rare Disease Experts on Newborn Genome Sequencing. Gold, NB., Adelson, SM., Shah, N., et al.[2023]

A new trigger tool was developed using a random forest algorithm to effectively identify adverse events (AEs) in hospitalized neonates, based on data from 782 patients, achieving a sensitivity of 70.7% and specificity of 92.0.

In a validation study with 655 neonates, the tool identified 1172 unique AEs, with skin damage, iatrogenic diarrhea, and fever being the most common, demonstrating a positive predictive value of 0.686.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal Adverse Events' Trigger Tool Setup With Random Forest. Feng, K., Zhang, L., He, H., et al.[2023]

In a study of 150 neonatal admissions, 360 adverse events were identified, affecting 52% of infants, with a high preventability rate of 84.7%, indicating significant opportunities for improving patient safety in neonatal care.

Preterm infants experienced a higher rate of adverse events compared to term infants, particularly within the first week of admission, highlighting a critical period for monitoring and intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying neonatal adverse events in preterm and term infants using a paediatric trigger tool. Dillner, P., Unbeck, M., Norman, M., et al.[2023]

A new NICU-focused trigger tool was developed and tested, revealing a high incidence of adverse events in hospitalized children, with 554 unique adverse events identified across 749 charts, averaging 0.74 events per patient.

The study found that 56% of these adverse events were preventable, highlighting the need for improved safety measures, as only 8% were reported through traditional hospital reporting systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in the neonatal intensive care unit: development, testing, and findings of an NICU-focused trigger tool to identify harm in North American NICUs. Sharek, PJ., Horbar, JD., Mason, W., et al.[2021]

In a review of adverse events (AEs) among 433 children with cystic fibrosis participating in clinical trials, a total of 8,266 AEs were reported, averaging 18.1 AEs per person per year, with respiratory AEs being the most common.

Cough was the most frequently reported respiratory AE, affecting 61% of participants, and the study found that AE rates were higher in the Spring, Fall, and Winter compared to Summer, indicating that seasonal factors may influence the frequency of AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rates of adverse and serious adverse events in children with cystic fibrosis. Pittman, JE., Khan, U., Laguna, TA., et al.[2022]

Implementing a standardized register for reporting adverse events in a neonatology unit over six months improved the consistency of reporting.

The analysis of these reports led to significant reorganizations in the unit and practices, enhancing the overall quality of care provided to neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse events in neonatology, contribution of a standardised register]. Normand, MM., Ejarque Albuquerque, M., Grouazel, AL., et al.[2017]

The feasibility of extending newborn screening to include genome sequencing is being actively explored, highlighting the potential benefits and risks associated with this advancement.

Discussions and funded trials are underway to address the scientific, organizational, and ethical issues that arise from genome sequencing in newborn screening, especially as some companies are already providing these services.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Sequencing babies?]. Jordan, B.[2015]

Genome sequencing of newborns presents a significant opportunity to identify rare genetic disorders early, potentially before symptoms appear, which can lead to quicker diagnoses and better management of these conditions.

Efforts are underway to implement genetic screening technologies for newborns, utilizing advanced biomedical informatics and computational biology to enhance the identification of genetic risks from the start of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

USE OF GENOME DATA IN NEWBORNS AS A STARTING POINT FOR LIFE-LONG PRECISION MEDICINE. Brenner, SE., Kingsmore, S., Mooney, SD., et al.[2022]

Newborn screening (NBS) programs aim to reduce disease burden in neonates by identifying conditions early, and advancements in multiplex technologies and next-generation sequencing are enabling faster and broader screening for genetic disorders.

The integration of whole exome and genome sequencing into NBS could allow for the identification of all genetic disorders at birth, facilitating timely interventions even before symptoms appear, though there are technical, ethical, and societal challenges to consider.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health. Woerner, AC., Gallagher, RC., Vockley, J., et al.[2021]

References

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

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. [2022]

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

A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases. [2023]

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

Development of DNA confirmatory and high-risk diagnostic testing for newborns using targeted next-generation DNA sequencing. [2023]

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

Dispatches from Biotech beginning BeginNGS: Rapid newborn genome sequencing to end the diagnostic and therapeutic odyssey. [2023]

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

Perspectives of Rare Disease Experts on Newborn Genome Sequencing. [2023]

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

Neonatal Adverse Events' Trigger Tool Setup With Random Forest. [2023]

7. Norway pubmed.ncbi.nlm.nih.gov

Identifying neonatal adverse events in preterm and term infants using a paediatric trigger tool. [2023]

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

Adverse events in the neonatal intensive care unit: development, testing, and findings of an NICU-focused trigger tool to identify harm in North American NICUs. [2021]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Rates of adverse and serious adverse events in children with cystic fibrosis. [2022]

10. France pubmed.ncbi.nlm.nih.gov

[Adverse events in neonatology, contribution of a standardised register]. [2017]

11. France pubmed.ncbi.nlm.nih.gov

[Sequencing babies?]. [2015]

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

USE OF GENOME DATA IN NEWBORNS AS A STARTING POINT FOR LIFE-LONG PRECISION MEDICINE. [2022]

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

The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health. [2021]